UNITED NATIONSREPORT OF THE
UNITED NATIONSSCIENTIFIC COI\IMITTEE
ON THE
EFFECTS OF ATOMIC RADIATIONNOTE
Throughout this report and its annexes cross-references are denoted by a letter
followed by a number: the Jetter refers to the relevant technical annex (see Tableof Contents) and the number is that of the relevant paragraph. \Vithin each technicalannex, references are made to its individual scientific bibliography by a number
without any preceding letter.
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Nations document.

Annex H

T H E GENETIC EFFECTS OF RADIATION

I. MUTATION..............................................
1. THEMECHANICS OF MUTATION

The gene ...........................................
Gene mutations ......................................
Chromosome breaks ..................................
The hereditary material ...............................
Linearity of dose-mutation curve .......................
Mechanism of mutation ...............................
Other possibilities of interference between irradiation andits effects at the cellular level ........................
Comparison between natural and radiation-induced mutations~ e t e h i o nof mutation .................................
2. MUTATIONRATESNatural mutation rates ...............................
Natural mutation rates in man .........................
Radiation-induced mutation rates .......................
Radiation-induced mutation rates in man .................
3. THE REPRESENTAT~X DOUBLING DOSE .....................
Estimates of the representative doubling dose for human............................................
genes
4. ESTIJIATESOF TOTAL RATE OF RADIATION-INDUCED ~ I U T A T I O N S
I N THE GENOME O F MAN.................................

11. T H EGENETIC CONSEQUENCES OF IRRADIATION
1. THECONNE-UON BETWEEN MUTATION ~3x1
GESETIC DAMAGE :SELECTION........................................... 75
2. APPROACHESTO QUANTITATIVE ASSESSMENT OF T R E GENETICCONSEQUENCES OF IRRADIATION OF HUMAN POPULATIOXS.. .. 80
3. THE CURRENT SOCL~LBURDEN OF GENETIC ORIGIN IN HUMAN
POPULATIONS, ITS CONNEXION \f71TH MGTATION AND RADIATIONEXPOSURE.

............................................ 87

Specific traits ....................................... 88
Biometrical characters ................................ 95
Fertility ............................................ 104
Pool of recessive mutants. ............................. 106

Table

I. Measured or calculated values of natural mutation rates in man
11. Measured or calculated values of natural mutation rates at single
loci of organisms other than man
111. Measured or calculated values of total natural mutation rates forclasses of loci in organisms other than man
IV. Rates of radiation-induced mutations at single loci in organisms
other than man
V. Total rates of radiation-induced mutations in classes or' loci inorganisms other than man
VI. Sunreys of human populations for purposes of radiation genetics
VII. Content of DNA in various types of cells
VIII. Calculated doubling doses in organisms other than man
IX. Comparison of approaches to quantitative assessment of mutational damage
X. Some over-all estimates of social burden

XI. List of specific traits, with estimated incidences :Category I(a) Autosomal dominant traits( b ) Autosomal recessive trsts(c) Sex-linked recessive traits(d) Summary of traits of Category I

XII. List of specific traits, with estimated incidence: Category I1XIII. List of specific traits, with estimated incidences : Category 111
XIV. Dominant conditions identified in the Northern Ireland population but not included in Categories I and I1 for the reasonsstatedXV. Classes of biometrical character

Table XVI. Calculated consequences of changes in the parameters governing birth-weight distribution

recognizable for the organism as serious somatic effects.
ranging from death or incapacity of cells fulfiling vital
specialized functions to unrestricted proliferation.

I. MUTATION
1. THEMECHANICS O F MUTATION

Chrottzosome breaks

The gene

1. The conventional concept of the gene has been thatof a functional hereditary unit. I n recent years this concept has required a more precise definition. since sensitive tests of allelism have indicated that a single f m c tional gene may be separable into component dements byrecombination and so shown to be capable of many
pseudoallelic differences?*= Single mutational events
which modify or prevent the action of the functional
unit may affect different large or small parts of thisunit.s During the same period, it is notable that featuresof the genetics of natural populations have indicated theextent to which individual functional genes can be invalved in larger complexes and lack complete
Possibly the most striking manifestation of this is atpresent in Salmonella typhimurium, in which it appears
possible that there are integrated linear sequences of adjacent gene-structures responsible for whole sequencesof biochemical operations, assembly-line fashion.'
Geftemutations

I

2. Take in its widest sense, mutation means any
change of the genetical constitution not due to recombination, ranging from whole genomes to alleles. Often
mutation is used in a more restricted sense, viz. as changeof the action of some specific gene. This is commonlyreferred to as p& mutation, which, however, may be amisleading term, as it is known, especially from the work
on Drosophilo by Dubinin and other^,^^^ that a change ofthe position of a gene may change its habit of action.
Moreover, the idea of a point mutation, as distinct froma deletion or rearrangement, was formerly based upon
the smallest unit of structure microscopically risible.
Because recent structural analysis of the gene has se.med
to penetrate almost as far as the much Smaller ultimate
units of its ph~sico-chemicalstructure, believed to be
the single nucleotides, it has already been suggested thatthe term "point mutation" be resenred for mutational
events invol~ingonly one such unit.8 Such ideas do notby themselves affect the distinction between intragenic
and intergenic mutationsg and may, indeed, dar$ these ;for example, it remains possible that further investigations of genes and chrom~somes'~
will lead to a distinction between a structural backbone and separate attachedgenes. There is no doubt that advances in this field will
eventually add greatly to the refinement of current ideas
concerning all aspects of mutation.

3. I n man, the primary genetic concern is with alltransmissible hereditary changes which simulate thechange to a new allele. These are perhaps best grouped
together under the term "apparent gene mutations",
whatever their structural nature. However, other formsof genetic damage require consideration in connexion
both with SOmatlc effects and with the requirement that
mutations must sunrive transmission through the germ
cells if they are to be observed. These latter forms ind u d e both gene mutations and chromosome structuralchanges in somatlc.ceU.s, which may well have a sensitivity to the radiation-induced process quite similar tothat of germ line cells?c4 hlutations and chromosomechanges in these cells could bring about consequences,

4. It remains a major question to what extent chromosomal or other genetic effects may be responsible forcell death or damage in somatic or germinal tissues ofman.11 Visible chron~osomalalterations resulting from
irradiation have been studied in cytoIogically favourable
material, principally of plants and of insects. They commonly arise through one or more chromosome breaks inthe cell rejoining in some new configuration. A frequent
result is dominant lethality through loss of substantial
chromosome parts or interference with cell division.
In spite of the difficulties of objective numerical scoringof cytological phenomena, many quantitative investigations have been made upon them :I2 it has been shownthat the more densely ionizing radiations are relatively
more effective in produang them12*13and that the numbers obsenred or recovered can be considerably affectedby various post-irradiation treatments if these are applied sufficiently early.12p14In this way, recent work hassuggested that there are some breaks at ionic bindings,
which reheal very rapidly, and others at co-valent bonds,
which heal more slowly,14as well as two separate effectsof radiation, one in causing the breaks and the other in
affecting the rejoining mechanism.14 The effects of oxygen, both at the time of irradiation and during the subsequent rejoining process, have played an important andcontroversial part in thislt would be ofinterest to learn to what extent inx-estigation of postirradiation modifiers of the rejoining process
biochemid
to those observed \+-ith
modifiers of fie cell lethality induced by irradiation.

5. Many investigations have connected ploidy withradiation resistance in unicellular organisms,
the extensive work of Mortimer and his colleagues onyeast;16 and this, together with the increased RBE of
the more densely ionizing radiations, has led to the idea
fiat much radiation-induced cell lethality has its
in dominant genetic changes. Certain cases are. however,lcnown inthis is not true; instead, lethality resultsfrom an imbalance or block in metabolism (as in very
heavily irradiated Habrobacon eggs,17) or a generalized
failure of the mitotic process hardly to betoindividual processes of the break-rejoin type. On thebasis of a turo-hit killing curve for mammalian tissue
cultureof various ploidies, Puck has recently argued that radiation-induced death in these is ,-hromosomal in origin ;lS,lg4cytological evidence will perhaps
be required before such a conclusion can be considered
as finally established. However, the reduction in growthrate observed by Puck et al. in colonies derived from
diploid mammalian tissue culture cells which had survived X-irradiation already provides printa fmie e+dence that even at doses of the order of 100 r, mostsurviving cells have suffered dominant deleterious
changes.lBJs bIoreover, Bender has recently demonstrated a rather high sensitivity of tissue culture cells
derived from human kidney to chromatid breaks inducedby X-raJrs.19
The hereditary tlurterial

6. Recent years have remarkably advanced the knowledge of genetic material and of the role played in it bydesoxyribonucleic acid (DNA). Indirect evidence from174

difierent sources has long led cellular physiologists tobelieve that DNA, in close association with protein,
forms part of genes and chromosomes ; this has included
the relative DNA content of haploid and diploid cells of
various tissues of an ~rganisrn,~"cytochemical evidence,of the presence
including thethe association of DNA
of DNA to the cell
More recently, a very
syntllesis with cell
between the asclose association
similation of radioactive .racers incorporated in DNA,and chromosome division.''' In addition, other evidence
has inclined many geneticists to believe that D N A may
be the actual material whose configuration constitutes
genetic information ;this evidence includes :( a ) The transformation of hereditary characters ofcells of P n e n s ~ o c o c c u sand~ ~ Haevrophilus" bacteria byapplication of solutions of pure DNA.

( b ) The role played by DNA in the growth andheredity of the coliphages of the T s e r i e ~ . ~ ~ * ? ~( c ) Indications from current work that increased
mutation in microbial systems occurs under conditionsof deficiency for an essential constituent of DNA suchas thymine, or in Presence of a competitive analogue ofa constituent, such as bromo~racil.~'~ 1 such
1 phenomena carry the promise of ne,v lines ofinvestigation of the mechanisms of gene mutation.

7. Concurrent investigations have remarkably advancedof the chemistry and structure ofDNA,
the X-ray diffraction studies of
Wikins et d.?sand the complementary biochemical relationships uncovered by Bargaff
and 0the~s.29leading to
the remarkable double helical structure proposed by
Crick and Watson,so so suggestive of the exact replicative process required for the transmission of hereditarycharacters, and already so productive of fresh ideas concerning the mechanics of mutation.

8. while none of these arguments is alone conclusive,andit is recognized that the gelletic material ofof higher ol.ganisms is organized into very substantial stainable structures. which must be more complphysically andthan the fine DNA fibrils
visible only under the electron m i c r o ~ c o p enonetheless.~~very many geneticists believe that the ultimate carrier ofgenetic information is likely to be the arrangement of
nucleotides in DNA.

9. I n that event, total radiation-induced mutation
rates, in the widest sense of change of the hereditary information. might be expected to be quantitatively correlated with the DNA content of the cells of the germ
plasm together with the biochemical operations whichconstruct and maintain DNA. It at least seems reasonable that when comparisons of mutation rates between
different species or physiological conditions are made,parallel DNA comparisons should be kept in mind. The
D N A contents of some relevant types of cell are listed
in table VII. hlost kinds of cell nuclei contain enough
D N A to form a structural molecule of great length which
could only be packed inside the nucleus by much folding.
This has given rise to the recent suggestion, now appearing on purely structural grounds, that the chromosome
may consist of a multi-stranded structure.''' I f the structure turned out to be, say. a proteinaceous backbone with
attached DNA molecules as side arms forming the genes(a possibility which is not excluded). the distinction
between inter- and intragenic mutations could eventually

come to have a very real physical basis, and the t\vo kindsof mutation could differ in mechanisms.

Linearity of dose-rjurtation ctrwe

10. The esperimental justification for speaking ofradiation-induced mutation rates at low doses rests upon
Drosophila data, in which the linearity oi fie dosemutation cunre, when it is investigated under suficielltly
rigorous conditions, has been confirmed down todoses of 25 rad for irradiation of spermatozoa by tilepainstaking work of Stem and his ~ ~ l l a b o ~ ~ t ~ ~ ~ , J l following earlier experimenter^.^'-^^ Mulle?' has recently argued cogently that there is no point in pressirlg
the test of linearity below 5 rad, and has indicated that
this limit could be reached in Drorophilo by techniques
at present available. Many geneticists ,%,auld agree
the implication of the cited passage, that linearity canalready be safely accepted, without the enormous iabo~lr
involved in its extension to still lower doses-at least in
the absence of a definite proposed basis for expecting a
non-linearity. However, it must be borne in mind thatlinearity has not been tested in this range of doses forspermatogonia~irradiation.
the case of irradiation ofthese cells it is still difficult to conceive a priori of a nonlinearity at low dose, followed by a linear portion of thecurve at medium or high exposures.'However. OakbergS8
has shown that some classes of spermatogonial cells of
the mouse are very sensitive to the lethal effects of low
doses ( 5 rad - 100 rad) of gamma-radiation. If thesesame classes were to turn out also to be unusually sensitive to the induction of mutations by radiation, the curveof recovered mutations as a function of dose might turnout to be linear in the range of moderate doses. but tohave considerably higher slope in the very low dose
range where an appreciable proportion of the cells surviving irradiation belonged to the sensitive group.

I

ll. The Committee has beenof current
periments upon mice which will enable the linearity ofthe dose-mutation curve for irradiation of spermatogonia, oogonia and oocytes to be checked down to 37.5
Attention must, however, again be drawn to thedependence of the whole quantitative assessment ofgenetic effects of low doses upon an assumed linearity
andirradiationa particular type cell in a dosera"geinyestigated.

Mechojrism of nzzctation

12. Many attempts have been made to affect theprocess of induced mutation after its initiation by exposure to ionizing radiation. Some of these have beensuccessful to a greater or lesser degree,4- and this fact
is of cardinal importance as demonstrating at least thepossibility of interference between the irradiation and its
principal genetic consequence. Unfortunately, in manyof these cases the precise genetic nature of the mutational
event is not known ; association with chromosome breakage or rejoining may therefore be suspected. Moreover,many of the esperiments refer to microbial material. In
which it is possible that the gene structures are far more
esposed and more easily able to be reached and affectedby external agents than are the mammalian chromosomes. Nevertheless, it is a hopeful sign that recent experiments reported to the Committee have extended thedemonstration of post-irradiation interference to a wellknown class of apparent gene mutations, the sex-linked
recessive lethals of Dr~sophiZa.'~These experiments
seem to show that a finite interval of at least some tens

175

of rnhutes exists in Drosophila before .'fixation" ofradiation-induced mutations.

13. In comesion with any possibility of ultimate
practical use of chemical or other modifiers of induced
mutations, it is well to remember that, in many populations. the largest man-made exposures of the gonads
occur through comparatively large doses delivered relatively infrequently in the course of medical work at
controlled times. The possibilities of modifying the mutational effects of radiation should be considered in thelight of the more general discussion of modifiers ofradiation effects in chapter IV and annex F of thisreport.

Other jossibiliiies of interference betweejz irradiation
altd its efects at the celltrlar level

either individual genes,$' strains.jS or physiological cond i t i o n ~result~ ~ in altered natural rates. Very little correlation is also found between radiation-induced mutability
and the natural rate in the sample of thirty biochemical
back-mutations examined by Glover.53 However, thewide variations in the ratio of radiation-induced to natural mutability found both in the work of Glover onbacteria and in extensive work on plantss0 do not seemto be correlated with the type or severity of the forward
or back-mutation involved, and it is generally acceptedthat the ratio of visibles to lethals is much the same fornatural and radiation-induced mutations in Drosophila,
although no explicit study of this point has. been made.
Atoreover, a very detailed investigation by Giles" of
purple-adenine and other mutants in Neurospora has
shown no evidence for a qualitative or quantitative difference between radiation-induced and spontaneous mutations at the same locus. The evidence of Stadler primarily
relates to the compound A locus ;consequently,a possible
esplanation is that A has a very low sensitivity to radiation-induced point mutation. I t is therefore reasonable
to accept as a tentative assumption that spontaneous andradiation-induced mutations are qualitatively similar :wide differences in the two mutation processes exist but
are functions of individual loci, and are not appreciably
correlated with the type or severity of effect exerted by
the mutant allele.

14. Interference with and control of genetic consequences of irradiation does not end with the completionof the mutational process. However, to look further
requires that the completed mutations be detectable. The
number of conditions in which carriers of unexpressed
deleterious genes can be detected has recently increased
this trend is closely associated with advances
greatly ;46147
in general biochemical and immunological genetics, and
it is to be hoped that Governments will foster and encourage its progress. -4second field closely related to thisand other aspects of the present subject is that of human
17. In connection with this problem, attention may be
chromosomal cj-tology. We are indeed a long way rebacdrawn to certain organisms such as Aspergill~ts,~?
moved from the beautiful situation which prevails in, ~which~ ~ ~ very sensitive tests
teria,"=and c ~ l i p h a g e in
Diptera where giant salivary gland chromosomes canof allelism are possible : tests which may be calculated51
be studied in minute detail : nevertheless recent technicale ~ ~can~ ~ ~ in some cases to be adequate for resolution of recombinaadvances in the field have been c o n ~ i d e r a b l andtion distances corresponding to one nucleotide pair if
give US great hopes of progress. Such advances may bringabout radical changes in human genetics and especially genes are primarily constituted of DNA. Such investigations might eventually shed much light on the real maghuman radiation genetics.
nitude of the structures disturbed by various types of
15. Other radical possibilities for dealing with radiamutational event of different origin, and indirectly on
tion-induced mutation, besides the cumbersome andthe "quality" of mutations caused by different agents.
often painful process of selection, beyond question exist.
Unfortunately, all the above organisms are microbial andAn example which must be considered, in the light of
not necessarily representative of the larger chromosomes
teclmological advance, is that of the natural or controlledof higher organisms.
transfer of genetic characters. This phenomenon is wellestablished in microbial materials," although usually but
18. In man, little information yet exists concerning
not always with very low frequency,51and as an eventual
the relative sensitivities of genes to specific mutagens.
aid in the elimination of harmful genes or their conseHowever, a notable beginning has been made upon thequences it cannot be'entirely dis~llissedas speculation.
* l ~ ~has analysed the mean
problem by P e n r o ~ e , ~ ' whoparental age at birth of propositi showing various conditions. and correlated these shifts with hypotheses as
Conzparison between xaturalto the principal kinetically different classes of mutagens,ana? radiation-kdziced nuta at ionssuch as natural radiation (expected to raise both mean
16. There has been a widespread belief among genetpaternal and maternal ages by an equal small increment).
icists, based largely upon the classical work of Stadler
copy-error (expected to raise mean paternal age somein corn" that radiation produces in general a differentwhat), or chemical mutagens (which might under some
type of mutant allele from those which occur naturallycircumstances raise the mean maternal age in such a way
more &reme, less likely to be reversible, more frethat incidence increased more than linearily with age).
quently a loss of function. However, Stadler's work may
Thus the prospect already exists of the analysis of
not be entirely typical even of plant material.ls8 Muller
human genes in ternls of sensitivities to different kinds
has recently reviewed the evidence against existence ofof mutagen.
Certainly, both the mechanism ofsuch a distin~tion.~
production and the distribution among loci of radiationinduced and natural mutations differ:53 there is also
some indication of small differences in the proportions
19. An apparent gene mutation can be detected if itof mutation to the different alleles at a single
results in a new allele ~ - h i c hdiffers so much in its action
Minute one-hit deletions do occur under the action of
from the original one that it can be scored by appropriate
radiation." and some radiation-induced point mutations
methods. There exist different alleles (isoalleles) whoseb Drosophilc may be associated with breaks or structural
phenotypic effects cannot at present be distinguished butchanges near them.56 3loreover, evidence in Drosoplzila
which may differ in other respects as. for esample. mutais against any appreciable correlation between naturalbility.OS Studies of natural and induced mutations are
mutation rate and radlatlon-induced mutability whererestricted to those which can be distinguished pheno-typically, and measurements oi their frequency will consequently be minimum figures for the total mutation
rates of the genes concerned.

20. I n Drosoplzila as well as in mice the rate of visible
mutations at specific loci has been studied after matingsof the stock to be tested with animals of the opposite sex
containing the marker genes whose mutation frequency
is to be examined. By this method the visibles scoredinclude both those which are recessive lethals in homozygous condition and those which are homozygous viable,
provided only that they are visible and viable as heterozygotes with the allele in the marker
As reported
by R u s ~ e 1 1 six. ~ ~out of twenty-one tested mutants induced in spermatogonia of mice were lethal, seven weresemi-lethals and eight were viable. The corresponding
data from Alesander'sio test of mutations in spermatogonia in Drosophila yielded three lethals, one semilethal and four viable. Excluding rare heterozygotes
combining a recessive viable visible with a recessive
lethal visible, what could be scored in any corresponding
study in man might be only those recessive visibles notrendered unscorable by their association with recessive
lethals. Supposing the same relationship behveen viable
and lethal visibles as in mice, one might easily underestimate the total mutation rates of genes in man by a factorof two or three.
21. I n estimating mutation rates it must also be bornein mind that the same phenotypic effect need not mean agenetically identical condition. In man, as in many otherorganisms, several different genotype? may exist whichgive rise to indistinguishable phenotypic expressions. I n
the case of man one must think of classes of genes eachcausing a similar effect, rather than of specific single
genes. The number of genes in each such class may varyconsiderably, causing a strong variation between theobserved rates of natural mutations in the various classes.
Thus in man? because test breeding cannot be used topin down an alteration to a specific locus, a mutation rateis always in fact measured for the whole class of genes
giving rise to one altered condition, recognizable trait,or clinical entity.

22. I n recent years many important studies of themutational process have been made in unicellular organisms. There are, however, several major problems inthe measurement of gene mutation rates in single cellmaterial, including a lag between application of radiationor other mutagenic agent and the observable expressionof mutations which enables them to be counted : this lag
can be due to various factors, segregational or physio10gical.~' Furthermore, there is always a possible effectof non-mutant cells upon the survival of mutants during
tests.72 A different problem, peculiar to back-mutations,is the difficulty of distinguishing apparent back-mutation
at the same locus from suppressor or modifier effect.
For this problem, which is related rather closely to theimportant question of the reversibility or otherwise ofradiation-induced as compared to spontaneous mutations, there are great advantages to microbial material
in which both kinds of forward and reverse mutations
have been and are being explored. Both radiationinduced and spontaneous mutation rates have beenmeasured with relatively high precision in unicellularorganisms, especially bacteria, under a variety of conditions ;73374it is to be hoped that the techniques andmethods developed ~villyield equally valuable results
when applied to the clones of mammalian tissue-culture
cells now available.

Natural i;tlctatio~trates
23. The basic difficulty in any quantitative stud,^ ofnatural mutation rates is to obtain large enough numbers,
for these rates are low (tables I, 11) and cannot of
course, be raised artificially for purposes of study.
Consequently, investigation has been confined to organisms which can be handled or are present in rather large
numbers, such as bacteria, Drosopltila, and humans. The
limit to the information on natural mutation rates which
can be derived from the very extensive and careful control observations in mice, in the work both of Carter,
Lyon and Philips'' and ofillustrates the difficulty. Because chromosome structural changes occur
naturally at much lower frequencies even than apparent' ~ ~the~ ~ study~ ~ " of rates has been
gene r n u t a t i ~ n s ~ andconfined almost entirely to the latter events, only thesewill be considered here. In man, individual cases, once
found, can be followed up with relative ease even inlarge populations, because the family and individual areindentifiable by name, etc. As a result, it is possible that
more information about natural mutation rates for single
phenotypic entities exists for man than for any otherorganism. I n man, however, as in other organisms, thebasic ~roblemof small numbers governs considerationof thekeld.
The rate and variation of natlcral mutatiom inexperimental organisnzs
23. In other organisms than man, it has been possible
by experiment and test breeding to examine more closely
the variations in natural mutation rates as well as theabsolute magnitudes. The general ranges of the latter do
not vary very widely (table 11).

Physiological variation.s
25. As noted above in another contest, physiologicalvariables affecting natural mutation rates of individualloci have been examined in bacteria by Novick andSzilardia who concludcd that the number of mutations
increased as a function of chronological time rather thancell division. This may, however, not be generally true:79
moreover, the genetic material of bacteria may not be
entirely representative of that of higher organisms.
Moreover, the general lack of systematic variation of
doubling dose among species of widely different generation times, militates against any assumed dependence of
number of natural mutations upon chronological time.
26. Work on physiological variables in DrosopIzila
has been carried out in relation to mutation at classes ofloci, such as the recessive lethals, rather than at single
loci. Differences behveen natural strainslT4and between
sesesaOand dependence upon ageB0have been established
for a number of organisms. These variations in natural
mutability are not known to be correlated with variationsin the radiation-induced rates.
*Strictly, the term mutation rate refers to the rate of occurrence of mutational events and not to the irequency of mutant
gametes among tested gametes, although it is also c o m m o n l ~used to refer to this latter measure. The distinction must,however, be borne in mind in certain situations: for e??mple.
if it is desired to compare true natural mutation rates esbmatedfor free living unicellular forms of life 11-ith the frequencies ofappearance o l mutant gametes in higher organisms, slnce thelatter do not directly reflect the rates of occurrence of mutational events in the germ line cells (see table 11).

Va.riatiots between lociIndirect ~twilzods:autosonz.al recessives (fable I )27. The difficulty, even in Dt.osophila, of obtaining
enough data to document significant variations in natural
mutation rates between loci other than esceptional unstable genes further underlines the basic problem of
numbers in the investigation of natural mutation rates.
Variation between loci, and in certain cases between
i s d e l e s at the same locus is, however, well-known inthis organism.6s I t has been far more extensively documented in the bacteria, at least for back-mutations; therates of these vary from 10-6 to the lower limit of detection near lVlO:they are correlated with mutability byradiation to only a very small extent.53

31. The mutation rate for autosomal visible recessives
is calculated indirectly, by a process originally due to
Haldane.s4 The observed number of propositi, together
with an estimated selective disadvantage in the homozygote, is used to calculate the rate of disappearance of themutant alleles concerned from the population, and abalancing rate of fonvard mutation is inferred from anassumption of genetic equilibrium. The uncertainties
concerning possible existence of small selective effects
in the heterozygote and of large departures from equilibrium render extremely uncertain the values obtained inthis way: indeed, perhaps the most notable use of such
figures has been to deduce a prior; expectation of heterOSIS from a few "unreasonably high" calculated mutation
rates, although most of them lie in the same order ofmagnitude as those for dominant entities (see table I).

2s. In extreme cases variations between loci may
originate in genes which are themselves unstable or confer instability upon others. \ f i e r e mutator genes affectall or a large part of the genome, they may in addition
be partially responsible for variations in spontaneous
mutability between strains. Again, such genetic modifications of spontaneous mutation rates is not known to becorrelated with change in radiation-induced rates.
Natural 9nutatio~crates ifa nzalz

29. Penrose, Nee1 and others have tabulated a numberof calculated rates for single clinical entities in man (seetable I ) . In examining these values, it is necessary to
bear in mind the limitations of the data and of themethods of calculation by which they are obtained.
Direct methods: autosonzd donzinattts a ~ z dsex-litzked recessives (table I )30. In the case of clear-cut autosomal dominant visible entities, the mutation rate is in principle directly
estimated by observation of propositi whose parents andother close relatives are normal. The various technicaldifficulties such as failures of ascertainment and occurrence of phenocopies. degree of penetrance, and the proportion of cases not due directly to fresh mutation havebeen discussed in the l i t e r a t ~ r e The. ~ ~ experimentally~~~
ideal dominant visible combining full penetrance, complete ascertainability and responsibility for total sterility
would be o i reduced value, since it could not be proved
directly to be genetic in origin. Moreover, in practicestudies are commonly made upon the natural mutation
rates in those populations where they are known to behighest, simply in order to obtain enough documented
cases to make the results statistically significant. It istherefore questionable whether the observed rates are
representative. They cluster around 10-Qer gamete ina distribution which is rather skew. If a population of
10' is surveyed during five years for an ideal condition,observable during thirty years, it already constitutes aconsiderable labour, and yet significant results are unlikely to be obtained unless the mutation rate exceedslo6. In practice, no such ideal conditions exist. I t is very
probable that some of the well-documented human mutationss3 have much lower frequencies. Perhaps the possibility should be faced that the sample of spontaneous
mutation rates which have been measured in man is not
representative, and that the true centre of gravity of therates for this group of entities lies at or below lo4 rather
thvl near lo-' per gamete. This encourages the suspicion
thzt among the autosomal recessive visibles for whichrates have been calculated indirectly, more than hitherto
suspected might show heterozygous advantage. There isneed for Governments to foster extension of the scope ofexisting methods, especially to conditions which are rare
or of weak or irregular expression.

Lower limit to detectiort of recessives

32. An autosonla1 recessive with a selective disadvantage of only 1 per cent in the heterozygote, in a population whose coefficient of inbreeding was 0.01 per cent,would, if its mutation rate were lo4, show up phenotypically in no more than about l in lo6 of the population. Even if the condition were fully penetrant, a mutation rate would be very difficult to estimate. Such genes,
if their natural mutation frequencies were in the rangeof lo-?, could hardly be observed at all. There is therefore reason to believe that the best documented sample ofrecessives for which indirect estimates of mutation rate
are available may be unrepresentative. If this is because
they show very slight heterozygous advantage, the mutation rates calculated for them are also too high ;but thenthere is a fallacy in the converse argument, that because
many of these turn out upon investigation to be heterotic,
most human mutant alleles are so.

33. The study of consanguineous marriages does notlead to estimates of natural mutation rates but to estimates of the numbers of recessive alleles present in
populations. In principle, these marriages constitute a
test-breeding for the presence of recessive alleles throughthe associated degree of homozygosity ($$s for firstcousins) which they bring about. It may, however, bequestioned whether a truly comparable control group canever be obtained, although internal controls by comparison of different degrees of consanguinity are usuallyavailable. The limited number of studies made -hOW as
yet no very consistent picture. Of them, those by Sutter~ Othe most extensive.
and Tabah6"= and by S c h ~ l l ~areand that by Books7 the most intensive. Morton, Crowand M ~ l l e r by
. ~ ~an ingenious argument, have shownhow to present the over-all reduction in viability, which
is observed in three of the surveys, in the form of anequivalent number of alleles n-hich ~vouldbe lethal if
homozygous, or lethal equivalents, carried per head of
population. From the surveys analysed by them they
conclude that 3-5 lethal equivalents acting before maturity were present per individual in the population, afigure with which the survey reported by Schull is insatisfactory agreement. Unfortunately, the intensive
examination carried out by Book shom-s an entirely different picture of viability, although in a very small
sample: the total deaths. includiig prenatal and up to
age 30, in Book's sample, were zlnlost identical in thecousin marriages and the controls.

31. The content of deleterious recessive genes of a
population: whether expressed in lethal equivalents orotherwise, is an important parameter indicative of its
genetic state. I t is also a valuable standard of comparison
for actual or postulated mutation rates. There is, however, another possible use for it. Comparison can bemade of the total recessives in lethal equivalents, derived
from vital statistics only, with intensive investigationof all the known recessive lethals present, such as that
undertaken by Book. (Ideally, the total reduction in viability and fertility up to the second generation beyond
the cousin marriages should be employed, (see paragraph 113 below) and the intensive examination should
cover all known recessive conditions.) I n this way it
might be possible to obtain some idea of what proportionof recessive damage is covered by the lcnown effects,
and what proportion remains unltnown : a factor of great
importance to our confidence in any estimates or predictions, based as they must be upon current limited knowledge. This possibility is discussed in more detail inparagraph 113.

35. It is clear that improved recording of such consanguineous marriages, in maternity hospitals or centresof vital statistics, would be of great value and should be
encouraged by Governments if they wish to be aware of
the general state of genetic well-being of their peoples.
36. The Committee has been informed of large-scalecurrent or pIanned surveys of consanguineous marriages
both in Japan, where the frequency of these is high, and,as regards vital statistics, in Canada.s"go

37. I t has. unfortunately, not been possible so far toestablish total natural mutation rates in man for verylarge classes of genes, such as that formed by the sexlinked recessive lethals of Drosophila. Such large classes,
if they could be investigated upon a firm genetic basis.
might more easily provide adequate numbers for reliable
statistical analysis than can be obtained from the laborious search for specific rare conditions. I n this connexion,
it is of interest that Lejeune and Turpins' have recently
attempted to interpret the decrease of sex-ratio at birthwith age of either parent in terms of a mutational
hypothesis. There is, however, no certainty that the secondary sex-ratio does decrease with the age of themother,'86 and the combined data upon irradiated andaged fathers appears at present to involve contradictions.
Since there does appear to be a decrease in sex-ratio withage of the father,la6Js7 it seems a reasonable possibility
that mutations to sex-limited detrimental autosomal
dominants are concerned and that they are due to natural irradiation or other non-cumulative, time-independent causative agents (Penrose's Class I,=' see paragraph 18 above). I t would evidently be of great value
if clear-cut interpretations could be established in someother mammal, such as the mouse, since secondary sexratio data are widely recorded in large populations,although not always in a form suitable for geneticalanalysis, and they are relatively free from the ambiguities of fine diagnostic distinctions. The possible interpretation of sex-ratio data is further discussed in paragraph 64 below.
Mutator afzd unstable genes
38. I n any consideration of variations in spontaneous
mutation rates, the evidence of mutator genes and unstable genes, well-established in corn, in Drosophila andin bacteriaag?must be borne in mind. together with thefact that these commonly do not affect the rate of induc-tion of mutations by irradiation. Minor efiects of thiskind might be more common than are supposed andcould perhaps give rise to some variations in natural
mutation rates between human populations. If that wereso, these in turn could be expected not to give rise to any
corresponding variation in radiation-induced rates.
Although variations in frequencies of appearance ofmutant phenotypes between difierent human populations
are well !mown to occursg3they have been inadequately
documented, especially for dominant conditions. I n thecase of recessives they are usually attributed to past
selective differences, although it is conceivable thatgenetic drift also plays a part.g'
Rads'atio?t-inducedinutation rates

39. Radiation-induced gene mutations have not yet
been observed with certainty in man, and so no quantitative dose-mutation relation exists for the genes responsible for any specific clinical entity. In consequence,quantitative assessments of the mutational affects of theirradiation of human populations must rely at present
upon tenuous arguments and upon extrapolations which
are often of uncertain validity. I n any event they depend
upon the well-established results of the investigation ofradiation-induced mutation in other organisms.
Mag~iitrrdeand variatio~tof radiatiolt-induced ?~tutatio?trates in orgaglisnrs other than matt
40. Since the field of mutational radiation genetics
was opened by 1\Iuller in 1927,95it has been establishedin all the many organisms tested that ionizing radiations
can induce apparent gene mutations: hence the same isbelieved true of man. X-ray induced mutation rates havebeen measured for a large number of single loci, especially in Drosophila. Both the range and average of suchrates are lcnown for a wide variety of individual visible
markers through measurements made under very carefully controlled conditions, and so also is the total rate
for certain large classes of markers such as the sexlinked recessives of Drosophila. A number of rates
observed in experimental species are listed in tables 111,
I V and V.
41. I n mammals, the most extensive investigation of
the X-ray induction of mutations at single loci so far
in which the rates at
carried out is that for mice,",75~i6*96
seven autosomal recessive visible loci have been in\-estigated in spermatogonia; the average of these rates isfound to be about fifteen times the average for a comparable group of loci in D r o s ~ p h i l a . ~ ~42. Extensive research has been conducted upon thevariation in sensitivity to radiation-induced mutation
with physiological condition. In the male it has now been
established that the mutability is low in spermatogonia,
rises to a pcak during the time of formation of spermatids, falls to a second minimum in immature spermatozoa, and then rises up to the time of ejaculation, bothin Dros0plzila~7~~~
and the mouse.B9 In the female
Drosophila, the oogonia show a mutability similar to thatof spermatogonia while late iiocytes are very mutable.37J00 The subject has recently been reviewed by
Glass.lo0Drosopltila is also the only organism for which
extensive determinations exist of the relative ratqs ofmutations in different selective and other classes, either
at single loci or summed over large parts of the
43. & I ~ l l ehasr ~ pointed~~
out that evidence in Drosophila indicates that mcltation rates in somatic and gonialcells are about equal. Estensioll of fllis principle to otherspeciesl~4and eventually to man might malie possible
very i n f o r l ~ a t i ~conclusions
efrom investigations On
somatic mutation rates in vivo in man.
Calculations have been 11lade by Haldanelos andthe practicability of observing nototherssingle locus rates but total rates over a large part of the
genome in a mammal such as the mouse. Such an experiment upon the very large scale necessary might beof considerable value at this juncture in the process of
extrapolation to man ; it would, however, involve theexpenditure of a great many scarce mouse-geneticistyears. The Committee has been informed of the existence of a pilot experiment on these lines.lO"

45. l-he collcept of genes as finite structures of different sizes which carry hereditary information largely
in he form of different arrangements of nucleotides in
DNA has recently made possible one particularly interesting interspecies comparison concerning induced mut a t i o n s . l ~ There~ l ~ ~ is evidence that in mice the total rateof induction of recessive lethal mutations in sperm ishigher ballthe corresponding rate in Drosop]%ilaby afactor of about 20.157 The same is true for the rate of
mutation per locus ayeraged over several different loci,and in addition there is a similar difierellce of aboutti\-enty-fold in the same direction in the DNA content
per nucleus. This suggests that perhaps mouse genes are
not more numerous but are larger than Drosophila genes-that the extra DNA has gone into building genes thatare bigger and more complex rather than more numerous.
The possible application of such an idea to man, an
organism in which mutational events cannot in generaleven be assigned to definite loci by test crosses, but which
has a DXA content per nucleus similar to that in themouse, might lead one to expect rather high mutation
rates, both spontaneous and induced, when measured
atperclinical entityt', as well as all the complesities andpeculiarities of large multiple allelic series. of which a
notable example has been uncovered by Dunn in the
t-alleles of the mouse.10s Penrosess has already drawn
attention to the possibili~of some unusually complex
genes in the X chromosome of man, in connexion withvery high observed natural mutation rates.
Radiation-induced r.trutatio~zrates in v~arr
S u r v e y s o f radiatioiz-iprduced gelle atutations in man
46. Whatever approach is adopted to the problem ofradiation-induced mutation rates, the gonad doses received both by control and by experimental groups
have to be known.
47. I n principle, the simplest method to obtain a qua,]titatix: relation between dose and radiation-induced genemutaoons in man is '0 ma'
a ~ o m ~ a r a t i vSurveyeofthe Progeny of an irradiated ("experimental") and a
com~arableu?-irradiated("control") population. Thosesurveys published so far are concerned only with thefirst generation born of irradiated parents. Hoivever.
it isto Show that. as human matings cannot be conaami?ati?n of the first generation provides
more information m itself than examination of subsequent generations.
48. I n the last analysis, all the obsened quantities
come do~vnto variations in frequency, and therefore:(a) All studies must be accompanied by the esamination of a control san~plepresumably issued from genetic
stock identical to that of the irradiated sample. This con180

dition greatly restricts the value of the results ~ublishedso far.
(6) All the results obtained are subject to an inevitable sampling error which necessitates the collection ofa v e v large amount
dataA number of quantitative characters. such as birthweight, size and various anthropometric measurements,
as well as statistical data, such as neo-natal mortaliq-.
have been suggested and examined. Unfortunately, theprecise genetic component in these variables is notknown ; on the contrary, they are known to be dependent
upon factors which are economic (standard of living).
demographic (age of parents. order of birth, etc.) andsociological (medical care).
49. The characters that can be utilized may be groupedin ~ I V O categories, according to whether they are connected with dominant (or sex-linked) visible mutations
or with dominant (or sex-linked) lethal mutations. The
detection of ~ i s i b l edominants is carried out in practiceby the observation of maiformations at birth. I t is in factreasonable to assume that an increase in the frequencyof dominant mutations associated with visible effects
would manifest itself to some unknown =tent as anincrease in frequency of malformations. The same would
be true of visible sex-linked recessives in boys born toirradiated women. Lethal mutations may be revealed infour ways :( a ) Increase in frequency of miscarriages (\-irtually
impossible to determine with certainty) ;(b) Increase in frequency of still-births (much morefeasible but subject to the demographic considerations
mentioned in connesion with neo-natal:(c)Reduction in fertilit)., or eren steriliq (\4rtually
inlpossible to measure in man) ;Disturbance in theof the seses at birth(deviation in the sex-ratio, an easily obsen-able criterion).

jo. The various studies \vhi& ma,, be taken into account at the present time are listed, together with pertinent results, in table VI. Given the very uneven qualityof the data presented by the various authors, and theparticular way in which they were arranged by each ofthem, it is impossible to add together the figures fromthe separate surveys. In general. none of the investigations makes a definitive demonstration of a genetic phenomenon. Only the decrease in the sex-ratio. which isfound in the three studies of irradiated mothers. seems
to be acceptably established as a reality. Although no ..
one of these studies concerning sex-ratio yields statistically significant results by itself, the fact that all
three deviate in the same direction gives some confidence
conce,~ng the realit,. of the
A~~~~~~~
ofthe studies to date rdse the possibility of an increase inco,snital malformations among the offsprillg of irradiated persons, the findings in this regard are much lessconsistent than those concerning
the sex-ratio. In thiscomesion,
it must constantlybe
in mind,vhere many comparisons are being
behveen M70
groups, on the basis ofalone oIle in twenty ofthese comparisons will
differencesthej per cent leXrelof significance+
observations
regarding the possibility of an increase in congenital
defect or early death are highly desirable.
51. In summary, it seems possible, although only withgreat difficulty, to distinguish a detrimental effect ofirradiation on the first generation issuing from irradiated parents. The possibility of firm demonstration and-.

measurement of this phenomenon suggest that all thesestudies be extended on the largest scale possible, wherever practicable surveys can be made with a reasonableprobability of yielding positive significant results in acomparison with adequate controls.

52. I n view of this possibility of future surveys of theprogeny of irradiated persons, it seems worthwhile toindicate the criteria which determine the value or "resolving po\ver" of any such study. In brief, five points must
be considered :( a ) The dose to the parents of the individuals understudy ;( b ) The number of individuals whose parents havebeen so esposed :( c ) The number of characteristics of genetic significance to be recorded ;(d) The manner in which information on these characteristics is collected;(e) The availability of a suitable control group.
53. To illustrate the manner in which ( a ) and (b)may be taken into consideration, a particularly simple
hypoethetical case has been selected, that of the detection of an ideal autoson~aldominant visible allele causing
complete sterility :Suppose the gene concerned to mutate at a rate m
per gamete in the control population and at an increased rate fm per gamete in the irradiated population. If the doubling dose for the mutational step
concerned is D2rad and the mean genetically significant exposure per parent of the irradiated group is
D rad, thenf - 1 = D/Dz
If P progeny of the irradiated group and Q of theunirradiated are examined with complete ascertainment for the visible allele. the numbers ex~ectedto beobserved are respective$ 2mfP and 2m&. The observed difference in rate between the two groups is
A = 2m( f - 1) and has an allproximate
variance dueto the limited s&nple size of
uA2 = 2m(f/P+ I/Q)In cOnsequencel even if
are considered,

other

i
:
>
-

I
of

calculated R values for the various exposure classes,
which add up to 2.3 X 1V2on the assumption that the
representative doubling dose is 30 rad. With respect
to the possibility of significant findings based on mutation at alry otle locus, then this study (and any otherstudy to date) is far below the level of significance.
54. Where multiple traits are involved in the inquiry,
the power of the study is a function of the precise number of traits under consider?tion. For example, if one
were to make the over-simphfied assumption that mutation at any one of 100 loci resulted in completely penetrant, dominant mutations responsible for congenital
defect, assuming independence In the ~xpressionof mutation at these loci, the calculated resolving power of thepreviously mentioned study becomes 2:3,.and the failure
to observe a significant effect of radiation on the frequency of congenital malformations in the aforementioned study might indicate that the assumed doublingdose was too low.
55. The sex-ratio is one of the more conveniently
studied indicators of possible genetic damage. Information on this point is relatively easy to collect and has ahigh degree of objectivity. The calculations corresponding to those of paragraph 53 are relatively simple andproceed as follows :Suppose a group of mothers receive gonad doses
averaging Dmprior to conception of children, and suppose the irradiation causes a shift in the secondary
sex-ratio s which is linear with the dose
Suppose Pmprogeny of these mothers are esamined. the variance in the determination of the sexratio of the progeny of the group, due to limited sample size, will be$ = s(1 - s)P,Since s is always approsimately 5, this may be
1

=-

4Pm
If such a group is compared with Q, progeny of acontrol group the variance of the observed differenceis

If we require that x" 4 for a significant increase of
mutation rate in the irradiated group t o be established, and denote x2/4 by R, then for a significant
increase in mutation rate a t a single locus,

and the significance of the observations is determinedby

In terms of D and D?

If we require ~2 3 4 before the shift can be considered significant, thenFor esample, in the study of Nee1 and Schull,lll
the progency of irradiated parents numbered 3.3 X lo4
and the progency of control parents. 3.2 X lo4.while
the average excess radiation exposure to the combinedparents of the former group is about 17 rad. Becauseof the known heterogeneity of Lxposures. R for any
single locus must be computed by adding together the

Similar formulae can be derived for comparison of theprogeny oi irradiated fathers with controls. whereA number of completed surveys, irrespective of thesignificance of their results, all show decreases in swhen the mother is irradiated from which values of
k of the order of - 1 X 10-*/rad can be derived. If thisfigure is adopted for purposes of calculation, thenO n the basis of the present limited information, valuesof Rf have been calculated using a similar numericalvalue of k but of opposite sign

Clearly, if kf and km do in fact differ in sign, thensignificant results may occasionally be obtained by thecomparison of progeny of irradiated mothers withthose of irradiated fathers, even where neither groupdiffers significantly from the controls. On the basisof the numerical values adopted here, the same condition upon significance would then become

where Pf is the number of progeny of irradiatedfathers examined and Pa is the number of progenyof irradiated mothers examined. The resolving powerof comparisons with controls of progeny both ofwhose parents have been exposed will, under these circumstances, involve Df - Dm and be relatively poor
if the doses to the hvo parents are quite similar. If kf
and kcm were to have the same sign, the situation would
be reversed. By way of a numerical example, the data
of Turpin and Lejeune117~11s~105
may be considered.
I n this study, Pa is 136 and Q, is 236. For the purposes of this calculation, Dmand Df will both be set at
450 rads. Then R, may be calculated to be 0.175. The
calculated Rf for the same data is 0.52. In passing,it might be noted that because of the many somatic
factors thought to influence sex-ratiot one would as amatter of principle have more confidence in the genetic
origi? of a sex-ratio change among the offspmg oflrrad~atedfathers than among oiispring of irradiatedmothers.

56. That comparisons of the progeny of irradiatedand non-irradiated groups must be carried out on rather
a large scale, if there is to be any prospect that they will
yield significant positive results, is emphasized by thehigh proportion of non-significant results obtained in thecompleted surveys of table VI. Moreover, they may
require rigorous and complex analyses of controls,111
and therefore involve considerable effort of a very specialized kind. While negative results on a sufficient scale
can be of great value in excluding the most alarming
possibilities,''' onIy positive ones will suffice for a quanhtative relation between dose and mutation frequency.
I n this connesion, a survey of the high radiation area ofKerala113*lg5appears to have a potentially somewhat
greater resolving power than any previously made, if anequally intensive investigation over a ten-year period isassumed.
57. -kt its first session, this Committee requested advice from the World Health Organization about the possibility of setting up a standard of recognition for one

or more clearly recognizable medical conditions thought
to be largely or solely genetic in origin. I n their discussions of this, the geneticists of the study group t ~ h i c hframed the reply of W-HO made clear that they strongly
questioned the feasibility of using a single condition as
an indicator of the mutation level in large p0pu1ations.l~~
Their feeling appeared to be based in part on the manifold
uncertainties which exist concerning almost every single
likely indicator condition,l1° and in part upon the belief
that reliability of results in this field depends upon intensive study of every case. The study group recommended
that simultaneous investigations always be carried out on
several conditions.l13 Indeed, the sense of the document
cited is such as to cast some doubt upon the practicability of such surveys, in view of the associated difKculties of obtaining sufficiently large numbers. I t does not,however, rule out large-scale survey plans ii the urgencyof the situation warrants them. Moreover, if the objective were to survey one population serially in time so as
to be able only to establish limits of possible relative
increases in the mutation rate, tvithout any interpretation
as to cause, some of the difficulties might diminish.'1°
One such difficulty seem to lie in combining the intensive
examination of cases. which is the classical a ~ ~ r o a cofh
human genetics, with' the extensive survey ofL;ery large
populations which is required if adequate numbers areto be obtained for studies of mutation rates at or near
the spontaneous rate in man. This dficulty is emphasized by the sharp limit of about 3 x lo6 set in discussion
upon the size of human population which can be coveredby an institute conducting epidemiological surveys of theclassical type (see also ref. 11).

58. The difficulties of comparative surveys of highresolving power have led Penroseg3to propose a modified
approach, by which a given class of mutant propositi
would first be collected from a large population heterogeneous in radiation exposure as well as in other respects. and only then would personal histories, including
radiation histories of the parents, be compiled for the
propositi and a comparable control group. The method
is a powerful one for the wider field of general human
genetics. since it can serve as a basis for quantitative
investigations of other mutagens than radiation. As applied to the radiation problem, this same possibility ofalternative and perhaps unknown causes complicates the
choice of a legitimate control group. Moreover, the burden of work is in part thrown into a sphere where rather
considerable difficulty also prevails : the quantitative
compilation of individual histories of irradiation.ll'
In order to obtain a quantitative dose-efiect relationfrom a survey of this type, it is necessary to know not
only the incidence of the condition under investigationin the general population, but also the general incidence
in that population of individuals having similar radiation
exposures to those of various classes of propositi. Many
features of the approach are exemplified by the recent
work of Steward et al.l15 on a somatic radiation problem.
Possible aids ill extrapolatwn of radiatiolt-ir~dztced
17zzttationrates fronz otlzer species to Inan
59. I n view of the difficulties of a formal human radiation genetics. it is necessary to consider possible ways
in which radiation-induced mutation rates can be measured in systems closer to the in vivo germ cells of man.
In this connesion a new field of work has been openedby the ability of Puck and his collabor~torsto growcolonies of tissue-culture cells, the majority of which
are viable and able singly to give rise to fresh colo-n i e s ~ x , ~ ?The? well-developed methods of microbial
genetics can in principle now be applied to such cultures
both for natural and radiation-induced mutations, although certain features are believed by many workers
still to limit the applicability of the material to thisproblem :(a) Tissue-culture cells usually need a more complex
medium than the whole organism from which they
originate.
( b ) Well-established l i e s tend to be poly- or aneuploid. They resemble both each other and the malignant
HeLa strain, with which Puck first developed his techniques. I n certain types of radiation experiment, thisdifficulty may be circumvented, as in the work of
Bender,lg who used tissue-culture cells very recently derived from human kidney (within four transfers) in acytological study of induced chromosome breaks. But
the repeated propagation of lines of stable diploids fromsingle cells appears to be a prerequisite for systematicstudies of gene mutation in human tissue-culture.
( c ) Some workers in the field doubt whether any lineof normal (i.e. non-malignant) cells has really been successfully propagated as such (but see Puck)( d ) It is not yet known what is the exact relevance ofstudies on the mutational behaviour of somatic cells
in vitro to that of mammalian germ c d s in vivo.
Points ( b ) and (c) can perhaps be circumvented inpart by applying the technique to cultures derived as
freshly as possible from normal tissues. However, adifficultyof principle remains : the tissue-culture cell is afree living organism, whereas the ancestral tissue cell ispart of an organism so that its growth. division and differentiation are subject to the developmental controls ofthat organism. In view of the close connexion of all, andespecially the genetic, effects of radiation upon the cellwith the process of cell division, some initial caution ininterpretation is undoubtedly required. Nevertheless, thefuture role to be played by the tissue-culture methods inthe making of comparisons between species so as toprovide a basis for extrapolating from the known in vivo
mutation rates or rates of occurrence of gross structuralchanges, does not seem open to doubt.
.18*121*"211B4

60. There is some e v i d e n ~ e ' ~ ~thatJ ~ ' the frequenciesof radiation-induced mutations in somatic cells is similar
to that in gonial cells. If this correlation could be extended to the variation between species, attempts tomeasure induced and/or natural mutation rates in humansomatic cells in vivo might provide information of greatvalue as a guide in estimating mutation rates in humangenes.
Continired need of research in fulldarnental genetics
61. It cannot be too strongly emphasized that there islittle basis either for planning or for interpreting ad hocradiation genetic surveys in man, or for making calculations concerning radiation-genetic effects in man, except the great volume of fundamental research uponother organisms which has been carried out for its intrinsic interest alone, and directed wholly as a contribution to human understanding. This foundation must be
extended and strengthened, and must not be weakened
in the interests of the applied superstructure.

62. Provided that the dose-mutation rate relation has
a linear form
rn = m,kD+

the relative increase of mutation rate per unit dose isreadily expressed by the ratio k/m,. Another convenient parameter t o use js the reciprocal of this ratio,
mo/k, which is the radiation dose required t o produce
a number of mutations equal to those occurring naturally, or the "doubling dose" (Dz). For a whole seriesof mutations r n ~whose effects sum up or are collectively observed Z ml = 2 mol D z ~ ,

+

1

1

1

v
L4

and one can define a mean D as

m01
=

7 k,

fS ,.

This procedure can be used to estimate a D, for as
representative a group of human genes as possible. I t
is not necessary to know how many genes are involved
or of what kinds, provided that they can reasonably be
assumed to be a representative sample a?d provided
that there is assumed to be no correlatlo? between
Dz,, k l or m o tand thedegree or kind of manifestation.
The representative D2 should then express the doseeffect relation for a n y set of radiation-induced mutational events in so far as this itself depends upon asufficiently representative sample of human genes:
usually the sets will be of a kind in which the mutations at a very large number of loci a r e summed, bothin calculating and in making use of Dt.
Estinzutes of the representative doubling dose
for lrurlran genes
Gerreral levels in other species

63. I t has been pointed out1isJ50 that a number ofdoubling doses calculated for different species clusteraround the range 3 0 4 0 rad (table VIII). However, thesignificance of this fact for present purposes is limited
by several considerations :(1) The majority of the experimental radiation exposures concerned were of gametic cells. Where irradiation of gonial cells is concerned, it is true that the best
estimate that can at present be made for a group ofgenes in the mouse (the only mammal so far investigated) is of the order of 30 rad, but this must be compared, for instance, with values for Drosophila ranging
up to 400 rad (see table VIII).
(2) No satisfactory interpretation of the observed
concurrence or range of values exists, and consequently
any empirical extrapolation to man would have to rest
upon an unsure basis.
(3) The lack of correlation of observed doublingdoses with life-span can be interpreted as an indicationthat mutation at a constant rate in chronological time is
not the dominant factor in determining the natural rates
in the ~xperimentalspecies. But man is so much longerlived than the experimental organisms that in his casean appreciable fraction of natural mutations is alreadyquite likely to result from time-independent causes suchas irradiation from natural sources. (See P e n r o ~ e l 'for~a preliminary investigation of this point).
Sex ratio

64. Observations have been made of a shift of the sexratio in the progeny of irradiated mothers (see paragraphs 50, 55). In a first attempt to make use of theavailable data, Lejeune and TurpinlZohave proposed acomparison between the effect of irradiation and theeffect of aging. These authors have calculated a significant decrease of the sex-ratio with the aging of themother alone, the partial regression coefficient being-3.36 X 1 P for an aging of five years. Taking a value
for one rad as an estimate of the decreaseof -6 Xof the sex-ratio following irradiation of the mother(table VI), and assuming that both decreases are related to the same -tent to newly arising sex-limited
detrimental mutations, they have proposed a doublingdose of-3.36

X 10-4 X 6- 6 X 10-5

+ 30 rad / From age 0magnitude as that calculated from purely mutational
experiment. Establishment of such facts would greatly
strengthen interpretation of corresponding observations
upon man.
68. Although today it is not possible to assign any
definite confidence to the use of the sex-ratio as an indication of mutation rates, it must be borne in mind thatthe parameter, even if not totally satisfactory, is the only
one easily surveyed in entire populations, and that it
represents the "cheapest" genetic trend available to research workers in terms of technical effort expended insurveys.

to age 30 years.

Unfortunately, as these authors themselves recognize,such a calculation cannot be considered as legitimate
before many problems have been solved. The needs
include :(1) A good estimate of the gonad dose effectively received by the mothers ;(2) A better estimate of the decrease of the sex-ratiowith irradiation, including a test of linearity of the relationship between these quantities, which is implicit in all
current calculations concerning sex-ratio ;(3) An explanation of the apparent contrast between
the sex-ratio's decrease with the father's aging1"JS7 andthe possible increase observed after acute irradiation of
the father's gonads ;111-124(4) The study of other variates such as birth rankle%
which might interact with the real effect of the aging of
the mother.

65. Only some preliminary data relevant to the problem of irradiation of the father are available, but these
indicate that a sex-ratio decrease after chronic irradiation may perhaps have occurred in manlZ6and in themouse.lZ5 The latter body of data, although not significant at the 5 per cent level, yields at face value a
representative doubling dose in satisfactory agreementwith other data for this speaes.
66. In summary, while the possibility esists in principle of deriving a representative doubling dose by comparing the changes in secondary ses-ratio when parents
either age or are irradiated, the relevant phenomena are,at present, not sufficiently well established either quantitatively or qualitatively for this procedure to be reliable.
Yet relevant surveys of the secondary sex-ratio are more
readily and widely carried out in human populations thanare others which must depend upon finer diagnostic
distinctions. Consequently, more extensive quantitative
data concerning comparable irradiated and non-irradiated human populations should continue to be sought.
I n particular, it may be worth attempting to search for adecrease of sex-ratio among the progeny of not too
h e a d y !rradiated human males ; the conclusion of sucha test might go far to determine the utility of the parameter in considerations relevant to the human genetic
radiation hazard.
67. I t is not at present certain, even in Drosophila,
whether the postulated genetic causes of shifts in the
sex-ratio play .the. quantitative roles expected of them ;and data of thls kind are needed. It is also possible thatfurther investigations upon experimental animals, especially vnong the progeny of male mice irradiated at low
doses, together with slmllar observations upon irradiatedfemale mice, may show that in both cases a doubling dosecan be derived from sex-ratio shifts which is of the same

69. A reasonable probability now exists that, in anintermediate dose range, the radiation-induced incidenceof leukemia is a linear function of the Exposure of thebone marrow, whatever the manner of delivery of thedose. Upon this hypothesis, it has been calculated that
30-50 rad mean exposure of the red marrow might
suffice to double the natural incidence of leukemia
among an adult group??'
70. Leukemia certainly involves a transmissible hereditary change in the tissue cells concerned. a "mutation"in the widest sense of the word. Whether the processof its induction in somatic cells corresponds qualitatively
or quantitatively in any way to the process of apparent
gene mutation as it is normally thought of in g e m cells
is extremely doubtful. Nevertheless, it is not entirely
excluded from providing an indication of the relative
sensitivity of human cells to natural and radiationinduced genetic changes. The indication must, however.
be regarded with great reserve : even if the most helpful
possibility eventually proved true, and leukemogenesis
were primarily a process of somatic gene mutation, asingle very atypical gene in a somatic cell might beresponsible, and might be entirely unrepresentative oftransmissible germ-line mutations.
Survey of Japatiese cities
71. Although the results were negative, the extensive
observations of Neel and Schulllll in Nagasaki andHiroshima provide some evidence of a lower limit for
the representative doubling dose for human genes. atleast for the dominant mutations which would havebeen observed by these authors. A difficulty of the typeof sunrey conducted by Neel and Schull must be mentioned here: in order to obtain significant data, it isnecessary to continue collection of it for some considerable time. Among a population who have been
subjected to heterogeneous, hea\y esposure, there may
perhaps be some infertility of a progressive kind selectively induced among the most heady exposed groups.
In that event, incipient positive results may be masked
by later data collected in the attempt to make the observations more significant. I t is possible that the si@cance of the observations made in this kind of survey,
because of its scale, complexity and uniqueness, canonly be evaluated adequately by the authors. I t thcrefore seems reasonable to accept the opinion of Neel and
Schull that their negative results make it improbablethat the representative doubling dose for human genes
irradiated in gonial cells lies below 10 rad.

The trafztral exposlire
72. The representative doubling dose for human genes
undergoing chronic irradiation cannot be less than thegenetically significant exposure of natural origin. In
most areas this is about 3 rad per generation. I n exceptional areas, the natural radiation may contribute soheavily to the natural mutation rate that the observed
representative doubling dose would be increased.*
Clcrrent best estimates

73. Iiot one of the arguments in paragraphs 63-71
gives a reliable estimate of the representative doubling
dose, yet each depends upon a different, independent
set of unproven ideas. This Committee recognizes aneed, in our existing state of knowledge. to make use of
every available source of information, however tenuous.
I t considers that the separate arguments and repeatedindependent observations of small changes, in spite of
the statistical limitations upon their significance. provide
a reasonable indication \\-hen taken together; the representative doubling dose for human genes irradiated inpregametic cells is likely to lie between 10 and 100 rad.
There is supplementary evidence that it cannot be lessthan 3 rad. The Committee notes that the value 30 rad iscompatible with the whole of the probable range cited,within a factor oi about 3 : it therefore has a certain
degree of utility for purposes of calculation wherevera "most probable" value of the representative doublingdose is required.

XfUTATIOKS IK THE G E S O J I E O F .\IAN

74. Because radiation-induced mutation has not yet
been observed with certainty in man. it is not possible
to give a satisfactory estimate of total induced mutation
rate: indeed, this is hard enough even in Drosophila.lo8
Nevertheless, it could be hoped that the total rate mightbear some relation to total genetic material : such a hope
has recently been supported by the only available comparison, that between calculated total induced recessive
lethal rates asd DNA contents in the mouse107 andDrosophi1a.i The DNA content of human cells is about
6/5 that of mouse cells, according to V e n d ~ e l yHence.
.~~upon the stated hypothesis, it might be expected thatroughly one recessive lethal per 250 rad would be induced in human sperm by irradiation. Again by analogy
with both the mouse and Drosophila, which behave
alike, it might be expected that in spermatogonia only
about one quarter as many gene mutations would occur.
However, in Drosopl~ilait has been estimated that the
total rate of mutation to appreciably deleterious alleles
is about four times the recessive lethal rate.'Os In theassunlptions made so far, it has been possible to rely
upon common quantitative behaviour of two diverse
species. But the induced mutation rates for single lociof mice, as well as the total recessive lethal rate, aregreater than those of Drosoplzila by a factor of 20,

corresponding approximately to the ratio of DYA contents per cell. This has suggested that perhaps the individual genes of the mouse are not more numerous
but are larger and more comples than those of Drosopltila. In turn, the ratio of total to recessive lethal mutations might be very greatly affected. That this isperhaps not SO is suggested by comparison of theinduced mutations at sets of v~siblerecessive loci inthe two organisms. In both cases, some hvo-thirds ofthe experimentally induced mutations have been foundupon investigation to be lethal. The similarity could be
a property peculiar to visible loci : but it at least suggeststhat the ratio of total to recessive lethal mutation rates
may be the same for these tsvo and possibly other species.
I f the Drosophila ratio is applied to man on these tenuous grounds, a total induced rate of appreciably deleterious mutations of about one for every 250 rad applied
to the gonial cells is suggested. It will be clear to thereader that based as it is upon so many tenuous hypotheses, this figure. must be regarded with the very greatest
reserve. In particular, it applies only to the sum ofoligogenes with individually detectable effects m dneglects the polygenes involved in quantitative inheritance, an especially serious omission for organisms
which may have considerably larger and more complex
genes than Drosopltilu, and may therefore be relatively
much more liable to small changes giving rise to many
isoalleles even at known loci.

11. T H E GENETIC CONSEQUENCES
OF IRPL4DIATIOX

75. The fate of a mutant allele newly introduced into
a population is determined by selection. Hence the connexion between mutation and the genetic damage due
to it depends primarily upon the selective properties ofthe mutant alleles concerned and, in particular. upon
the degree of dominance or recessivity of these. Our
ignorance of the relevant facts in man is very complete
and urgently requires rectification.

* T h e parameter of biological interest is, of course, the ratio

76. I t is useful to precede inquiry into the action of
the selective process upon mutant alleles by an inquiry
as to the origin of genetic variation in natural populations and its connexion with fitness. The question is an
old one. especially in connexion with plant material,
where the great extent of natural genetic variation was
early observed, and where breeding experimexits earlygave rise to the controversial notion of "hybrid vigour".
I-Io~vever,much of the agronomic literature is primarily
concerned with the rxxternally applied criterion of "yield"
rather than with fitness. hloreover. natural populationsof plants differ decisively from those of animals in the
aspects of genetic structure which are of immediateconcern here.

per unit dose. In man the spontaneous and induced componentsof the natural rate cannot be separated, and it is convenient todefine the representative doubling dose in terms of the total
natural rate. However, in situations such as that described here,
the distinction bet~\.een the spontaneous and natural rate
becomes of importance and must be maintained.
ti\ figure for tht total rate of induced recessive lethals ha:
also been given for yeast by the careful work of Bfagni."Vtappears at first sight to disagree with the hypothesis put forward
here, because of the exceptionally low DNA content of theyeast cell (table VII). However, yeast is known to possess 3.
relatively extensive non-chromosomal genetic apparatus."' It
has therefore not been used here for comparison.

77. What may be called the classical view of theadaptive norm of a natural population supposes the
optimal allele to be homozygous at most loci: this situation of mzximum fitness is disturbed by mutation.
continually restored by selection : rarely, due to chance,
to change in external conditions in time or space, o r tochange in other parts of the genotype, a mutant allele
will prove itself advantageous, displace the fornler predominant allele at the same locus, and become the new
wild-type allele (see review in ref. 130). I n recent
years this view has been increasingly strongly challengedof the spontaneous mutation rate to the induced mutation ratetion: the expressions o i these alleles also contribute toby some,'30 especially in conncxion with the accumuthe
genetic component of human ills.
lation of extensive evidence concerning the prevalence
and the superiority in many respects of structural heterozygotes in natural populatio~lsof D ~ o s o p l z i l a a, ~ ~ ~ ~81.
~ ~As
~ yet, nothing is known of the rate of induction
by radiation of the mutations responsible for any specificfinding which is itself, however, compatible with thecondition in man. I n consequence, the discussion whichclassical ~ i e wof genic homozygosity as the adaptive
norm. I t has also been argued on more general grounds1ss follows will be restricted to broad categories of effects.
Only by such a grouping together of the consequencesthat heterozygosity is the adaptive nonn at most loci andof mutation at a large group of loci can a representativethat heterozygotes are in fact intrinsically better able torate of induction of mutations per gene, or a representaadapt themselves and maintain their own stability in thetive doubling dose, be applied: these are the only two
face of changing environmental conditions. A recent
parameters expressing a dose-effect relation so far
experiment byseems to indicate that evenavailable.
random unselected radiation-induced heterozygosity ingeneral confers an advantage, at least upon individuals
82. I t is natural, in applying the results of an exotherwise homozygous for certain pairs of arbitrarily
perimental science, to try t o use a synthetic approach,chosen chromosomes in laboratory populations ofassessing an effect from the accumulated knou-ledge
Drosophila.
of various causes. In the present instance, this means
attempting t o assess the magnitude of the social con78. These two views lead to different general expecsequences of increased mutation by using mutation
tations concerning the consequences of mutation. On
frequencies per rad a t particular loci t o build up a
the first, most mutants alleles will contribute to the
combined estimate from the effects of induced mutalimited degree of heterozygosity, will be harmful, andtion a t all loci. T o use this method, let the total
will require to be eliminated, diminishing the fitness ofmutation rate to the set of alleles responsible for a n y
the population. On the second, mutational events, alspecific condition denoted by i be k,D, where D is thethough the majority of them will still be harmful andgenetically significant dose of radiation to the populawill require to be eliminated, will scarcely affect thetion. By a theorem originally due to Haldane8.i there
great degree of heterozygosity already existing, and willmust on the average be klD subsequent eliminations
diminish the existing reproductive fitness to only a corof the mutant alleles through differential failure of
respondingly small extent. However, this is a consereproduction. These are often referred to a s genetic
quence of the fact that since the mating of diploid
deaths, although they may take place through pheheterozygotes produces some homozygotes, on thenomena such as very early'abortions, which are of no
second hypothesis the population must pay for its built-insocial significance, as well as through more or lessadaptability and plasticity by a permanently reduced
severe disabilities or even premature death. Suppose afitness due to these.
fraction p l are eliminated by socially serious expres79. Unfortunately, while evidence now exists for the sions and think of p, as including some weighting factor
second view of natural populations of Drosophila, thiswhereby such qualitatively diverse end-results a sparticular organism has certain features (principally
death, physical disability, mental deficiency, etc. m a ychromosomal inversions) which bestow upon it a special
somehow be quantitatively compared. Then the concapacity for carrying structural heterozygotes, together
tribution t o the social burden is kIp,D and the wholewith all the consequences which may flow from thiscontribution of the dose D t o the future social burden
capacity; these features include the absence of crossingis HklptD over all such specific conditions. The above
over in the
coupled with a mechanism forargument continues to hold whether the mutation ineliminating undesirable products of cross-over between
volved is to an allele which from the selective point ofstructurally different chromosomes from the egg in theview is conditionally or unconditionally deleterious,
female.ls8 There is no reason to suppose man to possess
although if the mutant allele is only conditionallyeither this particular structural mechanism or an optimal
deleterious then (a) it cannot be eliminated in thosedegree of genetic heterozygosity, although the possibility
situations in which it is selectively favourable, andis not excluded that equivalent mechanisms may be( b ) the total elimination rate a t any one time may
found. Hence the Committee is compelled to assume that
greatly exceed the mutation rate, because the increased
the general genetic structure of human populations corfertility of carriers under the selectively favourable
responds more closely to the classical model in so far
conditions increases the gene frequency. If the natural
as this relates to known genes having individually demutation rate m, is known, then k t can be re-expressed
tectable effects. There is, however, no basis in ourin terms of the doubling dose D2, by jCIDzl = m i andpresent limited state of knowledge for deciding whether
for all mutations or a large class of them a mean
the genes responsible for quantitative inheritance dod s b l i n g dose I 3 2 can be defined by the equationo r do not maintain themselves by overdominance in so
kDz = m where k = Tk, m = fml. I t is unfortunate
far as they affect the over-all fitness. I t must be emthat in man we do not know any individual k lor D?,.
phasized that upon all the hypotheses discussed here, theStill more unfortunately, the fractions eliminated bygreat majorlty of radiation-induced mutations will be tosocially serious expressions, pl, are unknown and may
alleles which are UI the first instance harmful and undepend upon rather small positive or negative fertility
likely to be retained in the popuhtion.
differentials in those ~ v h ocarry the mutant allele without expressing it, if they greatly out-number those inwhom it is expressed. Nor can a mean p, be estimated
2. APPROACHESTO QUAXTITATIVE ASSESSMENT
for mutant human alleles. As a result, the synthetic
O F THE GENETIC COSSEQUEXCES O F IRRADIATION
approach leads t o an estimate in such terms t h a t i t
OF HEMAN P O P U L ~ T I O ~ S
cannot as yet be satisfactorily related to the social
consequences.
80. On the classical basis, the irradiation of humanpopulations is espected to result i11 mutations to alleles
83. There is an alternative formulation of the problem
whose expressions are harmful and lead to their eliminaby an analytic approach. based upon analysis of thepresent social burden in terms of naturally occurring
hereditary defects. In this, it is asked, ( a ) what is thesocial burden bl due to a given condition denoted by i,whose occurrence is related to the presence of adverse
genes? ( b ) Of the genetic burden bi, what fraction f
is due to recurrent mutation? ( c ) By what fraction gi
will this be increased immediately or in the future by agiven fractional change c, in the natural mutation ratem i Z If the change ci is caused by a genetically significant
dose D to the population.

For all conditions or a large class of them the total
genetic burden may be written b = f bl, that due torecurrent mutation fb = flbland that due to a givendose D asfglflbI. If it is assumed that g l = cl, this-.
may be written as

TIt may be assumed that bi and f t are independent of
D,,. Then the increased burden may be written

D/a2 $fib, which may be written (D/Dz)
f bwhere f = %fibl/ ?blT h a t is, the genetic burden due to a given dose
equals( p e of genetic burden
X ma~ntainedby recurrent
doubling dosemutation)

given dose

The relation behveen induced mutation rate and exposure enters here only through the representative doubling dose. In the present state of knowledge, the analytic
approach is more certain than the synthetic approach,because the relation between induced mutation rate andexposure enters only through the representative doubling dose.

84. Even supposing the necessary quantitative relations between mutation rate and dose or radiation exposure to be known. calculation of the social consequences still requires knowledge of one of the sets oi
parameters, pi or f dependent upon selective behaviourof the mutant alIeles. The hvo approaches are comparedfrom this point of view in table IX. I t will be seen that,
under conditions in which mutation contributes a largepart of the social burden, f l is relatively well known
but pi is not. Moreover, there is some reason to believethat most heterozygous carriers of individually detectable, socially deleterious recessive alleles are slightly~ * is' ~true,~ most f iless fertile than a ~ e r a g e . ~ ~IfJ ~thisare kno~cnbut most p1 are not. It is concluded that, formost purposes, the analytic approach starting from thecurrent social consequences of unfavourable alleles is tobe preferred to the alternative method at the present
stage of knowledge.

85. Certain assumptions are implicit but not stated in
the analytic approach to the problem adopted here :First. it has been assumed that the genetic componentof the social burden is directly related to the expressed
effects of unfavourable alleles. However, the actualsocial burden realized in a population will be modified
by environmental factors such as the cutent of caredevoted to those affected. For this reason, the actualsocial burden resulting from a given genetic situation
may be heaviest in those countries having the best medical care of the afflicted.
Second, the genetic component of today's social burden has been assumed to be related to the present natural rate of occurrence of mutations and to present
selective conditions. Certainly this assumption is not true-the number and distribution of recessive alleles isdetermined by a long history of past mutation rates andpast conditions of selection-yet with our present limited
knowledge of the distant past and future no alternative
assumption seems to present a possible basis of calculation. A number of considerations indicate that theerrors involved may not be too serious :( a ) Because of recent improvements in medical carethe present genetic burden may be below equilibriumwith today's rates of elimination of undesirable alleles,
so that the effects of a given increase in mutation rates
are underestimated. On the other hand, further improvements in medical care are likely in the future to reduce
the socially serious effects of mutations. This process
cannot by itself affect the influence of mutation upon
the Darwinian fitness of the population, but may affectthe future social burden due to present mutations if it
occurs without a corresponding effect upon the rates of
elimination of the socially deleterious alleles. If thiselimination takes place largely through rather trivial
effects in heterozygous or other carriers of unexpressed
alleles, alleviation of the expressions in grossly affectedindividuals might be accomplished with little influence
upon the process of elimination. We would then haveoverestimated the future social burden from present
mutations. Thus the two sources of error due to improving medical care act in opposite senses.

( b ) I n spite of changes in diet and living conditionsof all kinds, there is no reason to suppose that natural
mutation rates have changed very greatly; for example,
chondrodystrophy, which, in man, is largely a dominantdisease, has been prevalent at a low frequency sinceancient times.139 Selection has, by contrast. certainly
undergone great changes. This fact is relevant to therecommendation, contained in the report of a WHO
study group submitted to this Committee.ll that research
be initiated upon selection in primitive communities
while the opportunity to do this still exists." But manyof the specific detectable conditions with which we s h l lbe concerned here either arise from dominant alleles,and hence do not in general persist for so many generations as recessives, or else they confer a reduction in
selective fitness which has not yet been greatly modified
by advances in medical practice. The working assumption may therefore be not too greatly in error for thebroad categories of effects to be considered. I n point o ifact, the effect of improved living conditions and improved medical care is far from obvious. Penrosel'O haspointed out that, besides preserving less fit individuals,
this change may in recent years have removed the selective advantage of alleles which confer a degree of protection against an infectious disease in the heterozygote
while being grossly deleterious in the homozygote: theclassical example is siclcle cell anaemia.141 HOWmany
such situations exist is debatable. However, the consequences of improved medical care could be called eugemc
rather than dysgenic in such cases. It must also be bornein mind that the total potential intensiq of selection in
populations has, at least in recent years, not been e a n g ing anything like as rapidly as the qualitative.basls of
it.142,143 I t may be observed here that the possible dys--

genic effect of future improvements in social and medicalcare is limited by the fact that no more deleterious
mutant alleles can be saved for later generations thanarise by mutation; moreover, a subsequent withdrawalof improved medical care by some social catastrophe will
not cause more losses than would have occurred anyway
had it never been present. Only the distribution in time
will be altered. Thus, in a constant population, the dysgenic efiect of a changing selection does not increase
the total number of seriously affected individuals but
by contrast, the dysgenic effect of increased mutation
does increase the total number of seriously affected individuals. Finally, it has been assumed that radiationinduced mutations and spontaneous mutations are qualitatively similar: that there is no correlation between D,!
and the degree or kind of manifestation ( f i , bi. pi) of agiven mutation. This assumption has been discussed inanother section and is acceptable to the Committee.

86. On the basis of the above arguments, the Committee considers :(a) That the most satisfactory assessment of thegenetic consequences of irradiation of human populations which can be attempted at the present time must be
based on the present social burden due to hereditaryconditions. Because it must employ the representative
doubling dose, it must be restricted to rather broad
categories of effects ;(b) That the sources of error in an assessment of thiskind may not be too serious ;(c) That two principal sources of error are related tothe extent to which selection changes in the transition
from a technologically primitive to a technologically advanced environment and to the extent to which alleles
responsible for socially serious conditions may confer
small favourable differentials of fertility in the heterozygous, impenetrant or other "carrier" states. Both require to be investigated.
3. THECURREKT SOCIAL BURDEN O F GENETIC ORIGIN I N
H U N A N POPULATIONS, ITS CONNEXION WITH &IUTATION
AND RADIATION EXPOSURE

87. I n order to make use of the representative
doubling dose discussed earlier, there will be consideredhere only broad categories of damage, each of which
may be caused by mutation at any one of many loci.
such as the sums of specific clinical conditions or traits
within various genetic categories, or biometrical characters such as intelligence, life-span or birthweight, eachlikely to be dependent upon many genes, or fertility.
Specific traits
88. For the present purpose, the available information
concerning the incidence in man of specific diseases ordisabilities of genetic origin is severely limited. Only
very few sizeable populations have been surveyed, notably in den marl^,'^^ Michigan, U.S.A. and Northern
Ireland.14* hIoreol-er. good quantitative data are only
available for clear-cut traits or disorders. and, even here,
the genetic interpretation of the facts is almost neverstraightfon~ard.l10In the past, various estilnates havebeen made of the frequencies of such specific traits, but
the basis of the estimates has not aln.ay-s been clear.
Sometimes it has been uncertain n-hether the trait irequencies referred to were those at birth or in the whole
population. The latter estimate would aln-ays be expected
to be lower, particularly if the trait \\-as severe in its

effects. Independent over-all estimates, both in the literature and in reports to this Committee, seem to be inreasonable superficial agreement with each other and aresummarized in table X ; each of these implies consideration of one or another category out of a total of some
500 dear-cut disorders or traits.133 However, it has seldom been specified which traits are included and which
excluded in them.
S9. I n order to formulate, upon a precise basis, overall estimates to which a representative doubling dose canreasonably be applied, the Committee has made use in thepresent report of a single, definite list of traits and theirestimated frequencies of appearance in a single populathe popution, namely that compiled by Stevenson""orlation of Northern Ireland. I n so doing, it is recognizedthat the frequencies of specific traits will be different inother populations, so that some listed here may not occur
at all, and others not in the present list will be prevalent.
Nevertheless, such comparisons as can be made of the
population frequencies of traits in different parts ofEurope, North America and Japan suggest that, while
the contributions of individual traits to the total may
differ considerably in different populations, the totals,
and their division into principal categories, will not vary
appreciably so long as present methods of detection are
employed.
90. The list of traits compiled by Stevenson has beenbroken down into separate categories in the following
manner, which differs somewhat from that used in theoriginal compilation.lM
Category I (table XI (a)-(b)): Category I includes
traits detern~inedby single, harmful mutant alleles. The
majority of these are dominant with a ligh degree ofpenetrance, but some are autosomal recessive and a few
are sex-linked. Most are not recognizable in the affected
person at birth. I t seems reasonable to assume that inrespect of these traits there is no significant selective
pressure in either direction against apparently unaffected
carriers of the mutant alleles, although this cannot be
proved in our present state of knowledge. I t would
therefore be expected that the ultimate consequence ofan increase in mutation rate at each or all of these lociwould be a direct effect upon trait frequency. About 110
different mutations are required to explain these traits.
No doubt some similar, but separately identifiable, traits
are determined by alternative alleles. Of these mutant
alleles about 72 are dominant, 30 autosomal recessive
and 8 sex-linked recessive. The estimated total of liveborn affected is 1.1 per cent.
Category 11(table X I I ) : Category I1 includes a considerable number of traits mostly detectable at birth.
A proportion of them sometimes determines intrauterine death, but this fraction of these conditions isignored in the present contest. Maternal health andintra-uterine environment appear to play a considerable
part in determining whether and to vhat degree they are
expressed. Their familial patterns in a community seldom satisfy the criteria of a single mutant expression.
In all there is a familial concentration of cases greaterthan would occur by chance. In sorne, the family patternapproaches some of the criteria of those included in
category I, and it will be clear to the reader that arbitrary decisions have had to be made. The estimated toralof 1i1-e born affected is 1.0 per cent.
Category 111 (table X I I I (a) - ( b ) ) : Category 111
comprises t ~ v ounequal classes of traits. The first andsmaller proportion (categoq- 111 (a) : table XI11 ( a ) )consists of traits which appear to follow closely the es-

pected family patterns of a single recessive mutant genes,
but show a frequency too high to be explained on a basisof mutation pressure alone, unless it is assumed that
mutation occurs many times more frequently at the relevant loci thvl at those loci giving rise to dominant mutations in man or than in the general range of all types ofmutation in experimental animals. I n the data forand elsewhere in the United ~iNortherndom, only fibrocystic disease of the pancreas and deaf
mutism clearly fall into this category, although otherconditions well-known elsewhere such as sickle cellanaemia and thalassemia also belong to it. I t is possible,
although neither provable or disprovable at present, thatthe gene frequencies in these conditions are maintained
mainly by relative selective advantage in the heterozygous carriers. In deaf mutism several independent
mutants contribute to the trait frequency. The two conditions together determine about 37 per cent of the totalfrequency of recessive traits at birth in the population
have a combined
studied by Stevenson (lot. Cif.)frequency of 0.09 per cent of all live births. The secondand larger proportion (category I11 ( b ) ; table XI11
define and limit.
'I1 is(b , )
examples of serious, "constitutional," diseases are listed
in the table, but it is difficult to know where to draw theline thereafter. I n different communities the frequencies
will vary considerably. I t is impossible to estimate frequencies without malting some arbitrary decisions as towhat will be included: as an example, admission to hospita1 might be made a criterion. Furthermore, the frequencies depend on the ages to which people live in populations, as in the cases oi diabetes and the primary presenile psychoses. Finally, there are environmental factorsof importance which vary in different populations. I nsum, at least 1.5 per cent of those liveborn will sufferfrom one or another of this group of disorders.

I

91. I t must be emphasized that the list of traits, trait
frequencies and categories outlined above and in tables
XI-XI11 :( a ) Represents only tangible or detectable genetic
damage, which in principle, although in practice withgreat difficulty only, can be assessed by "counting
heads" ;( b ) Includes only defects of such severity as to be atleast very inconvenient to their possessors ;('1 Isanlist, even of such 'Onditions ;( d ) Ignores matemal/foetal incompatibility andmongolism ;in the latter the genetical component appears
to be weak, and in the former the relative frequency of
the alleles, which is the most important factor in determining proportions of affected infants, would probably
not be affected appreciably by increased mutation rates;( e ) Exdudes a group of individually rare or mild
traits which mostly appear to be determined by simple,
irregular, dominant genes and are listed in table XIV.
Nevertheless, the list gives rise to the expectation thatsome 4 per cent of the liveborn suffer or will suffer fromdefects predominantly of genetic origin. Certain comments are pertinent to this estimate :(1) Any present over-all estimate of total genetic
damage must of necessity be minimal. However, eventhough more sophisticated methods of detection can be
expected to increase the present estimates, it is unlikelythat in the near future more than a very small numberof new specific traits will be discovered, relative to thetotal so far known. (See also paragraph 104 below.)( 2 ) The present estimates refer to those born alive.
In addition, approximately another % to 5 per centfoetuses alive after the twenty-eighth week of pregnancy
are born dead mainly by reason of detectable developmental defects which may be of genetic origin.
(3) In about half of the affected liveborn, the defectwill
detectable
at or soon after birth, but in the other~ be ~
half the expression of the genotype will only be apparent
in later childhood or in adult life.
92. l-he division of the 4 per centlive-births
into categories as outlined above may be summarized asfollows :Category I: About 1 per cent of defects due to single
mutants of classical type (majority not recognizable atbirth) ;Category 11: About 1 per cent showing no consistentfamilial pattern compatible with a simple genetic hypothe ~ andi ~often having an environmental component intheir aetiolog~(majority recognizable at bidh) ;Category 111 :About 1.6per cent either ( a ) show trait
frequencies too high to be maintained by mutation pres( b ) determine constitutional illnesses whosesure,
frequency is also unexpectedly high in relation to theirseverity.
This division into categories is of great importance forpredicting the results of increased exposures of populations to ionizing radiations. The supply of recognizably disadvantageous mutant alleles in a population may be maintained either by recurrent mutationsbalanced by selection or by selective advantage amongindividuals in whom the disadvantage is not expressed;that is, by a balance between opposing selective forces.
A reasonably small increase in mutation rate cannot
be expected to affect greatly the pattern of gene elimination and so should cause at equilibrium an equal
fractional increase in the genetic damage due t o alleles
maintained in the first manner (corresponding t o traits
in category I above, together with an unknown fractionof those in categories I1 and 111), but a much smaller
increase in the genetic damage due to alleles mentioned
in the second n ~ a m ~ (correspondingert o an unknown
fraction of the traits in categories I1 and I11 above).
I t follows that permanent exposure of a population t oan extra genetically significant dose D per generation
may be expected eventually to give rise t o an increasein the incidence of live-births who are or xi11 beaffected of between D/D2 per cent and 4D/D2 percent where D 2 is the representative dose. If the increased irradiation were to occur in only one generation to a population of fixed breeding size P, it follows,
by a principle of detailed balancing, that the calculated total number of affected live births is expected
to lie between
DP
D
4P-X-and-XI32
100
Dz 10093. must be borne in mind that the mutant allelesconcerned in the above estimates range all the way frpm
severe dominant to true recessive, and the time durlngwhich the genetic damage either climbs to equilibrium orcompletes its expression after exposure of a single generation varies in turn from one or two to many tens ofgenerations. Thus, in the case of irradiation of thepresent population, the damage may well become expressed under social and technological conditions which
189

-

.

cannot even be imagined today, and which map grossly
affect the relation between gene elimination and its social
consequences. Some geneticists therefore question theutility of assessment of a hazard so far in the future.lc6

and confers greatest uncertainty. Mather's calculation isa useful guide to the upper limit of the social burden
expected to be conferred by radiation-induced genetic
changes in the variance of intelligence (but see footnote
to paragraph 102 below).

94. I n conclusion, it must be emphasized that even forthis most tangible kind of genetic damage, far more
Relatiotrship of gettetu cotnponertt ofwork is ~leededon family studies, on sib-correlations,variartce to ?nutation
incidence in consanguineous marriages, twin studies etc.,
so as to establish more accurately the genetic nature of
97. The relationships of selection, genetic variability
the traits listed here and other conditions. I f Governand mutation in a character of relatively low selective
ments wish to h o w the genetic health of their peoples it
importance (bristle number) have been smdied by\%'illbe necesrxy for them to Support the necessa~lvork. erd authors in ~ ~ ~ ~ ~ ppartidar,
h ; l ~ Clayton.
~t has been argued that, at present, ~ o ~ u l a undert ~ o ~ ~Robefison1SJ halle been able to show that thereview by single institutes of human genetics cannot conadditive genetic variancein an outbred pop*tion,
fromveniently exceed 3 X 10°.ll However, the problems reflies were originally dramrn,
which theirlated to both the scale and scope of such work involvethe spontaneous increase in genetic variancequestions of general medical education and co-opeation
per generation by a factor of l,m,and observat~onsby
as well as legal and administrative aspects which merit(quoted by Matherlsi,l~6~
suppan this concluthe attention both of Gove131menfs and public healthirradiated and unirra&ated popula,ion. By
authorities. For example, a number of human geneticists
tions, Clayton and Robertson further showed that somefeel that the present Manrial of the Itttertlational Stafiswould have been needed to produce an incrementtied Clmsifiation of Diseases, Injuries and Causes o jequal to the natural variance. w i t h selective neutrality
Death is inadequate in its present scope and form forsuch a genetic variance in the natural population is perscientific purposes in the classification of congenital
fectly compatible
m esrablished equilibrium beconditions.
tween mutation and a degree of inbreeding due to limited effective population size. For a character of greater
selective importance the genetic variance displayed by
Bio?netrical clzaracters
the population would exceed the increment per genera95. Many important characteristics of man, amongtion by a correspondingly smaller factor. Haldanel" haswhich specific mention must be made of intelligence, lifepointed out that, in the cited case of birthweight, selecspan and birthweight, vary continuously in natural p o p tion removes 10 per cent of the obsen~ablevariation perlations about some mean which is often close to a selecgeneration. If this selection makes no distinction between
tively optimal value. Where this is true, selection may
variation or' genetic and of environmental origin, it poses
act on the phenotype quite largely by reducing thethe question: HOWis the genetic component of variancevariance, rather than by shifting the mean; to thatmaintained?
extent, it is normalizing or stabilizing ~e1ection.l~~Suchasdiscussed the theoretical
98. R o b e r t s ~ n ~ ~ %recently
quantitative variation is often influenced by many genes
for
optimalcentral phenotype.
inwhose separate effects cannot be distinI t appears that this process cannot of itself maintainguished, in contrast to those exhibiting specific qualitagenetic variability, even though heterozygotes have intertive effects and discussed above. T~~~~
genes can onlybemediatevalues of the character (see Fisherls0). The
studied statistically, principally through that part of thegenetic variation must therefore be maintained either byvariance of the character for which theyare responsible,
the selective advantage, in some circumstances, of thehi^ variance may be of considerable importance as aheteroz~gotesas such (i.e., the majority of the genes aresocial burden or loss of population fitness. Discussion
individually heterotic) or by mutation. Lerner13' has arof the consequences of possible shifts in the mean ofgued for expecting heterosis among genes of this kind,such characters will be deferred t~ paragraph 99 below.
his argument being based partly upon an anticipation of
96. The genetic component of the variance has been
improved buffering or canalization in the developmental
tentatively estimated in the case of birthweight byprocesses of heterozygotes and partlyupon experimental
Penrose and by Robson as some 40 per ~ e n t , ~ ~ ~ . ' ~ " h aevidence (of which, however, a considerable fraction isof .it associated with maternal genotype, and in the casedrawn from Drosophila) and general experience of inof intelligence asor perhaps as high as %.lS0 In each
breeding. Paxman1Si.1B6has, on the other hand, failed toof these cases, the more extreme phenotypes of the disfind evidence of such heterosis, despite a search for it.
tribution are observed to be associated with a loss inThus evidence of the necessary heterosis is by no means
viability or reproductive fitness and with social burden.
conclusive and further data are much needed. A t theThus on the basis of P e n r o ~ e ' s land
~ ~ Karn and Pensame time, the high rate of selective elimination doesrose's1'' work it can be estimated (see appendix) thatnot seem compatible with replacement by mutation at
the genetic component of this variance was associatedthe low rates observed in experiment. This difficulty may
with the occurrence of some 1.6 per cent of stillbirths
ivell, however, be less than it seems, because where manyand neo-natal deaths among males. MatherlS2has calcugenes of similar effect contribute to the variation of alated that on an intelligence quotient scale normalized
character, only a portion of the total genetic variability
to mean 100 and standard deviation 15, 2.3 per cent ofpresent in the population is manifest as variation actuallychildren will fall below intelligence quotient 70. and aobservable by difference among the phenotypes of the
doubling of the heritable component of variance, assumindividuals. In a polygenic system, alleles at different lociing no shift in the mqan, would increase this number by
can =ert their actions in opposite directions and thus
a factor which may Ile between 2.2 and 2.9 ; this calcubalance out one another's effects, so that some of thelation depends upon the assumption of a Gaussian disvariation lies hidden as balanced differences within thetribution of the measured variable at the tails of the
genotypes of the individuals.19i The proportion of the
distribution, where the assumption is itself least sure
total variability so hidden increases directly with the

s,

190

number of genes in the system, and it may go up evenhigher if the genes are linked. The hidden variability isreleased by recombination of the genes which balance one
another, to become exposed as phenotypic differences,and this rather than mutation is the immediate source ofreplenishment of the observable variation eliminated bynatural selection. Ultimately replenishment must depend
on mutation : but, by virtue of the reservoir of hidden
variability, the accunlulation of new variation from mutation need balance loss through selection only in thelong term. Thus the rate of selective elimination observedat any given time need not provide a reliable indicationof the rate at which new variation is arising by mutation.
Furthermore, the selective elimination of any fractionof the observable variation represents the loss of a muchsmaller fraction of the total genetic variability. Thus withbirthweight. 10 per cent of the observable variation iseliminated in each generation, but this loss could represent as low a fraction as 1 per cent of the total genetic
variability for this character in the population if it
depended on the simultaneous action of no more than
10 polygenes. Mutational increments quite low in relation
to the total variability might thus suffice to maintain theplygenic variation of a character against the erosion of
selection. This is a matter on which more data areneeded ;but pending their appearance it would seem conof the genetic variability
servative to suppose thatof most quantitative characters is the greatest fraction
which it is necessary to envisage as replenished by mutation in each generation, and the fraction may indeed generally be very much smaller than this. The Committeeemphasizes, however, that there is at present no satisfactory experimental basis for determining whether thisfraction is large or small even in experimental species,
much less in man. Clearly, further data are much neededin this whole area.

xo

Shifts ilr mean vaktes of metrical characters
99. Besides contributing to the variance of a metricalcharacter, genetic factors may impose a social burden byaffecting the position of its mean. Three quantities must
be considered : the population mean, the selective optimum and the social optimum. The three may all differ,as is illustrated in table XV for the characters mentioned
in paragraph 95.
100. The great majority of well-studied single-locus
mutants in experimental organisms are hypomorphic ;15e*160
that is, they appear to lead to a reduction in
the function or character most immediately affected.
There is good a priovi reason to expect this, as random
interference with a complex machine will more often be
destructive than constructive. In consequence it might be
expected that most mutations and mutant alleles would
act so as to diminish the population mean relative to theselective optimum. However, it must be questioned
whether there are sufficient grounds for extrapolating
this view to polygenes affecting quantitative characters.
Provided that the changes are not so large that they
excessively disrupt the organism's general control of thedevelopmental channels concerned, is it not just as reasonable to suppose that a particular organ of social
import-for
example, the brain-may in fact benefit
from hypomorphic changes in most other organs, due to acompensating diversion of resources, so that many suchchanges would be hypermorphic for it ? Among the characters of table XV, it is of interest that the facts concerning birthweight151 fit the classical expectation, but thatthose concerning intelligencelsl possibly do not.
101. I n the case of birthweight, it can be calculated(see appendix) that the di&erence by which Karn andPenrose observed the selective optimum to cxceed the
population mean in males is associated with 0.4 times as
many deaths at or near birth as the total variance andabout 0.7 times as many as the estimated genetic component of variance. What proportion of this deviation is
genetic in origin is not known, but it is clear from thearguments outlined above that recurrent mutation could
easily be the principal cause ; if so, co~ltinuedapplicationof a doubling dose to every generation might eventuallybring about an increased incidence of some 1.2 per centin the deaths at or near birth. This selection acts so as todiminish the difference between the mean and the selective optimum by about 7 per cent per generation.15' If it
does not distinguish between genetic and environmental
components of the difference, the genetic effects of analtered mutation rate upon the mean must be expected to
be spread over some ten generations, and any shift to a
new equilibrium value will take a comparable period oftime.
102. The case of intelligence is somewhat different.
Here the social optimum lies far away from the selective
optimum, and it is not simple even to decide what must
be computed to assess the social implications of a givenchange. Moreover, the genetic picture is complicated bya high degree of phenotypic assortative mating.lS8 For
the purposes of this report Mather's calculations152basedon United Kingdom figures have been available. Mather
based his calculations concerning the effect of increased
variance upon an unchanged mean but he also considered a situation in which increased mutation was
associated also with a falling mean. such that the effects
mediated through mean and variance were roughly comparable in magnitude. However. there is no indication in
the figures at present available for the United Kingdom
nlies below the selective o ~ t i that the ~ o ~ u l a t i omean
mum; thtlsLgives rise to a presumption that increased
mutation might not depress the mean appreciably. I t
seems important to try to find out if this situation is true
and, if so, whether it is peculiar to the somewhat special
demographic situation in the United Kingdom or is moregeneral, since it raises a question as to how such a position might arise and be maintained.15s I n the meantime,it seems premature to attempt here any assessment of the
expected effects of increased mutation rate upon mean .
intelligence. The social consequence of hereditary shifts
in intelligence probably occur mainly as a result of shift
in the numbers at the extremes of the I.Q. distribution(of which only changes at the lower end are numericallycited in para. 96 above) ;* a change in variance will in any
event affect these more markedly than an equal change
in the mean. Part of the difficulty in discussing shifts ofthe mean intelligence as measured by intelligence quotient may lie in the need to consider small intelligencequotient differences; it is possible that present tests ofintelligence are not sufficiently well-developed and freefrom bias associated with other variables to serve as
suitable material for close quantitative analysis. The
problem of further progress in this field may thus depend upon developments in pure human biology. I n any*An increase in variance without change in mean also causes
an increase in the classes of highest I.Q.upon which it has been
claimed that much of human progress depends. Any judgement
concerning the relative value of this increase is a social one;it has therefore not been computed here and np attempt has
been made in this report to offset its value a w n s t the soclal
burden represented by a calculated increase in the numbers ofindividuals with I.Q. <70. It must be borne in mlnd e a t there
is some reason to believe that the distribution of variance due
to new mutations would not be symmetrical, and that most of
the increase would be in the direction of lowered ~ntelllgence.

over-all discussion of intelligence, it is necessary to bearin mind that it is affected not only as a biometrical character by many genes with small interacting effects, but
by known specific loci, radiation-induced mutations at
which will almost always cause serious harm to any individual in whom the mutant alleles are expressed.
103. In the case of the life-span, the d a b of Russell'"on the progeny of male mice irradiated by fast neutrons
suggest the existence of the kind of effect which would
be expected from classical hypomorphic mutations ; thatis, the occurrence of radiation-induced mutations to aseries of weakly dominant alleles which collectively
cause a shortening of the life span. However, the magnitude of any corresponding effect which might be expected in man is entirely unknown. I t might seem at firstsight as if increased variance in life span I \ ~ o u I ~confer
little or no increased social burden, but be selectively
neutral as long as it affected only groups be~olldthe ageof child-bearing. However, if themechanism of shortening were related to an effective contraction of time-spanof the physiological processes, the reproductive period
might be adversely affected. and the selective o~timutn
for life-span might then be very long. It is essential thatthe work of Russell be confirmed and extended in orderto have an adequate experimental basis in other organ,isms for consideration of the possible implications forman. Russell's experiments are in line with effects observed in irradiated mammalian tissue culture cells andother organisms, among which the survivors frequently
carq7slightly deleterious dominant alleles,ls"84 as well aswith observed correlations between the life-spans ofrelated individuals suggestive of genetic iIlfluenCes.l~sFertility
101. The most direct expression of the effect of undesirable mutations is tllrough the net reproduction per
generation or fertility differentials. Penroseo3 has suggested that, in man, some 50 per cent o f the zygotes ofeach generation fail to contribute to the next one byreproduction, and has suggested, by analogy with othermetrical characters, that some half of this might be ofgenetic origin. Penrose also points out that, on the same
be due to theanalogy, much of the infertility mightpresence of conditionally deleterious alleles 1%-hicharenot primarily maintained by mutation and are essentiallyby changes in mutation rate. However, one
may compare such a rate of elimination with an estimateof the total rate of mutation to unconditionally deleterious alleles such as was derived in paragraph 74 above.
105. Applying a representative doubling dose of 30
radthe estimate of paragraph T4! therate
mutation
would amount to%(i.e.? a ~ ~ r o x i m a t e30/2j0)l~
Per haploid gamete or %per diploid zygote. At equilibrium, these C O L I be
~ ~ eliminated by % of zygotes failing to reproduce. These estimates of mutation are therefore consistent with that ofPenrose concerning fertility, and with the assumption ofgenetic equilibrium, which suggests the possibility that atpresent of d l rygotes fail to contribute to the ncxt generation because of the presence of deleterious alleles
maintained by recurrent mutation. Taking this to be anof a doubling doseupper
to each generation mlgllt eventually extend the fractionof non-contributlng zygotes f ram 5 to % and require aof average
size for a previously constant population to maintain itself. This appears to bewell within human capacity. If it be further supposedthat thc mixture of donllnants and recessives concerned
has an average persistence in the population of 10-100

generations, then exposure of one generation to 10 or
100 times the doubling dose would impose the equivalentof the same load for a period of 10 or 100 generations.
Such doses are ofmagnitude 300-3000 rad, and in arange which is such as to render further considerationsof genetic problems redundant. It therefore seems probable that the human race has ample breeding capacity to
the genetic consequences of any foreseeable

Pool of recessive nrlitants
106. Examination of the offspring of consanguineous
tnarriages can give information concerning the total ofdeleterious rcccssive mutant alleles in a population, andMorton, Crow and &IulleIgBhave recently sholvn how theresults of statistical suneys of this kind can be expressedin the form of a number of lethal equivalents per m a ber of the population. In the absence of a figure operationally equilralent to the total number of genes per
individual, this information does not relate directly tothe social burden upon the population nor, lTithout assuming an average dominance, can it be related to thenatural mutation sate. The number of lethal equivalents
per head is, however, in its own right, a most importantparameter describing the genetic state of a population,
derivable from a purely demographic type of information. Governlllents would do well to investigate it intheir populations.
107. I t is also possible in principle to compare thenumber of lethal equivalents, derived from vital statistical information, with the number of recessive deleterious genes found in the direct intensive surveys ofsmaller numbers of consanguineous marriages. IdealIy,such studies should cover the whole period during which
identical alleles are together and so liable to give rise toan effect through homozygositl'; thus not only the number and viability but also the fertility of the Progeny ofconsanguineous marriages should be i~~vestigated: a preliminary study of this kind has been initiated by
Fraser-lg3 Such a comparison could be of great importance as indicatingurhat fraction of the total recessive
deleterious pool we know about, through recognizable
specific effects. At the present time the evidence of bothkinds is very scanty. By direct examination of a north
Swedish population, Book has estimated that about threerecessive deleterious genes are carried per individual-s7
However, using the criteria of Stevenson, this figure
would be only 0.8-1.7.'" Stevenson, himself, in a somewhat smaller sample, has found 0.5-0.9.1U I t is not possible t~accurately >:hat is the reproductive
fitness of the afflicted individuals, relative to the general
population, but it is reasonable to suppose that the average would lie between 20 per cent and 80 per cent.
Probably, therefore, the best direct intensive investigations today sholv up about 0.2-0.8 p ~ s t - ~ ~ lethaltalquivalents per individual in the generalpopulation.
Following I\Jorton. Crow and Mullerls analysis of thework of Sulter and Tabah,ss,ss but excluding stillbirths
and nm-,-natal deaths, it is likely that a total of some
2-2.8 post-nabl lethal equivalents per individual are present in their population. This suggests that present recognition encolnpasses sonle\vhere behreen j per cent anddamage40 per cent of the total deleterious
which arises. These numerical figures reflect the strictness of the particular criterion employed by Stevenjon
in his use of the term arecessire.y.
108. The specific genetic conditions whose incidence
is reported by Stevenson are divided into dominant and192

recessive conditions ; a most striking feature of the datais that the total inadence of rare dominant conditions
exceeds that of recessives by a factor of 10. If a correction is applied for those recessive conditions not atpresent recognized, using the figures derived in the preceding paragraph, the ratio of total incidence of recessive conditions to total incidence of dominant conditions
shifts from 0.1 to between 0.25 and 1.3 and the total
incidence is increased by a factor of between 1.2 and 2.3.
The calculation is now relatively insensitive to the exact
providedthat it is thecriterion of recessivity- employed,- same throughout. It perhaps serves to give some idea ofthe limits of confidence which can be placed upon current estimates of the genetic social burden due to specificrecognizable conditions.

109. I t is of some interest to compare the ratio of theobserved rates of elimination of deleterious recessive anddominant alleles, corrected as in the previous paragraph,with that to be expected from equilibrium with fonvard
mutations. In mice, the ratio of recessive to dominantlethals occurring naturally appears to be about 2.5 :1 or
3 :1.10iJ6" It is very different for Drosophila, perhaps as
low as 0.1 :I, but if Drosophila has much less complex
genes t4an mouse or man, it may be a poor guide.)
If the ratio of natural rates is similar in man and mouse,
the corrected ratio of elimination rates, between 0.j :I
and 2.8 :1, is in reasonable agreement with it, but suggests that the recessive alleles might, if anything, tend
to be on the average slightly deleterious rather thanadvantageous in the heterozygous state.

TABLE111. MEASUREDOR C~~LCULATEDV ~ U E SOF
TOT-4L N-4TURAL 31UT-4TION RATES FOR CLASSESO F LOCI I N ORGANISMS OTHER THkV &L4N
Trait studkd.

Rare domirant
Porcupine. ..............................
Sex-linked recessives (direct)
Hemophilia. .............................
Duchenne's type muscular dystrophy.. ......
Autosomal recessives (indirect)
Albinism. ...............................
Ichthyosis congenita.. ....................
T o t d colour blindness.. ...................
Infaotle amaurotic idiocy.. ...............
-4myotonia congenita. ....................
True microcephaly.. ......................
Phenyketonuria.. ........................
Average of 7 loci.. .......................
a

Mutants pn
leslrd game&C h s s of nrufanfsstudied

Autosomal dominants (direct observation)
Epiloia ................................
~ c h o n d r o ~+lal a ...........................
-'
Aniridia.. ...............................
Retinoblastoma ..........................
Partial albinism with deafness.. ............
Microphthalmos ..........................
Neurofibromatosis ........................
Average of T loci. ........................

D. inelunogasterSex-linked recessive lethals:
1.0 x 10-3

aged sperm.. ........

2.0 x 10-3

range for various wild
type stocks. ....... 0.7-1 1 s 10-3
mutable Florida stock
1.1 x 10-3

<10-9~XXY females. .......

3 x 10-5
4-10 s 10-5
2.8 x 10-5
1.1 x 10-5
2.8 x 10-6
1.1 x 10-5
2.0 s 10-5
4.9 x 10-5
2.5 s 10-5
2.4 x 10-5

young sperm.. ......

7.0 x 10-3
1.8 x 10-3

Spencer and Stern32{Uphoff
and Stern31
Caspari and Sterns${Uphoff and Stern81
Demerecli4
Demerecl74
Muller et al.171
Mullerlos

TABLE
IV. GTESOF UDIATION-I~DUCED

MUTATIONSAT SINGLE LOCI I N ORGANISMS OTHER THAX NAN

Very rough estimate: see ref. 83,

TABLE
11. ~~IEASURED
OR CALCULSTEDVALUES OF
NATURAL MUTATION RATES AT SINGLE LOCIO F ORG-4NISMS OTHER THAN h U N
Mtrfanls per&sled somete

Mufonts strcdicd-~-

D. melanogasterAverage for 9 seslinked recessive
visibles in XXY
female. ........

3 x 10-58 Iluller, Valencia andValencialTl

Average for 4 autosomal recessive
visibles in Oregon-R females.
2.5 x 10-6
Average lor 4 autosomal recessive
visibles in Oregon-R males.. ..
4.5 x 10-5
Average for about
12 sex-linked recessive visibles
in Oregon-R females. .........
2.4 s 10-6
White eye..
0.1-3.7 s 10-5
8 ses-linked recessive visibles inmutable Florida
stock. .........
~Ufce-4verage of 7 autosomal recessive
visibles in maleca. 7 x 10-6
Bacleria
Average of about
30 biochemical
back-mutations.
4.5 s 10-9.

......

Glass and Ritterhofl7"

Average of 9 recessive
visible autosomals
in oocytes, oogonia

1.4 x 10-8

Average 01.9 recessive
visible autosomals:
spermatogonia . .
1.5 x 10-6
mature sperm.. .
6 x 10-8
mature sperm.. .
4.4 x 104
mature sperm..
5.2 x 10-8
White eye mature
sperm.. ......... .0.&1.2 s 10-7
D. cirilis
A v e r a g e of 7 s e x l i n k e d recessive
visibles:mature spern~
7.6 s 10-8.

...

Glass and Ritterhof172

Glass and RitterhoPT?
Bonnier and Lihingl"

Muller, Valencia andValencial"

Alesander70.4lesanderiO
Pattersonl7j
Demerecli6
Bonnier and L ~ n g l 7 3

Gin611177

E.

Average of about 30
biochemical backmutations. .......
Mice
Average of 7 recessive
risible autosomals:
spermatogonia . .

2.7 s 10-10 Glover in Demerecet al.3

2.5 x 10-7

Russel176

TABLE
V. TOTALRATES OF RADIATIOS-INDUCED
Russe1176, Carter et a1?5

BIUTATIOKS IX CLASSES OF LOCI IX
ORGANISlIS OTHER THAN 3L4N

Glover in Demerecet ~ 1 . 5 ~ D ,nzelanogasterSex-linked recessive lethals
inaged
snerm... . . . ............ 2.3
1 0 - U n- hr o f f and Stern31---.. .,--.....
.. s
....
young sperm. ........ 2.8 s 10-5 Uphoff and Sterns1

Range of abo1-e. .. lo-" to 4 s 10-8 Glover in Demerecetal.53
a But approximately 5 x lo4 if allo\r.ance is made for the factthat the Kte of sex-linked recessive lethals was abnormallv hiehin this experiment. Droso@hilarates vary very widely wit& staieof life, cell-development, etc.

~ - - --~--

Na~rrberof irrntlinladpnrcnls

Rcjero~~cr

Dose rnnga
i~rrsds

Ab~~rlior~s
Irrad.

Control

Irrnd.

Slill-bb-llts

innlf~ttrnlions"(livc bir1h.r)
C o ~ ~ l r o l Irrud.
Co~rlrolS.x-ralio(live births)
Irrud.
Colrtrol--

Survey of p r c ~ ~ ~ a n c i cNecls
and Sch~~ll'l' approx. 27,000 O
i l l I l i r o s l ~ i ~;111dn;~Nagasaki

Survey of olTspringof Fre~ichpiltic~ltsapl)l'ox. 14,000 8

l'urpin, L e j e ~ r ~ ~ candRethorell7. 1~05-

I
- - - - t~;~scdL I ~ O Iscv-

546

408

300

294

rc.yrcssio~l lines

8-200

33,181

31,55933,52731,904cr.11 doses: forraw d a t n YCC
I . 1 I C a p
ter V11.

8

-

7

9
405

8
696

8-200

47

289 d

4-450''

-

18

7
-

5
-

5
-

-

1

63
-

130
-

D i n ~ i n ~ ~ tofi osex-rationfor irradiatedmothcra sig-ni6ca~~t
conlpa~ecl L oirrr~tliatedfathers ( x 2 = J.2), notsignificant con~pnrcd to controls.
k I ~ t w c e n 6 X 10*/rntl and
12 X I0 -5/r:1d.

254

13G

236

136

236

1.16

236

No;~cco~~~~(.~alcc~~ofi~~cnn

46

-

-

-

225

--

358

452
742
405
696
405
696
---26

97 O

40-450"Obscrvatio~lsincl~~tle
scx-ratio, frcqucncy of stillbirths and 11co11atnl
dc;ttl~s,birtIiwc.i):l~t,o c c u ~ r c ~of~rc
c o n ~ c ~ ~ rnalfor~~~ations,ital
all(\,fora r.~~~tlom
30% sanlple reexn~nincda t age 9 ~ n o ~ ~ t lcertainls,bodilymcast~rcn~cnts
and the occurrence
notof adclitional n~allormatio~~sapparent a t birth.
Non-sig~~ifiwnt
dccrcase i l l sex-ratiok = -5.5 X IO*/md for irradiated mothers: arriong earlier
births12' lc wiis -8 x 10-6 ant1
significant.
Sligllt IIOII-significn~lt
ic~crcasefor irradiatctl fathers in earlier birtlls12S.

I62

Inquiry by qucstionr~aire.
Follow-up 011 progenyof women trc;ltcd forsterility
Surveys ofchildre~lof
Anicrican
ri~tliolo~ists

I<aplan119

311 O

ca. 60

91

2

513

3

-

No control as yet. Very low ses-rntic*
sig~lificantlydilTcrcnt fro1110.51 5,
IC -8 X lO-'/riltl.

191

-

-

-

513

513

409

Aborlions nrrtl Slill-births
Irrad.
CoirlrolCrow1@

RIacht and
Lawrence~~

654 d

5,461 dUnknowrl
accuniulalion ofmany s~ualldoses

No data on malformations or scxratio. Inquiry by questionc~airc.

274

215

-

-

1,653

1,348

-

766

-

-

328

216

2,090

5,461

:4,484

5,461

4,484

4,127

548

-

1,766

3,390

Non-significant incrcase i~dstill-births
a ~ ~abortions.
tl
Significnnt increase in n~alformalio~ls( x 2 c.6.7) incl~~tlcs
many very slighttnalforl~~ations
or other discnses,
if restrictedI)t~tr c n ~ a i sig~iilicant~~s
to cardiac ~nalfor~nations
only. Inq~liryby question~~~~ire.

7
7
a Enrlicr literalure surveys by M a ~ ~ r e r and' a t ~ yMurpl~yant1 G o l c l s t e i ~ ~respectivclyl~rcvcalerl!'andmalforrnotions anrollg r ~ ~ o i l ~whoe r s llad rcccivcd heavy doses, bul229
417
without co~ltrols.
b Taking the gonad dose to be 1 /3 the skin dose.

-TABLEVII. CONTENTO F DNA I N V-4RIOUS TYPES O F C E L L S ~ ~ ~Organism and cell !j9pcs

gm DNA-phosphorus

gm DNA

per u l l

Bacteria.. ...... B. h t . aerog.
2 x 10-15
E.coli
2.3 x 10-15(compare T2 bacteriophage
Microbes. ......Penicilliun~
Aspergillus
Yeast
Drosoplrila.. ... Salivary glands d
2.6 r 10-110
2.8 x 10-u
Diploid cells (limb)
0.6-1.0 x 10-12
Rat.. ......... .Diploid cells
Mouse. ........Submaxillary glands (diploid) 0.7-1.4 x 10-12
8.7 s 10-19
hlan. .......... B.M.
Leukocytes
8.6 x 10-19
RBC
7.0 x 10-13
Liver
1.0 x 10-13
Kidney8.7 x 10-15

per cell3 x 10-16 per particle)
I .5 x 10-13 per spore
1.9 x 10-12 per spore
6.2 x 10-15
1.7 x 10-13

For a further extensive table, see ref. 21.

TABLE

Organism

VIII.

CALCUJ-~TED DOUBLING DOSES I N ORGAhTSYS
OTHER THAN l
f
~
~
~
Loci

Zea-mays. ......... .4 recessive visibles
Oenolhera, Prusus.. ..Self-incompatibility
Drosophila ..........Sex-linked lethals
Mouse.. ........... . 7 recessive autosomal
visiblesDominant lethals~

C a d i l i o n s of+radiated cell

Doubling
dose ( r 4

Rcf.

PollenPollenspermatozoa
aged spermatozoa
o6cytes and o6gonia

28
60
50
140
390

179
180,181
31-33
31-33
171

spermatogoniat h r o u g h spermiogenesis except timeof peak sensitivity
spermatogonia

Approximate calculation for natural rate corresponding to age of mice used in 76,69, 75.

TABLEIX.

CONPARISON
OF APPROACHES TO QUANTITATIVE ASSESSXENTO F hIUTATIONAL DAMAGE

KnwsIcdgc
o f fipi = 1Higher than average. .....
Lower than average.. .... .Small but unknown

Small but unknown
f:=lRrZatirc effccio f
mlrloti~n~p~nfrequency ofcondifion

Small

Large

TABLE
X. SOMEOVER-ALL ESTIBL4TES O F SOCLiL BURDEN
AuthorShensonlt4

Class of trails

I n populalioa

Rare heterozygotes.. ................. 1.36 X 10-2
Rare homozygotes. ................... 1.0 X 10-3
Rare sex-linked. ..................... 1.6 X 10-4
Common traits of hard interpretation.. . 1.0 X 10-2

U.S.A. Panel16 Tangible defects of genetic origin (1/2
total) .............................
Kernpls. 191
Physical malformations and defects.. ...
Severe hereditary afflictions.. ..........

~TABLE
XI . LISTOF SPECIFIC TRAITS. n?m ESTIM-ATED INCIDENCES: CATEGORYI(A) ALTOSOM.~.
DOJIINAST TRAITS

Phenotype
Ircc:unfY

pcr million
Remarks

Trait

Achondroplasia ............................. Chondrodystrophy 'Foetalis'
Arachnodactyly ............................. RrIarian's syndrome
Brachydactyly (major) ...................... Hands and feet affected-mean stature reduced
Ectrodactyly ............................... Including all types of 'split hand'hlultiple exostoses .......................... Only a minority are troublesome
Osteitis deformans ..........................
Osteogenesis imperfects.. .................... Fragilitas ossium. Several types. all irregular dominantgenetical relationship not known
Cranio-facial. cranio.cleidal. mandibulo-facial
dysostoses ................................ A series of separate disorders individually uncommon
Hypertelori sm ..............................
Ataxia ..................................... Dominant hereditary ataxia-agroup of which Friedrich's
is the best defined
Epiloia .................................... Tuberose sclerosis (9 living sporadic cases in N.I.)
Huntingdon's chorea ........................ (Three families in N Ireland known)
Hydrocephaly internal obstructive ............ Includes stenosis of and forking of aqueduct of Sylviusprobably each due to irregular dominant gene
Peroneal muscular atrophy ................... Charcot-Maric-Tooth discase
Spastic diplegia .............................
Dystrophia myotonica .......................
h l u x u l a r dystrophy, limb girdle .............. Faces affected
Myositis ossificans ..........................
Deaf mutism (Deafness total hereditary) ....... Estimated 3 per cent of all hereditary deaf mutism due todominant genes
Deafness perception ......................... Early onset dominant type
Deafness and cataract ....................... Severe early onset deafness and cataract
Deafness ................................... Absence of or atresia of external auditory meatus
Neurofibromatosis ........................... Von Redclinghausen's disease
Polyposis of colon, multiple ..................
Alopecia areata .............................
Anhidrotic syndrome ....................... Anhidrotic "ectodermal" Dysplasia
Cephalo-facial haemangiomatosis .............. Naevoid Amentia
Epidermolysis bullosa .......................
Pityriasis rubra pilaris .......................
Telangiectasis haemorrhagica .................
Tylosis palmaris et plantaris ..................
Urticaria pigmentosum ......................
Xanthoma tuberosum multiplex .............. Cutaneous xanthomatosis and essential hypercholesteraemia
Willebrand's disease ......................... I-Iaemophilia-like syndrome
Polycythaemia vera .........................
Spherocytosis ............................... Acholuric jaundice
Thrombocytopenia chronic recurrent ..........
Porphyria .................................. Dominant type genotype detectable but seldom causes illness.

Diabetes (insipidus) .........................
40
500
Cystic disease of lungs....................... (Included here "congenital" bronchieaasis)
hlegacolon ................................. Hirschsprung's disease100
Aniridia .................................... Dominant very irregular degree of manifcstatio~and~prob60
ably several dominant mutants can cause
Cataracts "congenital" ...................... Types detected at birth or early-probably several different
types
160
2.000
Cataracts. senile and pre-senile ...............
Choroidal sclerosis .......................... Several types varying in severity and depending largely on
location for disability caused
500
Colobornata ................................ Common-vary from slight iris defect t o big defects OGAS
250
choroid and retina involving macula
140
Corneal dystrophies ......................... Several types of very variable severity
Fundal dystrophies ..........................
150
100
Glaucomas. infantile and juvenile .............
Hypermetropia ............................. Can only be arbitrarily accepted as a segregating trait a t
about 10100
Keratoconus ................................
20
100
Macular dystrophies ......................... At least two dominant types occur
Nystagrnus ................................. Familial idiopathic non-albinotic usually lateral
700
150
Retinitis pigmentosa ........................ Relatively mild regular dominant type
Retinoblastoma .............................
58
6
Subluxation of the lens ...................... Primary and not part of Marfan's syndrome
Optic atrophy ..............................
7

-

TOTAL

9.555

TABLE
XI . LIST OF SPECIFIC TRAITS. WITH ESTIMATED INCIDEKCES: CATEGORY
I (continued)(B) AUTOSOM.
4 ~ RECESSIVE.
TRAITSPh=**
ficoufnfy

Trait

pn mason
Birihr
L i..?'ng&marks................................... Usual type with ocular signs. More than one mutant(?allele). can cause
Alkaptonuria ...............................
Methaemoglobinaemia .......................
Phenylpyruvic acid amentia .................. Phenylketonuria
Porphyria congenital ........................ Recessive light :ensitive type
Galactosuria ...............................
Gargoylism .................................
Amaurotic idiocy ........................... Warran-Tay-Sachs disease. Various types with difierent agesof onset. Different loci mutants? Alleles?
Hepato-lenticular degeneration ............... Wilson's disease
Albinism

Lawrence-hloon-Biedl syndrome ..............
Microcephal y. true
Microcephalic imbecility
AtaxiaChoreo.athetosis
M yodonic epilepsy
Spastic diplegia
Spastic diplegia familial often with oligophrenia
Muscular dystrophy limb girdle type .......... Face not affected
Poikiloderrnia
Epidermolysis bullosa dystrophica .............
Ichthyosis congenita ......................... May be more than one type
Anophthalmos
Corneal dystrophies
Severe recessive type
Glaucomas
More than one recessive type with buphthalmos
Macular dystrophies......................... Juvenile and adult types
Miaophthalmos ............................ Pure type as distinct from those associated u-ithrother eye
defects Mental deficiency often associatedMyopia. highSegregating traits overlapping with ordinary refraction v w i ations 3-6 types with other associated defects induded
here. e.g. with microphakia and spherophakia
Optic atrophy
Very early onset type
Probably several independent mutants contribute
Retinitis pigmentosa..........................
.....................................

............................
..........................

.............................

..............................

..............................
.........................
.................................

...............................

.

.

..............................
........................

TOTAL

130
5
5
100
50
50
20

130
3
5
30
5
2
4

50
10
40
40
40
70
50
50
30
10
20
10
100
5
15
10

5
3
6
21
20
15

100

100

150
50
60

150
50
60

6

18
16
3
6

50
5
15
10

-

-

1.260

738

(C) SEX-LI~XEDRECESSIVE T R ~ I T S
Phcnolypr

frrpuf=f~

pn m d w a
Trait

Rcnzarks...........................
.. ...............................

Diabetes insipidus
Haemoph~l~a
Christmas disease
Iclithyosis vulgarisMuscular dystrophy ......................... Duchenne's type
Megalocornea .............................. ? Only sex limited
Optic atrophy .............................. Leber's typereally sex linked
Retinitis pigmentosa ........................

...........................
..........................

TOTAL

OFRTRAITSYOF CATEGORYI(D) S U ~ ~ A W
Frcgucncj* grr miliion-%utosomaldominant .......................................
.A utosomal recessive........................................
Ses-linked recessive ........................................

9.555
1.260
397

i.100
738
155

BirthsLioinr

50
100
10
6
176
20
15
20

5
66
4
6
24
20
10
20

-

-

397

155

TABLE
XII. LIST OF SPECIFIC TRAITS, WITH ESTIMATED INCIDENCES: CATEGORY
11
Pknorypc
frepurncy

per nill lion

Tr~i!

Remarks

Bir!h-4bsence of limbs or pans of limbs.. ........... .Congenital endogenous amputations
200
Cleft palate and hare lip, together or separately. .Not including these anomalies occurring as parts of syndromes or
associated with other gross defects
9iO
Congenital dislocation of hip.. ............... .Mostly limited in effects to females
900
Osreonecrosis. ...............................Includes osteochondritis di-cans and local, e.g. dk-si~f,Kienbock, Kohler, Perthe and Schlatter
200
Radio-ulnar defects.
.Varying degrees ol absence and deformity, radius usually:primaryand determining also hand defects
205
Talipes-equino-vans, ........................ .Excluding, where recognized, those with neurological determining
causes and when part of severe syndromes e.g. anencephalus
800
Vertebrae, defects and fusions.
.A large group including I<lippel-Fiel syndrome, Sprengel's anomaly
400
etc.
Psoriasis. .................................. .Not known if all of one ori-gin-varying age of onset, duration of
attacks and severity
3,000
Ichthyosis vulgaris.
1,100
Deafness, otosclerotic..
200
Anencephalus. ...............................
i.e. The live born with these defects usuallyl
360
Occipital meningocoele.. .....................
80
dying shortly after birth, with and withHydrocephalus (Arnold-Chiari).
spina bifida or rachischisis
300
Lumbo-sacral spina bihda.. ...................
800
Other central nervous system malformations.. ...
320
Cardiac malformations. ......................
1,200
Digestive tract malformations. ................
630
Urogenital tract malformations.
200.........................

...............

..........................
.......................
...............

...............

(A)

80
700
900
200
205
700
200
3,000
1,100
200

-

-

100

-

400
100
40

- -

T O T . TUIT~FREQUESCYTABLEXIII.

LLiling

9,825

8,725

LIST OF SPECIFIC TFbiITS, WITH ESTIMATED INCIDENCES: CATEGORY111

Remarks

Deafness total from birth. ................... .97 per cent of all genetic deafness a t birth. A number of independent
mutants involved. Relative fertility of homozygote about 1/3
Fibrocystic disease of pancreas.. .............. .A generalized disorder of external secretory glands. For practical
purposes, relative fertility of homozygote is zero
TOTAL TRAIT FREQUESCY

BirthsLinn g

264

264

600
15
864

279

TABLE
XIII. (B) LIST OF SPECLFIC TRAITS, WITH ESTDIATED INCIDENCES: CATEGORY
111 (continued)
Phcnarypc
ficq~f"~
per mrllron
Trai:.......................

Marks

Anaemia, pernicious..
.Addison's anaemia
Diabetes mellitus.. ..........................
Exophthalmic goitre.. ........................Graves's or Basedow's disease
Manic depressive reactions. .................. .Based on severity requiring hospital admissions
Schiiophrenia..
.Based on severity requiring hospital admissions
Epilepsy. .................................. .Secondary to disease or injury.............................

T ~ A PHENOTYPE
L
F~EQUENCF

Births

Li?ing

1,300
4,000
4,000
1,300
2,500

1,000
3,000
1,500
2,500
1,100
1,200

14,80010,3001,700- -CO-WITIONS IDENTIFIED I N THE NORTHERNI R E L ~POPULATIOND
BUT XOT IKCLUDEDTABLE
XIV. DOMINANT
IN CATEGORIES
1 AND I1 FOR THE REASONS STATEDTHELR EFFECTS ARE SLIGHT (most are common)
A BECAUSE

Hand dejects: Brachydactyly thumbs, brachydactyly 1st finger, brachydactyly l s t , 3rd, and 4th hgers: mmptodactyly; clinodactyly; polydactyly (not part of syndrome) of radial side and of ulnar side (more common) of hands; syndactyly and symphalangim
mostly 3rd and 4th finger (hundreds of cases of the above types are known but have not been sought out for special investigation);
Dupuytren's contraccure familial.
Foot defects: Garber's toe deformity; hallw valgus (familial cases may be associated with metatarsal anomalies); hammer toes
(many are familial); syndactyly and symphalangism.

0 t h skelhl:

Diaphyseal achalasia, epiphysitis punctata.

Teeth anomalies (Other than parts of syndromes): Defective or absent enamel (various types) ;opalescent dentine; additional teeth(many types); absence of permanent incisors and pre-molars; some such anomalies are present in about 1.3 per cent of the population.
Skin and kuir anomalies: Adenoma, cystic multiple benign; cysts, epidermoid; dermatomyomat multiple; anonychia and hypoplasia of nails; leukonychia totalis; pachyonychia congenita; hair, white patches; hair kinky; hair woolly; hydroa aedvale; porokeratosis

Eye anomalies: Eyelids-spasm, absence of tarsal plates, uncomplicated ptosis; absence fstula of lacrymal ducts; retina, opaquefibres; strabismus convergent and divergent (primary).
Miscellaneous:

Pelger's anomaly, elliptocytosis.

Ear anomalies:

Cat's ears, microtia; pre-helicine pits; lobule pits: accessory auricles.

BECAUSEEVEN IF THE EFFECTS ARE SEVERE, THE ASOU.4LIES ARE PROBABLY PRESENT LT LESS T E 4 N FIVE PERSONS PER ?dUL.IOK

B.

Skektul: Osteo-petrosis (Albers-Schbnberg) ; phocomelia; ankylosing spondylosis; polyostotic fibrous dysplasia (Albright's disease) ;multiple enchondroma; fibula absence or defect; oxycephaly; acrocephaly; syndactyly.
Skin: Ichthyosiform congenital erythrodermia; keracosis follicularis spinulosa( Darier's disease) ;monilethriu; urticaria pigmentosa;
tylosis palmaris et plantaris; pili torti; ma1 de hleleda; lipodystrophy progressiva without gargoylism.
Miscellaneons:

Milroy's disease: periodic paralysis; dominant microcytic anaemia; Waardenberg's syndrome: anotia.

TABLE
XV. CLASSESOF BIOIIETRICAL

CHARACTER-

Prrtumed posiliol: ofsocial optimum

Charackr

Birrhweight ................................. At selective optimumIntelligence (measured as intelligence quotient) . 4-.

Life-span ...................................

"+=

Position ofs c k d i x o$!itnum

Position of
gopulation mean

Intermediate finite value
Intermediate finite value

Below selective optimumljl
Near and possibly even above
present selective optimum:*far below social optimum
Below social optimum: probably
below selective optimum

Unknown: perhaps+ cca"+-" implies positive and indefinitely large, always greater than the population mean.
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ed. A. Hollaender, BlcGratv Hill (1954).
Giles, N. H., Brookhaven Symposia in Biology,
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Pontecon~o.G., and J. A. Roper, Kature. 178, p.
83 (1956).
Demerec, M., and Z. E. Demeyec, op. cit. ref. 4,
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66. Benzer. S., The Chen:ical Basis of Heredity, p. 70
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71. Ryan, F. J., h e r . Natur. 89, p. 159 (1955) andearlier references therein.
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73. Reviewed by D. G. Catcheside. The Genetics of
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81. kmer. J. ~ u h Genet.
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--

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91. Lejeune, J., and R. Turpin, C.R. Acad. Sci., 244,
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93. Penrose, L. S., op. cit. ref. 11, gives some examples
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Amer. J. Hum. Genet. 2, p. 111
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105. ~ a l d i eJ., B. S., J. Genetics, 54, p. 327 (1956).
106. Verbally communicated by the Delegation of theUnited Kingdom.
107. Carter, T. C.. Proc. Roy. Soc. (B), 147, p. 402(1957).
108. Muller, H. J., Proc. Int. Corrf. on Peaceful Usesof Atom. Energy, 11,p. 387, U.N., 1956.
109. Dunn. L. C., Proc. Nat. Acad. Sci. U.S.A., 43, p.
158 (1957) and earlier papers, also adjacent paper
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110. Stevenson, A. C., op cit. ref. 11, p. 125.
111. See especially Neel, J. V., and W. J. Schull, The
Effect of Exposure to the Atonric Bolnbs on Pregftarzcy Termination in Hiroshima and Nagasaki,
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112. Gopal-Ayengar, A. R., op cit. ref. 11, p. 115.
113. Document A of UN document A/AC.82/G/R.58.
114. Expoacre of Mali to Iorzisi~zg Radiation Arising
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82/G/R. 117.
115. sielvart, A., J. Webb, D. Giles and D. Hewitt,
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utter;

116. The subject is reviewed by B. Colombo, Cold
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117. U N document A/AC.82/G/R. 16.
118. Lejeune, J., op cit. ref. 11, p. 87 and refs. therein.
119. Kaplan, I. I., J. Canad. Med. Assn. 76, p. 43(1957).
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p. 2125 ( 1957).
121. Puck, T. T. and H. W. Fisher, J. Exp. Med. 104,
p. 427 (1956).
122. Marcus, P. I., S. J. Ciecura and T. T. Puck, J. Exp.
Med. 104, p. 615 (1956).
123. Neel, J. V., and W. J. Schull, Science, 118, p. 537(1953).
124. ~ u r p i n R.,, J. Lejeune and M. 0. Rethore, Acta
Genet. et Stat. PIfed. 6, p. 203 (1956).
125. Communicated by T. C. Carter.
126. Macht, S. H., and P. S. Lawrence, Amer. J.
Roentgenol. 73, p. 442 (1955).
127. Court-Brown, W. M., and R Doll Leukaemia andAplastic Armentia itr Patients Irradiated for Ankylosing Spondylitis, H . M . Stationery Office, London ( 1957) and UN document A/ACS2/G/R. 105.
128. bfagni, G. E., C. R. Carlsberg, Lab. Physiol. Serv.
26, p. 273 ( 1956).
129. Ephrussi, B., et al, Ann. Inst. Pasteur, 76, p. 351,
419,510, 77, p. 47,64 (1949).
130. Dobzhansky, Th., Cold Spring Harbor Symposia
on Quantitative Biology, 20, p. 1 (1955).
131. Dobzhansky, Th., 0. Pavlovsky, B. Spassky and
N. Spassky, Genetics, 40, p. 792 (1955).
132. Dobzhansky, Th., and H. Levene, Genetics, 40,
p. 797 (1955) and references therein.
133. Lerner, I. M., Genetic Honteosta~is,John Wiley,
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134. Wallace, B.. Proc. Nat. Acad. Sci. U.S.A., 43, p.
404 (1957).
135. For indication of cross-over in Drosophila malesby X-rays or chemical agents, see U N document
A/AC.82/GfR.90.
136. Sobels, F. H., and H. von Steenis, Nature, 179, p.
29 (1957).
137. ~ h i t t i n ~ h i lM.,
l , J. Cell Comp. Physiol. 45, Suppl.
2, p. 189 (1955).
138. Sturtevant, A. H., and G. IV. Beadle, Genetics,
21, p. 554 (1936).
139. Kemp. Tage, Getretics and Disease, klunksgaard,
Copenhagen ( 1951) .
140. Penrose, L. S., Adv. Sci., 11, p. 387 (1955).
141. Allison, A. C., Ann. Hum. Genet. 19, p. 39 (1954).
142. Crow, J. F., Human Biology, 30, p. 1 (1958).
143. Neel, J. V., Human Biology, 30, p. 43 (1958).
144. Stevenson, A. C., UN document A/AC.82/G/
R. 104.
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U.S.A. (1956), U N document A/AC.S2/G/R. 1.
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147. Pansel F., Dig Erbchorea, Thieme. Leipzig (1932).
148. See Haldane, J. B. S., Caryologia, Supp. to Vol.
XI, Proc. 9th Int. Cong. Genet., p. 485 (1953).

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document A/AC.82/G/R.2.
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147 (1952).
152. Mather, K., Appendix G of ref. 124.
153. Clayton, G. and A. Robertson, h e r . Natur. 89,
p. 151 (1955).
154. Haldane, J. B. S., Caryologia, Supp. to Vol. XI,
Proc. 9th Int. Cong. Genet., p. 480 (1953).
155. Robertson, A., J. Genet., 54, p. 236 (1956).
156. Fisher, R. A., Genetical Theory of Natural Selection, Clarendon Press, Oxford, 1930.
157. Quoted by Mather in Appendis F of ref. 150.
158. Penrose, L. S., Proc. Roy. Soc. (B) 144, p. 144(1955).
159. &fuller, H. J., Genetics, Ettgeftics ajrd the family,
1, p. 106, Proc. 2nd. Int. Cong. Eug., p. 7 (1921).
160. Muller, H. J., Vol. I Radiation Biology, p. 351,
ed. A. Hollaender, McGraw Hill (1954).
161. OF cit. ref. 158, Fig. 14 and data in references.
162. Russell. W. L., Proc. Nat. Acad. Sci. U.S.A., 43,
p. 324 (1957).
163. Beeton, M., and K. Pearson, Biometrilta, 1, p. 50(1901).
164. Bateman, A. J., Nature, 178, p. 1278 (1956).
165. Turpin, R., J. Lejeune and M. 0. Rethore, Acta
Genet. et Stat. Med. 6. p. 204 (1956).
166. Crow, J. F., Amer. J. Roentgen., 73, p. 467 (1955).
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168. Maurer. Zbl. Gynk., p. 819 (1933).
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171. Muller, H. J., J. I. Valencia and R. &'I.
Valencia,
Genetics 3j, pp. 125, 126 (1950).
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314 (1956).
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Quantitative Biology, 2, p. 110 (1934).
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178. Based on a table compiled by H. C. Waddington
and T. C. Carter, Appendix H of ref. 150.
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186. Novitski, E., and L. Sandler, Ann. Hum. Genet.
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Calculations concernirtg survival at or near birth and the
distribution of birth-weights
110. Both Karn and Penrose151and Fraccaro18' havefound in samples of several thousand births that the distributions both of survivors S and non-survivors N
through birth and the subsequent 30 days are Gaussian.
Under these conditions the influence of the mean andvariance of the over-all birth-weight distribution uponsurvival at or near birth can, at least approximately, betreated algebraically. Suppose birth-weight w to be measured from the birth-weight at which S is maximal.
Let S = S o exp - w2/2u92

N = N. exp - 1/2(-)lq*
Then the curve determining survival is
S
-=

N

1(

1
-exp - so

exp
2u,2
No
2
1
1
1
where - = - - 0 ~ 2
u32 ud2
and the over-all survival is 1 - Ewhere
174 Nok =a 3 0 f u4NO
Moreover, optimal survival is a t o,,, =and at this point~ 4 2 '732

-m'Ug2uca - 432

Then the survival a t w = a,,, is 1 - kml,

N./s, exp - 1/2
where k,l,

( ""-2 1
'74"

=

I

+ NJS. exp - 1/2 (u,2 - .a2

andk in terms of (1) the variance 422 of the over-all distribution of birth-weights
T(W) = S(W) N (W)and(2) the difference m between the mean of the over-all
distribution of birth-weights and the birth-weight for
optimal survival, andCalculated numerical changes in r and in for 1 percent changes in variance and in departure of meanfrom optimal birth-weight are given in table XVI
calculated from the data of Kam and Penrose andFraccaro.

-I t is desirable to express the relation between k,,,

.

-

+

(3) the variance u12 which determines the shape of thebirth-weight-survival relation.

In terms of the parameters describing S(W) andN(W)If it is assumed that is small by comparison withunity, it -is. possible to write

k

(

0 4

m'2

)+om

r=-=exp 112
kml, at
4 4 2 - 43
and so since a 2 = a52 o(E)and a42 can be eliminatedin terms of a12 and ~ 7 3 ~+'Comparison ofas observed by Karn and Penrose
with values calculated from the above formula andthe parameters of their experiments gives
To&

Males
Females

2.07
2.21

C
'&

2.23
2.36

111. On the basis of equ. (1) it is possible to estimate
the consequences of small shifts in the mean or variance of the distribution of birth-weights, assumingthat the survival curve (k,,,, ul) remains constant, by
the relations

T-ABLE XVI.

112. I t has been estimated by Robsonla and byPenrose'4Q that some 40 per cent of the variance ofbirth-weight in a United Kingdom sample was due
to genetic factors, either of the mother or of the foetus.
Possibly only a small fraction of this is maintained byrecurrent mutation. The other extreme possibility isthat recurrent mutation maintains the \\?hole of thegenetic component of the variance 412. In that eventa 10 per cent change in mutation rate might lead toa 4 per cent change in 422 and so to changes in survivala t and near birth amounting to 0.2-0.7 per cent. If therepresentative doubling dose for the polygenes concerned were to be 30 rad, this would then correspond
approximately to the genetical influence of natural
sources of irradiation upon survival a t or near birth.
113. The part played by genetic factors in maintaining the difference between the mean birth-weight andthat for optimal survival is not known, but the mostextreme possibility is again that recurrent mutation
may be responsible for the whole of m. In that eventa similar change in mutation rate might lead tochanges in survival a t or near birth amounting to
0.2-0.8 per cent. These calculated upper limits apply
to regions in which the total loss of infants a t or nearbirth is in the range 4-7 per cent. They are illustrativeof the need to resolve the underlying and more fundamental problem of the part played by mutation inmaintaining the current distribution of birth-\$-eights
against the pressure of selection acting through thisphenotype.

CALCULATEDCONSEQUENCES OF CHAKGES IN THE PARAMETERS
GOVERNING BIRTH-WEIGIIT DISTRIBUTION

Swrcy Sampk

IGrn and Penroseljl.. ............................

...........

Chnngcs due fo 1 pn cear chongc in a12

Changes due lo I pcr cetrl chczgc in m

Fractional change
in r (parcnr)

A b ~ l u fchongctin fr (pcr cent)F r a c f i d chaalc Aberrlc change
in r (p,cent)in k Cpcr ccnl)

hlales 1.5
Females 1.3
Males 1.6
Females 2.9

0.072
0.053
0.11
0.18

0.50
0.84

0.024
0.034

Appendix

LIST O F SCIENTIFIC EXPERTS
The scientific experts who have taken part in the preparation of the report while attending Committee sessions
as members of national delegations are listed below. The Committee must also express its appreciation to the many
individual scientists not directly connected with national delegations whose voluntary co-operation and good willcontributed in no small measure to the preparation of the report.
ARGENTINA:
Dr. C. Nuiiez (Representative)
Dr. D. J . Beninson
Professor E. Favret
Dr. N. Nussis
Dr. J. A. Olarte
AUSTRALIA:
Dr. C. F. Eddy (Representative-first
Mr. D. J . Stevens (Representative)
Dr. A. R W. Wilson

Dr. A. Halawani (Representative)
Dr. H. T. Daw

session)BELGIUM:
Professor Z. Bacq (Representative)
Mr. R. Boulenger
Dr. M. Errera
Professor F. Twisselman
BRAZIL:
Professor C. Chagas (Repesetrtative)
Dr. B. Gross
Professor N. Libanio
Professor C. Pavan
Father F. X. Roser, S.J.
CANADA:
Dr. E. A, Watkinson (Representative)
Dr. R. K . Appleyard
Dr. P. M. Bird
Dr. W. E. Gnunmitt
Dr. Colin Hunter
Dr. G. H. Josie
Dr. C. A. Mawson
Dr. H. B. Newcombe
Dr. F. D. Sowby
CZECHOSLOVAKIA:
Professor F. Hertik (Representative)
Professor F. BEhounek
Dr. M. HaSek
Dr. L. Novik
Professor V. Sobek
Dr. I. Ulehla
Dr. V. Zelenf

Professor L. Bugnard (Representative)
Dr. A. Allisy
Dr. J. Coursaget
Dr. H. Jammet
Dr. J. Labeyrie
Dr. J. Lejeune

INDIA:
Dr. V. R. Khanolkar (Representative)
Dr. A. R. Gopal-Ayengar
Dr. A. S. Rao
JAPAN :

Dr. M. Tsuzuki (Representative)
Dr. Y. Hiyama
Dr. D. Moriwaki
Dr. K. Murati
Dr. M. Nakaidzumi
Mr. S. Ohta
Dr. N. Saito
Dr. E. Tajima
MEXICO:
Dr. M. Martinez Baez (Representative)
Dr. F. A. Andrade
Dr. H. Zalce

Professor R. M. Sievert (Representative)
Dr. B. A. A. Aler
Dr. R. G. Bjarnerstedt
Professor G. Bonnier
Professor T. 0. Caspersson
Professor C. A. T. Gustafsson
Dr. A. G. A. Nelson* Now in the United Arab Republic.

UNIONOF SOVIETSOCIALISTREPUBLICS:
Professor A. V. Lebedinsky (Representative)
Professor K. K. Aglintsev
Professor B. M. Isaev
Professor P. M. Kireev
Professor A. N. KraevsLy
Professor A. bZ. Kuzin

UNITEDKXNGDOM
OF GREATBRITAINAND
NORTHERNIRELAND
Professor W. V. Mayneord (Represetltativefirst session)
Dr. E. E. Pochin (Represelztative)
Dr. T. C . Carter
Mr. A. C. Chamberlain
Dr. W. G. Marley
Mr. N. G. Stewart

Dr. Shields Warren (Represe~rtative)
Professor G. W. Beadle
Dr. A. M. Brues
Professor J. Crow
Professor Th. Dobzhansky
Dr. C. L. Dunham
Mr. Merril Eisenbud
Professor Sterling Emerson
Professor G. Failla
Dr. J. H. Harley
Dr. J. S. Laughlin
Professor J. V. Nee1
Dr. M. Zelle