UNIVERSITY OF CAMBRIDGE : DEPARTMENT OF GENETICS

HEAD OF DEPARTMENT
K. J. R. EDWARDS. MA.. PH.D.

Balfour Professor of Genetics
J. M. THODAY. Sc.D.. F.R.S.

Our Ref:GAD/JH

DOWNING STREET
CAMBRIDGE CR2 3EH
    0223 69551

5th November, 1982.

Ms. Christine Gilbert, (Letters)
Science AAAS,
1515 Massachusettes Ave. N.W.
Washington D.C. 200025,
U.S.A.

OPEN LETTER FOR PUBLICATION.

While in general we have

                   few quibbles over the substance of R, Lewin's
clear description of the genetic system of molecular drive (Science 1982 218
'552-3), we feel that several comments in the report merit further discussion.
Lewin's report basically asks two questions: how real and how important; and
some commentators have offered answers.

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In our two papers

in which we have detailed the factual basis and

theoretical implications of molecular drive, we have defined it as a process
of fixing a mutation within multigene and non-genic families in a population,
as a consequence of DNA turnover.
that individuals of a sexual population would change in unison with respect to
the changing'composition of a family.
widespread phenomenon of concerted evolution.
phenomenon is incontestable, we cannot accept the definitive statement of
Lewin's,drawing in particular on remarks made by A. Jeffreys on the human
globin cluster and - Alu family, "that it is not a universal phenomenon".
Concerted evolution is occurring in the globin cluster; indeed this phenomenon
was first defined as such in this cluster due to the homogenisation of pairs
of ct and y genes, and their flanking sequences, by unequal exchange or gene
conversion.

clearly, concerted evolution is not a rare phenomenon, and seems to occur
between even distantly related genes and between active genes and pse~dogenes"~.
In the case of very large families, such as - Alu, detailed consideration needs to
be given to the rates of homogenisation relative to the mutation rate.  A 10%
level of sequence variation between 10 cloned Alu repeats from the human
genome4 reflects the constraints on homogenisation imposed by the presence of
500,000 copies finely dispersed over 46 chromosomes.
the very low levels of homology revealed by hybridisation between human and mouse
Alu families reflects a much greater between-species than within-species
divergence.
by an imperfect dimer whilst the mouse
Turnover is occurring in the - Alu family, albeit slowly.
families, whether tandem or interspersed, genic or non-genic that are
imune from such processes.
molecular drive and the subsequent interaction with natural selection is expected
to be very different

Consi-derations of rates of turnover indicate

At the heart of molecular drive is the

Although the reality of this

In reviewing such events in the globin cluster Jeffreys has written,

I1

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Despite these constraints

I_

Furthermore the human _I Alu family has been homogenised throughout
              family consists only o monomers4.

We are not aware of

The evolutionary progress of each family under

The importance of molecular drive as a genetic system can only be assessed

            An instructive example is provided by the phenomenon

by consideration of the way in which the genetic and phenotypic cohesion of a
population is maintained.
of hybrid dysgenesis in - Drosophila. In this example the molecular process is one

continued

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of transposition; one of the three mechanisms underlying molecular drive.
slow rate of transposition of P elements would lead to a genetic situation
in which there would be little variation in the number of P's in each individual
at any one time during the initial accumulation of  the element.  The small
variance in P number would not lead to dysgenesis within the population, as
is observed.
and a non-P population does lead to dysgenesis.
variance pattern of fixation would result from the slow rateso
unequal exchange or gene conversion involving the homogenisation of existing
families for one variant or another.

A

A large difference, however, in P number between a P population
                    Precisely the same low

  Given this cohesive system of genetics, which contrasts remarkably with
the classical population genetics of single-copy genes, we allowed ourselves
some freedom in speculating on its involvement in the origin of the ontogenetic
and reproductive differences between species,
there are few experimental tests of the genetic mechanisms which are thought
to underlie species differences.  We do not disagree with the conventional
viewpoint that such differences might be consequential upon natural selection
and genetic drift working within mendelian populations. Nevertheless such
external processes of fixation are inadequate in explaining species differences
in multiple-copy families, i.e. the phenomenon of concerted evolution. The
evolution of such families and their manifold phenotypic effects can be partly
explained by the genetics of molecular drive, which is precisely based on
internal molecular mechanisms of turnover.
that Drs. Doolittle and Selander consider our speculation on the evolutionary
biology of molecular drive ta be unhelpful.
biology may be,in essence, a manifestation of molecular events,  and the
artificial separation of molecular and evolutionary biology is itself unhelpful.

So far as we are aware,

Consequently, we are perplexed

We consider that all evolutionary

Part of the problem seems to stem from a mistaken supposition that turnover

is only observed in non-genic families whose biological effects have yet to
be ascertained.
Concerted evolution is an extensively documented observation in many multigene
families.
these families cannot be seriously challenged.  It could well be that even
the species differences in behaviour emphasised by John Maynard-Smith, are
under multigene control,
transformation in behaxiour under the aegis of the genetic system of molecular
drive

It would be a pity if this misunderstanding was widespread.

The biological effects and evolutionary significance of changes in

A population could undergo a long-term collective

  We do not consider molecular drive to be a catch-all for all genomic
rearrangements and exchanges. If some rearrangements, for example inversions,
deletions, or duplications turn out to be one-off events, then they are
analogous to most point mutations which rely for their evolutionary progress
on selection and drift. They do not contribute to the process of molecular
drive.

Prom what we now understand of the activities of unequal exchange, ger,e

conversion and transposition in so many different families, the evolutionary
differences between species must be considered a complex outcome of three
processes of fixation - adaptive, accidental and cohesively driven.  Despite
Che seeming pitfalls in trying to promote a new perspective, we see no reason
to be unenthusiastic about the implications of molecular drive.

G. A. DOVER, ?'. STRACKAN, E. S. COEN, S. D. M. BROWN* *Dept. Biochemistry,

address as above --..rl St. Mary's Hospital,

London.

1. Dover, G.A., Brown, S.D.M., Coen, E.S., Dallas, J., Strachan, T. and

Trick, M. (1982) in 'Genome Evolution' (eds. G. A. Dover and R. 5. Flavell)
Acad. Press. p.343.

2. Dover, G.A. (1982). Nature 299 111.

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3. Jeffreys, A. (1982) in"Genome Evolution" (eds. G. A. Dover and R. 13. Flavell)

Acad. Press. p.157.

4. Jelinek, W.R. & Schmid, C.W. (1982). Ann. Rev. Biochem. 51 813.

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