bluuebunny/crossref_metadata_2025 huggingface dataset:
X‐linkage and genetic heterogeneity in bipolar‐related major affective illness: reanalysis of linkage data
Authors: RISCH N. , BARON M.
Published: September 2007

It has been suggested that an X‐linked dominant allele operates in the genetic transmission of bipolar (manic‐depressive) illness. Linkage studies with X‐chromosome markers have remained inconclusive, showing both positive and negative results. Some of the ambiguity may be attributed to imprecise analytic methods and genetic heterogeneity. In this report, recently published pedigree series are reanalysed for linkage using a systematic method of pedigree analysis (Liped 3) with an accurate age‐of‐onset correction. Linkage heterogeneity is assessed through a two‐recombination fraction heterogeneity test suggested by Smith (1963). The results are as follows: (1) Close linkage of bipolar illness to colourblindness (deutan and protan) and glucose‐6‐phosphate dehydrogenase deficiency appears to be present in some pedigrees, with estimated recombination fractions of θ= 0.05 and 0.00, respectively; (2) Linkage with the Xg blood group cannot be supported. These results are consistent with known linkages on the X chromosome.
The response of cells from patients with Huntington's chorea to mutagen‐induced chromosome damage
Authors: EVANS H. J. , VIJAYALAXMI  , NEWTON M. S.
Published: September 2007

Cultured blood lymphocytes from 15 patients with Huntington's chorea (HC) and matched controls were exposed to a series of graded doses of mitomycin C and ethyl methane sulphonate and examined for the incidence of sister chromatid exchange (SCE). The spontaneous SCE levels did not differ between HC patients and controls and although cells from the majority of HC patients showed a slightly enhanced response to SCE induction by the mutagens, the enhancement was small and significant only on the pooled data. Cultures from 4 HC patients and controls were exposed to a graded series of X‐ray exposures and no difference was observed in the spontaneous aberration frequencies between HC cells and controls, or in their response to aberration induction by X‐rays. Skin fibroblast cultures derived from three HC patients, two xeroderma pigmentosum patients and two healthy controls were exposed to MMC and the levels of unscheduled DNA synthesis determined. There was no difference between the response of HC cells and normal controls, although such synthesis in the xeroderma cells was severely depressed. It is concluded that: (i) fibroblasts and lymphocytes from HC patients show a normal response to the three mutagens studied; (ii) there is no evidence for any defect in processes involved in repairing the lesions induced; (iii) the slightly elevated response of HC lymphocytes to SCE induction may reflect the presence of a different proportion of a slightly more sensitive T cell sub‐set in HC patients, and (iv) HC cells do not show a hypersensitivity to mutagens that could be used as a basis for diagnosis.
Evolutionary trees and admixture: phylogenetic inference when some populations are hybridized
Authors: LATHROP G. M.
Published: September 2007

Maximum likelihood estimation of admixture parameters and divergence times for an evolutionary tree in which some populations may be hybridized is developed. A test of treeness against the alternative of hybridization using a hierarchy of admixture models is proposed as an adjunct to the goodness‐of‐fit test suggested by Cavalli‐Sforza & Piazza (1975). The method is illustrated by an application to gene frequency data from Makiritare Indian villages in southern Venezuela.
Regulation of expression of liver‐specific enzymes
Authors: KIELTY C. M. , POVEY S. , HOPKINSON D. A.
Published: September 2007

1. The expression of twelve liver‐specific enzymes was analysed in twenty‐one independent rat hepatoma x human somatic cell hybrids, and in some cases up to forty‐one subclones were also tested.

2. Seventeen hybrids continued to express most of the rat liver‐specific enzymes and in some cases human isozymes of glutamate‐pyruvate transaminase, α‐glycerophosphate dehydrogenase, guanine deaminase, alcohol dehydrogenase and pyruvate kinase were clearly identified.

3. Analysis of the segregation of the human liver‐specific enzymes in these hybrids led to the assignment of human GPT to chromosome 8 (previously reported, Kielty, Povey & Hopkinson, 1982) and suggests the assignment of human GPD1 to chromosome 12.

4. The expression of the various liver‐specific enzymes in these hybrids appeared to be controlled by independent regulatory mechanisms.

5. Four unusual reverse segregant hybrids were also analysed, and in these no liver‐specific enzyme activity was demonstrable.
Gene order and localization of enzyme loci on the short arm of chromosome 1
Authors: CARRITT B. , KING J. , WELCH H. M.
Published: September 2007

Analysis of hybrids containing different rearrangements involving human chromosome 1 suggests that GDH and ENO1 are distal to PGD, and that all 3 loci are distal to 1p36.13. Evidence is presented indicating that FUCA and AK2 are in 1p34.
Analysis of linkage relationships of Co, Jk and K with each other and with chromosome 2 loci ACP1 and Km
Authors: LEWIS M. , KAITA H. , PHILIPPS S. , STEINBERG A. G. , GIBLETT E. R. , ANDERSON J. E.
Published: September 2007

Linkage analyses of locus pairs involving ACPI, Co, Jk, K and Km indicate: probable linkage between Co and Jk (ẑ=+3.80 at θ= 0.29); possible linkage between Jk and Km (z =+1.93 at θ= 1.30); a mild hint of linkage between Co and K 9z=+1.01 at θ= 0.30); inadequate information for Co: Km linkage for K: Jk, K: Km, ACPI: Jk, ACPI: K and ACPI: Km. The compiled information does not allow assignment of Co, Jk or K to chromosome 2.
Bias of the estimated recombination fraction and lod score due to an association between a disease gene a marker gene
Authors: CLERGET‐DARPOUX F.
Published: September 2007

An association between a recessive disease gene and a biallelic codominant linked marker is shown to induce some bias in the estimation of the recombination fraction by the lod score method. We demonstrate that ignoring the association may lead to an underestimate of the true recombination fraction and the lod score.
Extensions to multivariate normal models for pedigree analysis
Authors: HOPPER J. L. , MATHEWS J. D.
Published: September 2007

Lange, Westlake & Spence (1976) used the assumption of multivariate normality to apply a likelihood method to the analysis of quantitative traits measured over pedigrees. We now introduce a test of the assumption of multivariate normality and methods for the detection of outlying families and outlying individuals. We also introduce a method for the estimation of effects of measured genetic markers as variance components, a flexible parameterization to estimate effects of shared family environment, and a method to allow for the ascertainment of pedigrees through probands. These innovations have been applied using numerical methods for maximization of the likelihood. Simulation studies and available theory suggest that the likelihood ratio criterion used in significance testing follows the expected asymptotic distribution with sample sizes encountered in typical applications.
Immunological detection of the sixth complement component (C6) following flat bed polyacrylamide gel isoelectric focusing and electrophoretic transfer to nitrocellulose filters
Authors: Whitehouse D. B. , Putt W.
Published: September 2007

A method for the electrophoretic transfer of C6 molecules to a nitrocellulose filter is described. The protein is detected by the use of anti‐C6 antibodies and a peroxidase conjugated antibody. Using this method typical isoelectric patterns of C6 variant phenotypes are found. Inheritance and population data are presented. Three rare structural variants, one of which appears to be previously unreported, were discovered among a sample of 202 individuals. The method is discussed from the viewpoint of its flexibility and its value as an additional tool for revealing inherited variations in structural gene products.
Analysis of human erythrocyte 5‘‐nucleotidases in healthy individuals and a patient deficient in pyrimidine 5’‐nucleotidase
Authors: Swallow D. M. , Aziz I. , Hopkinson D. A. , Miwa S.
Published: September 2007

Electrophoretic and quantitative analysis of pyrimidine 5′‐nucleotidase in human erythrocytes from healthy individuals and a patient deficient in pyrimidine 5′‐nucleotidase, using a range of substrates, has shown that the patient has a marked deficiency with UMP, CMP and dCMP as substrates but near normal levels of activity with dUMP and dTMP as substrates. The observations suggest that two separate structural gene loci coding for distinct 5′‐nucleotidases with similar electrophoretic mobility exist in man. The genetic determination of these enzymes seems therefore to be homologous with that found in rodents.
The impact of legal termination of pregnancy and of prenatal diagnosis on the birth prevalence of Down syndrome in Denmark
Authors: MIKKELSEN M. , FISCHER G. , HANSEN J. , PILGAARD B. , NIELSEN J.
Published: September 2007

A considerable reduction in number of livebirths for mothers over 35 was observed in Denmark from 1960 to 1980. Birthrates for those aged 35–39 fell by 58.8%, for those aged 40–44 by 78%. In 1979–1980 100 infants with Down syndrome were born among 116757 newborns, a birth prevalence of 0.86 per 1000, which was significantly lower than the incidence of 1.17 per 1000 when the prenatally diagnosed cases were included. The reduction was noticeable for the age group over 35 where it fell to 1.89 per 1000 for mothers 35–39 and 6.48 per 1000 for mothers over 40.

The utilization of prenatal diagnosis was 72 per 100 livebirths for women 35 and older in the Copenhagen area and 56 per 100 livebirths for the rest of the country, with differences in different areas.

The number of induced abortions for women 35 years and older was 9265 against 6597 livebirths. The estimated number of Down syndrome cases averted by unrestricted abortion was 61, twice the number prevented by amniocentesis (31), with the greatest impact for mothers over 40.

An increased risk of Down syndrome for the age group 35–39 was observed when liveborn and prenatal cases were considered together showing an incidence of 6.89 per 1000, with the highest incidence in the Copenhagen area, 8.70 per 1000, more than double the incidence of 3.04 observed in Copenhagen from 1960 to 1971, for the same age group.
The affected sib method. II. The intermediate model
Authors: LOUIS E. J. , THOMSON G. , PAYAMI H.
Published: September 2007

An iteration procedure is outlined which uses HLA haplotype sharing data from sib pairs in which both sibs have the disease of interest. The procedure allows estimation of the degree of dominance of the HLA linked ‘disease’ allele, and its frequency in the population, for intermediate models where it is assumed that individuals who do not have at least one copy of the ‘disease’ allele do not contract the disease. Parameter estimates from sib‐pair data on multiple sclerosis, insulin dependent diabetes mellitus, haemochromatosis, coeliac disease juvenile rheumatoid arthritis, and Graves' and Hasimoto's diseases are given.
Genetic polymorphism of the LW blood group system
Authors: SISTONEN P. , GREEN C. A. , LOMAS C. G. , TIPPETT P.
Published: September 2007

Family studies of rare LW(a‐b+) propositi confirm the recent finding based on frequency studies that the LW blood groups are polymorphic in Finland (Sistonen & Tippett, 1982); they are controlled by two alleles LWa (0.97) and LW* (0.03) independent from most other common blood group loci. Loci scores for LW and the loci for 27 markers are presented.
Immunological and biochemical characterization of the human alcohol dehydrogenase χ‐ADH isozyme
Authors: Adinolfi A. , Adinolfi M. , Hopkinson D. A.
Published: September 2007

1. The recently identified χ‐ADH isozyme was purified from human liver and used to raise immune sera.

2. The χ form of ADH showed no structural resemblance to the ADH1, ADH2 and ADH3 (class I) or ADH4 (class II) isozymes, as judged by its immunological properties.

3. χ‐ADH was found in most human tissues including fetal specimens of 16 weeks gestational age and showed a preference for long chain primary alcohols with a double bond in the β position.

4. We conclude that the locus, designated ADH5, encoding the χ isozyme has a separate evolutionary origin from the other ADH genes.
A two‐susceptibility‐allele model for genetic diseases and associated marker loci: differences and similarities to a one‐s‐allele model
Authors: Falk C. T.
Published: September 2007

A model for genetic diseases and associated markers is defined where two distinct susceptibility alleles are possible, each associated with a different marker allele. Marker genotype distributions in a disease population are then expressed in terms of haplotype frequencies and penetrance parameters. It is shown that, if the heterozygote with two different disease alleles has a higher penetrance than the two disease homogzygotes, the observed to ‘Hardy‐Weinberg‐expected’ ratio of associated marker genotypes (the α/β ratio of Falk, Mendell & Rubinstein, 1983) will always be greater than or equal to one. When all disease penetrances are equal, the model becomes indistinguishable from a recessive one‐s‐allele model with α/β= 1.

Application of these observations to several data sets for insulin dependent diabetes mellitus suggests the possibility that different marker genotype distributions in different samples may be due to different penetrances of the disease genotypes in the samples. If a particular environment causes the heterozygote disease genotype (with two different disease alleles) to have the highest penetrance, the marker genotype distribution would be compatible with the 2‐s‐allele model. In other environments where the three disease genotypes have essentially equal penetrances, the marker distribution would be compatible with the 1‐s‐allele model.
On the lod score method in linkage analysis
Authors: Chotai J.
Published: September 2007

Genetic epidemiology deals with the interaction of environmental and genetic determinants in common diseases. Linkage analysis is an important branch of this field. The current practice of claiming linkage between two genetic loci when the maximum lod score z(θ) exceeds 3 has not received theoretical justification, whether considered as a sequential or as a fixed sample size test. Within the framework of significance testing, Wald's (1947) formulae are not applicable to allow this procedure a sequential interpretation. Considered as a fixed sample size test, we find that a X2approximation would instead be very adequate. Since repeated significance testing is performed on linkage data, the nominal significance level should be more stringent for each test than the overall level. Some recent developments in group sequential trials by Pocock (1977) and in repeated significance testing by Woodroofe (1979) seem to indicate that the critical value of the maximum lod score should lie roughly between 0·9 and 3·3, depending on the maximum number of repetitions anticipated, on whether the significance level is desired to be 0·05, 0·01 or 0·001, and on whether the test is derived from a one‐sided or a two‐sided consideration. In terms of the group sequential approach, if a maximum of twenty repetitions is allowed, if z(θ) > log10A is considered as a one‐sided test and assumed to be symmetric when linkage is absent, then the type I error is approximately given by 1/A. We also treat the confidence interval approach for exclusion of unlikely recombination values.
Assignment of the human gene for δ aminolevulinate dehydrase to chromosome 9 by somatic cell hybridization and specific enzyme immunoassay
Authors: BEAUMONT C. , FOUBERT C. , GRANDCHAMP B. , WEIL D. , N'GUYEN VAN CONG , GROSS M. S. , NORDMANN Y.
Published: September 2007

A non‐competitive enzyme immunoassay specific for δ aminolevulinate dehydrase has been devised and applied to rodent–human hybrid cell lines. Two different conditions have been used, one specific for the human enzyme and the other indicative of both rodent and human enzymes. The ratio of the values obtained under the two conditions was used to discriminate between positive and negative clones. By this method the gene for ALA dehydrase has been assigned to chromosome 9.
The role of lysosomal sialidase and β‐galactosidase in processing the complex carbohydrate chains on lysosomal enzymes and possibly other glycoproteins
Authors: SWALLOW D. M. , WEST L. F. , ELSEN A. VAN
Published: September 2007

Previous studies using the lectin RCA‐I from Ricinus communis have indicated that several lysosomal enzymes in the fibroblasts of patients deficient in β‐galactosidase carry excess terminal galactose. Electrophoretic studies have shown that the same enzymes and the non‐lysosomal adenosine deaminase also show excess terminal sialic acid in patients deficient in sialidase. In this paper we confirm, using Jack‐bean β‐galactosidase, that the binding to RCA‐I of the purified N‐acetyl‐β‐d‐hexosaminidase from a patient with Gm1 gangliosidosis depends on a terminal β‐linked galactose. We provide evidence, using bacterial sialidase and measuring the binding to RCA‐I, for excess subterminal galactose on the enzymes of patients deficient in sialidase. We also show that adenosine deaminase from the fibroblasts of patients deficient in β‐galactosidase has increased binding to RCA‐I. These observations suggest that in healthy individuals the carbohydrate structure of the precursors of lysosomal enzymes and possibly some other glycoproteins also includes extended carbohydrate side chains with terminal sialic acid and subterminal galactose, and that the mature enzyme extracted from tissues is the product of degradation.
A human cell‐surface antigen defined by a monoclonal antibody and controlled by a gene on human chromosome 1
Authors: ANDREWS P. W. , KNOWLES B. B. , PARKAR M. , PYM B. , STANLEY K. , GOODFELLOW P. N.
Published: September 2007

An antigen expressed by most human cells, but not erythrocytes, has been defined by a murine monoclonal antibody, TRA‐2–10. This antigen is expressed on the surface of human‐mouse somatic cell hybrids, and segregation analysis indicates that it is controlled by a gene located on human chromosome 1. From lysates of most human cells, surface‐labelled with 125I, TRA‐2–10 immunoprecipitates two polypeptides with molecular weights in the range of about 55000 to 73000 depending upon the cell line. Since the TRA‐2–10 polypeptides from a fibroblast cell strain and a hepatoma cell line from one individual differ, we conclude that the observed difference in molecular weight has an epigenetic origin.
Chromosome assignment, biochemical and immunological studies on a human aldehyde dehydrogenase, ALDH3
Authors: SANTISTEBAN I. , POVEY S. , WEST L. F. , PARRINGTON J. M. , HOPKINSON D. A.
Published: September 2007

The biochemical properties of ALDH isozymes have been examined in human tissues and one set, designated ALDH3, has been studied in detail. These components occur at highest levels in lung and stomach, but were not expressed in fetal tissues, or in blood, hair roots and fibroblasts. The ALDH3 isozymes show optimal activity with benzaldehyde and can use either NAD or NADP as cofactor. Antiserum against a partially purified ALDH3, from stomach, selectively precipitates this isozyme from human tissues and selectively recognizes an homologous component in the rat. Human and rodent ALDH3 were not immunoprecipitated by anti‐ALDH1 or anti‐ALDH2 antisera. High levels of expression were found in human‐rodent hybrids, constructed using rat hepatoma cells, and these hybrids were used to assign the human ALDH3 gene to chromosome 17.
Meiotic chromosome pairing in the normal human female
Authors: WALLACE B. M. N. , HULTÉN M. A.
Published: September 2007

The synaptonemal complexes of oocytes from 16–22 week human fetuses were spread using detergent, and silver‐stained for examination by light microscopy. Zygotene chromosome synapsis generally begins at the telomeres, without obvious prealignment, and proceeds towards the centromeres. Synapsis is not synchronous and longer bivalents may sometimes be completely paired before shorter ones. At pachytene, when pairing is usually complete, some regions presumed to correspond to the heterochromatic blocks of chromosomes 1, 9 and 16 may remain unpaired. Residual univalents are uncommon, and little interlocking is evident at this stage. Desynapsis indicating the beginning of diplotene frequently begins at the telomeres, although there is a general relaxation of pairing throughout the bivalents which become increasingly diffuse as diplotene proceeds. The total synaptonemal complex complement length at pachytene in the female is 519 μm, which is about twice that found in the human male. The implications of these results for genetic mapping are discussed.
The use of measured genotype information in the analysis of quantitative phenotypes in man
Authors: BOERWINKLE E. , CHAKRABORTY R. , SING C. F.
Published: September 2007

Improved laboratory methods allow one to investigate the contribution of measured allelic variability at a locus physiologically involved in determining the expression of a quantitative trait. We present statistical methods that incorporate measured genotype information into the analysis of a quantitative phenotype that allows one simultaneously to detect and estimate the effects of a measured single locus and residual polygenic effects. Likelihoods are presented for the joint distribution of the quantitative phenotype and a measured genotype that are appropriate when the data are collected as a sample of unrelated individuals or as a sample of nuclear families. Application of this method to the analysis of serum cholesterol levels and the concentration of the group specific component (Gc) are presented. The analysis of the contribution of the commonGcpolymorphism to the determination of quantitative variability in Gc using smaples of related and unrelated individuals presents, for the first time, the simultaneous estimation of the frequencies and the effects of the genotypes at a measured locus, and the contribution of residual unmeasured polygenes to phenotypic variability.
Estimation of inbreeding parameters in stratified populations
Authors: COCKERHAM C. C. , WEIR B. S.
Published: September 2007

A clarification is given of the differences in approaches to the estimation of F‐statistics of Nei & Chesser [Ann. Hum. Genet. (1983) 47, 253–259)] and Cockerham [Genetics (1973) 74, 679–700]. The principal difference is that Nei & Chesser define quantities with respect to fixed extant populations, while Cockerham allows for evolutionary variation between populations. Weighted and unweighted analyses are compared, and a numerical example given.
The development of human linkage analysis
Authors: SMITH C. A. B.
Published: September 2007

The principles of linkage detection and measurement are traced from the first discovery of linkage to its present‐day use in human genetics. Some indications are given of their success and of the present problems and challenges facing them.
The limits of ascertainment
Authors: EWENS W. J. , SHUTE N. C. E.
Published: September 2007

The concept of a proband, and a formula frequently used to give the probability that a family with r affected children has t probands, have led to frequently used, but incorrect, ‘limits of ascertainment’ in estimation problems involving ascertainment sampling. Data suggesting a sampling scheme outside these incorrect limits are discussed. An estimation procedure not using the proband concept is available which is not bounded by the incorrect limits.
The gene for human muscle specific carbonic anhydrase (CA III) is assigned to chromosome 8
Authors: EDWARDS Y. H. , LLOYD J. , PARKAR M. , POVEY S.
Published: September 2007

A cDNA clone complementary to the mRNA encoding the human muscle specific carbonic anhydrase CA III has been used as probe in the analysis of DNA from panels of rodent/human somatic cell hybrids. The presence of the CA III gene in all hybrids correlates with the presence of chromosome 8. This is the first assignment of the CA III gene in any species and, together with published mapping data, indicates that all of the human CA loci are situated on chromosome 8.
Phenotypic resemblance in birth weight between first cousins
Authors: MI M. P. , EARLE M. , KAGAWA J.
Published: September 2007

Birth weight data on 72078 liveborn singletons representing 5981 paternal and 7036 maternal single first cousin kinships were assembled by computerized record linkage from all marriages and livebirths registered in Hawaii during a 38‐year period from 1942 to 1979. These kinships represented incrosses of five selected racial groups. An additional 15536 livebirths from 1134 paternal and 1679 maternal cousin kinships provided data on outcrossing between racial groups, and 28952 livebirths from 2379 paternal and 3538 maternal cousin kinships provided data on both incrossing and outcrossing within kinships. Phenotypic resemblance in birth weight between single first cousins was estimated by the covariance and intraclass correlation. The covariances between maternal cousins were generally much higher than those between paternal cousins. Neither heterogeneity in maternal genotypes nor heterogeneity in newborn genotypes had any significant effect on the resemblance between first cousins. These observations have led to the conclusion that maternal influences of non‐hereditary origin are of primary importance in determining birth weight in man. The observed non‐zero correlation in several groups of paternal cousins was explained in part by the process of preferential selection of mates within and among racial groups by brothers, and probably by the similarity in some maternal characteristics associated with age at childbearing among their wives.
The gene for human αaL‐lactalbumin is assigned to chromosome 12q13
Authors: DAVIES M. S. , WEST L. F. , DAVIS M. B. , POVEY S. , CRAIG R. K.
Published: September 2007

A cDNA clone complementary to the mRNA encoding human αaL‐lactalbumin (ALA) has been used as a probe in the analysis of DNA from panels of rodent/human somatic cell hybrids. The presence of the ALA gene correlates with the presence of chromosome 12. In situ hybridization localizes the ALA gene to 12q13.
Tests of gene order from three‐locus linkage data
Authors: LATHROP G. M. , CHOTAI J. , OTT J. , LALOUEL J. M.
Published: September 2007

Exact tests for gene order are derived and compared for three loci using linkage data from phase‐known, completely informative marker loci (i.e. parents are heterozygotes with at most one allele identical at each locus), or from triple back‐cross matings. A simulation method, based on resampling genotypes of children, is introduced to obtain approximations to the distribution of the test statistics for general mating types in families consisting of children and parents, with or without grandparents, as are used in many studies in human gene mapping. The method is illustrated by an application to linkage data on chromosome 13.
Electrophoretic and immunological analysis of human glutathione S‐transferase isozymes
Authors: SUZUKI T. , COGGAN M. , SHAW D. C. , BOARD P. G.
Published: September 2007

Several electrophoretically distinct glutathione S‐transferase isozymes from different tissues have been purified and characterized. The data confirm the suggestion that GST‐1, GST‐2 and GST‐3 are the products of separate genetic loci.

An apparently muscle‐specific isozyme termed GST‐4 has been identified and shown to differ structurally from GST‐1, GST‐2 and GST‐3. It is likely that GST‐4 is the product of an additional gene locus.

Two isozymes termed GST‐5 and GST‐6 were purified from brain. GST‐5 has a different isoelectric point, but shares many structural features with GST‐1. GST‐5 may be a brain‐specific post‐translationally modified product of the GST‐1 gene. GST‐6 is an acidic isozyme found in many tissues. The data indicate that GST‐6 is composed of two dissimilar subunits that do not cross‐react with antiserum directed against GST‐1, GST‐2 or GST‐3. These observations therefore suggest that GST‐6 may have an independent genetic origin.
Genetic heterogeneity of X‐linked mental retardation with fragile X Association of tight linkage to factor IX and incomplete penetrance in males
Authors: GIANNELLI F. , MORRIS A. H. , GARRETT C. , DAKER M. , THURSTON C. , SMITH C. A. B.
Published: September 2007

X‐linked mental retardation with fragile X or Martin–Bell Syndrome (MBS) is a frequent cause of mental retardation. So far segregation analysis of MBS in pedigrees ascertained by different, incomplete criteria has produced results, difficult to interpret, which suggest genetic complexity (Sherman et al. 1985). Biochemical and cell biological studies have failed to provide an assay for genetic heterogeneity in MBS and linkage analysis is the only available method. Such analysis, however, is complicated by the incomplete penetrance of the disease in males and the variable penetrance and expression of the defect in heterozygous females.

We have used a new approach to test the heterogeneity of recombination between MBS and the coagulation factor IX gene or the anonymous probe 52A in a group of nine families who have sought genetic counselling at Guy's Hospital. We find that both our families alone and our families plus apparently complete samples of pedigrees reported in the literature, separate into two groups: one tightly and one loosely linked to factor IX. In the combined family sample these represent respectively 0·3 and 0·7 of the total and show recombination fractions of 0·0–0·15 and 0·25–0·5. Furthermore, the families with non‐penetrant carrier males show tighter linkage to factor IX than the others, thus confirming the suggestion of a systematic difference among MBS families in the recombination between the disease and the factor IX locus. By contrast, no significant differences were found in the recombination between 52A and factor IX in the two groups of MBS families or in these families versus those with Hunter syndrome examined in our laboratory.

The causes of the linkage heterogeneity we describe are not known. At least two alternatives can be considered: The existence of two MBS loci or differences in the recombination between a single MBS locus and the factor IX gene. The association between incomplete penetrance and tight, linkage to factor IX as well as the discontinuous variation in recombination fraction we have observed seem to favour the former alternative.
The structural gene for lecithin:cholesterol acyl transferase (LCAT) maps to 16q22
Authors: AZOULAY M. , HENRY I. , TATA F. , WEIL D. , GRZESCHIK K. H. , CHAVES M. E. , McINTYRE N. , WILLIAMSON R. , HUMPHRIES S. E. , JUNIEN C.
Published: September 2007

We have used a eDNA clone for human lecithin: cholesterol acyl transferase (LCAT) and Southern blotting techniques to identify the human LCAT gene in DNA from a series of rodent x human somatic cell hybrids. Our results are compatible with the location of the gene on human chromosome 16, and this has been confirmed using in situ hybridization of the LCAT eDNA to human metaphase chromosomes. These results confirm the earlier studies on LCAT‐deficient patients, indicating that the structural gene for LCAT is on human chromosome 16g22.
Physical mapping of genes and sequences at the end of the human X chromosome short arm
Authors: MONDELLO C. , ROPERS H.‐H. , CRAIG I. W. , TOLLEY E. , GOODFELLOW P. N.
Published: September 2007

Human–rodent somatic cell hybrids containing deleted and translocated human X chromosomes have been used to map genes and sequences in and around the pseudoautosomal region. The following order was found: (DXS69, DXS70, DXS143)–(DXS31, STS)–MIC2. This order is consistent with the known inheritance patterns of DXS31, STS and MIC2. Assuming that the translocations and deletions we have studied are not complex rearrangements, we conclude that the pseudoautosomal region consists of less than 5 times 106 bp of DNA.
The human placental alkaline phosphatase gene and related sequences map to chromosome 2 band q37
Authors: MARTIN D. , TUCKER D. F. , GORMAN P. , SHEER D. , SPURR N. K. , TROWSDALE J.
Published: September 2007

A human placental alkaline phosphatase (PLAP) eDNA was isolated from a Λgt10 library of the cell line HEp‐2. Southern blots probed with a fragment of the eDNA clone showed that the human genome may contain more than one PLAP‐related sequence. The PLAP probe showed person‐to‐person variation in banding pattern with a number of enzymes. Using a panel of human/rodent somatic cell hybrids the PLAP sequences were mapped to chromosome 2. In situ hybridization confirmed this assignment and localized the gene(s) to chromosome 2 band q37.
Recombination between the X and Y chromosomes: implications for the relationship between MIC2, XG and YG
Authors: GOODFELLOW P. J. , PRITCHARD C. , TIPPETT P. , GOODFELLOW P. N.
Published: September 2007

Three loci affect the levels of expression of the 12E7 antigen on red blood cells: MIC2, the pseudoautosomal structural gene for the 12E7 antigen; XG, an X‐linked red cell blood group locus and YG, a polymorphic Y‐linked locus. In this report we describe recombination between XG and MIC2 and an exchange between the X and Y chromosomes which included YG. These results have prompted us to propose a new model describing the genetic relationship between the XGa and 12E7 antigens.
Linked polymorphic DNA markers in the prediction of X‐linked muscular dystrophy
Authors: LINDLÖF M. , SISTONEN P. , CHAPELLE A. de la
Published: September 2007

Ten polymorphic DNA markers, including gene specific markers of loci DXS164 and DXS206, were tested for allele frequencies, degree of heterozygosity and linkage in 34 Finnish families with X‐linked muscular dystrophy. With the exception of the BamHI RFLP of DXS164 subclone pERT87‐15, allele frequencies and the degree of heterozygosity failed to show any significant deviation from the data published elsewhere. We document a high degree of linkage disequilibrium between several RFLPs belonging to locus DXS164. Our linkage data include one recombination between DMD and DXS164 enabling a tentative location of the mutation site distal to DXS164. The maximum lod score for linkage between the disease locus and DX164 was 7.828 at a recombination fraction of 0.02. According to our data DXS28 and DXS43 may be located further away from the disease locus than previously thought. We use only gene specific markers for genetic counselling. Excluding deletions, 97.1 % of women were heterozygous for at least one such marker. A diagnostic procedure in which useful information can be obtained in over 90 % of all diagnostic situations, using only four filters, is proposed.
New variants of Ps salivary polymorphic proteins
Authors: MINAGUCHI K. , SHIROTANI T. , SUZUKI K.
Published: September 2007

Electrophoretic analysis of the Ps protein demonstrated the existence of phenotypes additional to those described by Azen & Denniston (1980). A hypothesis that the polymorphism of the Ps protein is determined by five expressed and one unexpressed alleles was supported by family studies. The gene frequencies in a Japanese population were Ps1F= 0.0016, Ps1= 0.2983, Ps2F= 0.0288, Ps2S= 0.0079, Ps3= 0.0111, Ps0= 0.6523.
Klinefelter's syndrome: an analysis of the origin of the additional sex chromosome using molecular probes
Authors: JACOBS P. A. , HASSOLD T. J. , WHITTINGTON E. , BUTLER G. , COLLYER S. , KESTON M. , LEE M.
Published: September 2007

The results of our study of the origin of the additional X chromosome in 39 males with a 47, XXY chromosome constitution are reported. We used a total of 20 X‐linked RFLPs and successfully determined the origin of all 32 patients in whom DNA from both parents was available, and a further 3 in whom DNA was available from the patient and mother only. Males whose additional X chromosome was maternal in origin were further investigated using an X‐linked centromere specific probe to determine the cell division at which the error occurred. Our results showed 53% of the non‐disjunction to be attributable to pat mei I errors, 34% to mat mei I errors, 9% to mat mei II errors and 3% to a post‐zygotic mitotic error. In the great majority of patients resulting from an error of maternal meiosis there was clear evidence of recombination involving the non‐disjoined chromosomes, suggesting that absence of recombination is not an important aetiological factor in non‐disjunction of the X chromosome in female meiosis.

There was no alteration of parental age associated with the paternally derived 47, XXY males but a marked increase in maternal age among the maternally derived 47, XXY males, the increase being associated with mat mei I but not mat mei II errors. The proportion of paternally and maternally derived cases was similar among different ascertainment classes, suggesting that there is no dramatic effect of parental origin of the additional X chromosome on the phenotype of 47, XXY males.
Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes
Authors: HING S. , DAY A. J. , LINTON S. J. , RIPOCHE J. , SIM R. B. , REID K. B. M. , SOLOMON E.
Published: September 2007

Using cDNA probes for Factor H (FH) and C4 binding protein (C4BP) on a panel of somatic cell hybrids, we show that both of these genes map to the long arm of chromosome 1.
The human alpha‐1‐antitrypsin‐related sequence gene: isolation and investigation of its expression
Authors: KELSEY G. D. , PARKAR M. , POVEY S.
Published: September 2007

A genomic sequence approximately 5 kb in length designated the alpha‐1‐antitrypsin‐related gene (ATR), showing considerable homology to the human alpha‐1‐antitrypsin (AAT) gene, was identified 10 kb downstream of the authentic AAT gene. The AAT and ATR genes were introduced separately into L‐cells by transfection in order to establish a method for distinguishing between expression of the two genes. RNA probes from the cloned ATR region were then used in a ribonuclease protection assay against RNA from a range of human adult and fetal tissues. No evidence of expression of ATR was found, indicating that this region is probably a pseudogene.
Genetic polymorphisms of the Pmol and Pmo2 salivary proteins detected by the modified protein staining method
Authors: MINAGUCHI K. , SUZUKI K.
Published: September 2007

Two polymorphic proteins, Pmo1 and Pmo2, were found in human parotid saliva by modifying the protein staining method of Sung & Smithies (1969). The inheritance of each polymorphism was controlled by a dominant allele at an autosomal locus. This hypothesis was supported by studies in 50 families including 103 children. The gene frequencies were Pmo1+= 0.308, Pmo1‐= 0.692, Pmo2+= 0.026, Pmo2‐= 0.974. The Pmo1 and Pmo2 proteins reacted immunologically with antisera prepared to salivary proline‐rich proteins (Pr and Gl). The isoelectric point was in excess of 8.58. These results showed that the Pmo1 and Pmo2 proteins belong to the basic proline‐rich proteins in human parotid saliva.
Inheritance and linkage data for an unusual combination of genes (at the LKE, PI and C6 loci) in a single large sibship
Authors: WHITEHOUSE D. B. , ATTWOOD J. , GREEN C. , BRUCE M. , McQUADE M. , TIPPETT P.
Published: September 2007

Analysis of the groups of a large sibship showed that the locus for the blood group LKE is not closely linked to the loci for MNS, Rh, HLA, Pi, Gm and C6 and is genetically independent of the loci for P1, K, Xg, Au, secretor, and C3. The locus for the Auberger (Au) blood group was shown to be genetically independent of the locus for the blood group Kell and of the loci for C3, C6, Gc, HLA, Pi and Gm groups.
A genetic history of Italy
Authors: PIAZZA A. , CAPPELLO N. , OLIVETTI E. , RENDINE S.
Published: September 2007

Statistical techniques for displaying the geographical distribution of many genes in few synthetic images have been used to represent the various patterns of gene frequencies in Europe and in the world (Menozzi et al. 1978; Piazza et al. 1981a). It has also been shown that such synthetic displays are particularly useful in detecting clines of genetic differentiation associated with movements of populations like those accompanying the Neolithic expansion of farmers from the Near East or, in more recent times, the putative diffusion of Indo‐European‐speaking populations (Ammerman & Cavalli‐Sforza, 1984; Gimbutas, 1973).

In this paper we use the same combination of statistical and graphical techniques to study the genetic structure of Italy, a European country whose unity of people and cultures was quite a recent event. The possibility of studying genetic differentiation in a small geographical area is tested and trends of genetic differences are tentatively interpreted in terms of historic and linguistic knowledge. The few demographic pieces of information taken from historical sources and compared with linguistic records support the hypothesis that the genetic structure of Italy still reflects the ethnic stratification of pre‐Roman times.
Confirmation of the relationship of HLA (chromosome 6) genes to depression and manic depression II. The Ontario follow‐up and analysis of 117 kindreds
Authors: STANCER H. C. , WEITKAMP L. R. , PERSAD E. , FLOOD C. , JORNA T. , GUTTORMSEN S. A. , YAGNOW R. L.
Published: September 2007

HLA typing was conducted on 577 family members of 86 families having at least two first‐degree family members with a lifetime history of major depression or bipolar disorder. The results were combined with a follow‐up study of 10 Newfoundland kindreds and with the data obtained from our previous studies, giving a total cohort of 117 families of diverse ethnic and geographic origin. There was increased sharing of HLA haplotypes, as compared with random expectation, over all possible pairwise comparisons both in the follow‐up studies (P < 0.025) and in the total data (P < 0.01). The increase in HLA haplotype sharing over random expectation was greater if comparisons within heavily loaded sibships (by prior convention, sibships with three or more affected siblings) were omitted from the analysis (P < 0.002). There was also non‐random transmission of HLA haplotypes in 50 families selected for a low‐load, unaffected parent (P < 0.005). Thus, we conclude that genes in the HLA region of chromosome 6 constitute one of the elements in the multifactorial etiology of affective disorder. This conclusion does not depend on any assumption concerning genetic heterogeneity or epistasis or on specific modes of transmission, penetrance values or linkage distances. In addition, the data suggest that chromosome 6 region genes may have a different effect in unipolar and bipolar illness.
A cytogenetic study of 47, XXY males of known origin and their parents
Authors: JACOBS P. A. , BACINO C. , HASSOLD T. , MORTON N. E. , KESTON M. , LEE M.
Published: September 2007

A number of patients with both sex chromosome aneuploidy and the fragile X syndrome have been reported and this has led to the hypothesis that females heterozygous for the fragile X mutation have an increased rate of meiotic nondisjunction. Furthermore the suggestion has frequently been made that a predisposition to meiotic nondisjunction is associated with an increase in mitotic nondisjunction.

We have tested these two hypotheses by examining the chromosomes of a series of 47, XXY males and their parents. In the majority the parental origin of the additional sex chromosome was known. The cells were cultured under conditions suitable for demonstrating the fragile X and 100 cells were scored ‘blind’ from the patients and both parents. No fragile X individual was seen and there was no difference in the proportion of aneuploid cells between the parents in whom the nondisjunction event occurred and the control parents. Therefore, our results lend no support to the suggestions that the fragile X is associated with an increase in sex chromosome aneuploidy or that individuals in whom meiotic nondisjunction occurs have an increased level of mitotic nondisjunction.
Evidence on incest based on homozygosity The use of multiple hypervariable probes for the probable detection or exclusion of incest
Authors: EDWARDS J. H.
Published: September 2007

An opinion is sometimes requested on the future health of a child who is up for adoption when parental incest is a realistic possibility and it is impossible or inexpedient to acquire blood from both parents. In such circumstances evidence of incest may be obtained by an analysis of blood from the child alone.
Molecular characterization of human X/Y translocations suggests their aetiology through aberrant exchange between homologous sequences on Xp and Yq
Authors: Ballabio A. , Carrozzo R. , Gil A. , Gillard B. , Affara N. , Fferguson‐Smith M. A. , Fraser N. , Craig I. , Rocchi M. , Romeo G. , Andria G.
Published: September 2007

Several DNA sequences from two homologous regions, localized on the distal part of the human X chromosome short arm and on the long arm of the Y chromosome, have been hybridized to DNAs from seven human‐rodent hybrids containing human X; Y translocation chromosomes. Molecular characterization of the translocated chromosomes has revealed, in all but one case, transfer of the Y cluster of sequences and complete deletion of the corresponding X‐chromosomal sequences. The possible role of X/Y homology in the aetiology of X; Y translocations is proposed.
Cloning, experession and chromosomal localization of a member of the human cytochrome P450IIC gene sub‐family
Authors: Shephard E. A. , Phillips I. R. , Santisteban I. , Palmer C. N. A. , Povey S.
Published: September 2007

We have isolatd and sequenced a cDNA clone (pB8) that codes for a novel member of the dcytochrome P450IIC sub‐family of man. Analysis, by Southern blot hybridization, of DNA isolated from a panel of nine independent human‐rodent somatic cell hybrids demonstrated that the corresponding gene (CYP2C) is located on human chromosome 10. Northern blot hybridization of RNA isolated from human livers revealed a 10‐fold inter‐indicidual variation in the expression of the gene.
The nonrandom participation of human acrocentric chromosomes in Robertsonian translocations
Authors: Therman E. , Susman B. , Denniston C.
Published: September 2007

The present study explores the origin of human Robertsonian translocations (RT) and the causes of the nonrandom participation of the different acrocentrics in them. Satellite associations have been analysed in 966 cells from 8 persons, and 1266 RT with ascertainment have been collected from the literature. The observation that the chromosomes preferentially taking part in satellite associations vary between individuals is confirmed. However, since a preferred chromosome appears to associate at random with the others, this phenomenon should not add to the nonrandomness of the RT.

Most RT presumably arise through adjacent chromatid exchanges corresponding to mitotic chiasmata, in the pericentric regions of the acrocentrics. Our working hypothesis is that there is a basic exchange rate between any two acrocentrics. The surplus of t(14q21q) is presumed to depend on these two chromosomes having a homologous pericentric region. The 10–20 times higher incidence of t(13q14q) as compared with other RT is best explained by crossing‐over between homologous, but relatively inverted, segments in these chromosomes. Of the 246 RT ascertained through repeated abortions or infertility, 56 were found through the latter. Of these, chromosome 14 was involved in 51. The infertility may be caused by a small deletion of 14q, as is often the case in 15q in Prader‐Willi syndrome. In all RT ascertained through 21 or 13 trisomy, respectively, the relevant chromosome is one of the participants. Our data thus do not give any support to the idea of interchromosomal effects exerted by RT.