bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromosome maps of man and mouse. IV
Authors: SEARLE A. G. , PETERS J. , LYON M. F. , HALL J. G. , EVANS E. P. , EDWARDS J. H. , BUCKLE V. J.
Published: September 2007

Current knowledge of man‐mouse genetic homology is presented in the form of chromosomal displays, tables and a grid, which show locations of the 322 loci now assigned to chromosomes in both species, as well as 12 DNA segments not yet associated with gene loci. At least 50 conserved autosomal segments with two or more loci have been identified, twelve of which are over 20 cM long in the mouse, as well as five conserved segments on the X chromosome. All human and mouse chromosomes now have conserved regions; human 17 still shows the least evidence of rearrangement, with a single long conserved segment which apparently spans the centromere. The loci include 102 which are known to be associated with human hereditary disease; these are listed separately. Human parental effects which may well be the result of genomic imprinting are reviewed and the location of the factors concerned displayed in relation to mouse chromosomal regions which have been implicated in imprinting phenomena.
Different polymorphic variants of glucose‐6‐phiosphate dehydrogenase (G6PD) in Italy.
Authors: FIORELLI G. , MANOUSSAKIS C. , SAMPIETRO M. , PITTALIS S. , GLUGLIELMINO C. R. , CAPPELLINI M. D.
Published: September 2007

SUMMARH

Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is common in Italy and recent biochemical and kinetic studies have demonstrated the presence of polymorphic variants associated with severe or mild enzyme deficiency. We performed a biochemical characterization of G6PD in a large number of Italian G6PD deficient men in an attempt to identify the most reliable biochemical indices for discriminating polymorphic G6PD variants and to define their distribution throughout the country. Three polymorphic G6PD variants, respectively named Mediterranean, Cagliari and Sassari, were identified. The elution profile on DEAE‐Sephadex column chromatography, substrate analogue utilization and the Michaelis constant for G6P were the most significant parameters to discriminate polymorphic variants among the variants with activity levels lower than 0.8 IU/g Hb. The distribution of the polymorphic variants, in relation to the origin of the subjects studied, differs throughout the country.
Subtypes of HLA‐DQ and ‐DR defined by DQB1 and DRB1 RFLPs: allele frequencies in the general population and in insulin‐dependent diabetes (IDDM) and multiple sclerosis patients
Authors: GOGOLIN K. J. , KOLAGA V. J. , BAKER L. , LISAK R. P. , ZMIJEWSKI C. M. , SPIELMAN R. S.
Published: September 2007

We have used the HLA‐DQB1 gene as a Southern hybridization probe with TaqI‐digested genomic DNA in a study of 600 haplotypes from unrelated individuals and have characterized HLA‐DQB1 RFLP patterns associated with the DR specificities DR1‐DRw10 and DN1. For six of the specificities (DR2, 4, w6, 7, w8 and 9), we have also identified subtypes (multiple DQB1 band patterns), In a previous study (Cox Pt al. 1988), we identified RPLPs and subtypes with a DRB1 probe. Using the present results from DQB1 RFLPs to supplement those from DRB1 RFLPs, it was possible to discriminate among all the DR specificities with the exception of a minority of DR7 and DR9 subtypes. A comparison of DQB1 and DRB1 subtypes in the same subjects showed strong linkage disequilibrium for subtypes of some but not all DR specificities. We have also determined the allele frequencies of the DQBl subtypes in controls and in patients with insulin‐dependent diabetes mellitus (IDDM) or multiple sclerosis (MS). A consideration of subtypes in patients and controls indicated that for most DR specificities, neither IDDM nor MS was more strongly associated with any of the DQBl subtypes than with the serologically defined DR antigens. The exveptions were the DQBl patterns corresponding to the DQw3.2 subtype of DR4 and the rarer subtype of DR2, which were found in higher frequency in IDDM patients, as has been previously reported.
Common glucose‐6‐phosphate dehydrogenase (G6PD) variants from the Italian population: biochemical and molecular characterization
Authors: VIGLIETTO G. , MONTANARO V. , CALABRÒ V. , VALLONE D. , D'URSO M. , PERSICO M. G. , BATTISTUZZI G.
Published: September 2007

By biochemical characterization of glucose‐6‐phosphate dehydrogenase (G6PD) from the red cells of seventeen subjects of the population of Matera (Southern Italy) we have identified six genetically determined common variants. Among these, G6PD Metaponto and G6PD A(–) Matera had been already fully characterized. We have now found that A(–) Matera is genetically heterogeneous since one of two subjects examined had the two mutations at codons 68 and 126 characteristic of a typical A(–) variant, while the other subject had only the codon 126 mutation. G6PD Pisticci and G6PD Tursi are two new variants whose molecular lesion is not yet known. G6PD Cagliari‐like has biochemical characteristics reminiscent of G6PD Cagliari, isolated in Sardinia, and was found to have the same nucleotide substitution as G6PD Mediterranean. G6PD Montalbano is a new variant, with nearly normal properties, due to a G→A transition which causes an Arg→His amino acid replacement at position 285.
Isolation and use of chromosome 1 probes for linkage studies on Charcot‐Marie‐Tooth disease
Authors: GRIFFITHS L. R. , ZWI M. B. , MESTEROVIC N. , ROSS D. A. , BOARD P. G. , CALLEN D. F. , MOHANDAS T. , BUCKLAND R. , FLETCHER J. M. , DRIESEL A. J. , McLEOD J. G. , NICHOLSON G. A.
Published: September 2007

Nine probes were isolated from a human chromosome 1 enriched library and mapped to regions of chromosome 1 using somatic cell hybrid lines. One clone, LR67, which mapped to 1q12 → q23 detected a BglI RFLP. This probe, as well as 4 other known chromosome 1 markers, α‐spectrin, Factor XIIIB, DR10 and DR78, were used for linkage studies in 15 Charcot‐Marie‐Tooth disease (CMT1) families. Close linkage of CMT1 to any of the 5 markers was not indicated. Total lod scores excluded linkage of CMT1 to LR67 and to DR10 at 5 cM or less, to DR78 at 10 cM or less, α‐spectrin at 15 cM or less and Factor XIIIB at 20 cM or less. Possible linkage, however, was shown between LR67 and CMT1 at a distance of 30 cM. Also linkage at a distance of 5 cM was detected between this probe and α‐spectrin.
A centromere map of the X chromosome from trisomies of maternal origin
Authors: MORTON N. E. , KEATS B. J. , JACOBS P. A. , HASSOLD T. , PETTAY D. , HARVEY J. , ANDREWS V.
Published: September 2007

A centromere map is derived from XXX and XXY trisomies of maternal origin. Preliminary data suggest reduced recombination in the tetrads giving rise to mei I nondisjunction, but an excess of recombination in the pericentric region. As in Drosophila, multichiasmate tetrads may be more at risk of nondisjunction than nullochiasmate tetrads.
Multilocus ordering strategies based on sperm typing
Authors: GORADIA T. M. , LANGE K.
Published: September 2007

Sperm typing is a promising new approach for fine‐structure human gene mapping. We examine three‐locus sperm typing and its implications for the estimation of recombination fractions and for locus ordering. In particular, we compare some sequential stopping rules for three‐locus order assignment and develop methods for approximating their mean stopping times and error probabilities. A stopping rule recently described by Thompson and Boehnke et al. appears to be nearly optimal. Under this rule, one stops sampling as soon as the number of sperm of the least frequent recombinant type is s fewer than the number of sperm of the next least frequent type. We develop a random‐walk algorithm and some heuristic formulas for assessing the performance of this rule.

Since the broader goal of linkage analysis is to order many more than three loci, we propose a trisection strategy for ordering a new locus relative to an existing ordered set of loci. The crux of the trisection strategy is to restrict attention to the smallest block of ordered loci among which the new locus can fall and to divide this block into thirds for the next comparison. This trisection strategy is optimal in the sense that it has the best worst‐case performance of any strategy. When it is applied sequentially to order a collection of loci, it is only nearly optimal, as we demonstrate by specific counter‐example. However, it does become asymptotically optimal as the size of the collection increases.
Comparison of simple and modified Bernstein's methods in estimation of recessive allele frequency in the HLA system
Authors: NAM J.‐M.
Published: September 2007

Bias and inefficiency of Bernstein's estimator of the recessive allele frequency in generalized ABO‐like systems are important for situations where the frequency is small and the number of codominant alleles is large. A modified Bernstein's estimator of the recessive (Smith, 1967) has much smaller bias and higher efficiency than Bernstein's for large samples. Analogous findings are generally observed for small and moderate samples by Monte Carlo experiments. The modified method is preferred for the recessive frequency in the HLA system. The results are illustrated by numerical examples.
Counting algorithms for linkage
Authors: MORTON N. E. , COLLINS A.
Published: September 2007

The Lander‐Green algorithm is algebraically different from the EM algorithm that maximizes likelihood. In our experience the numerical difference is very small. Since computations are no easier or convergence faster for the Lander–Green algorithm, there is no reason to prefer it to EM. As suggested by Green (personal communication), layering is advantageous. Occasional updating of the information weights might also be considered to accelerate mapping.
The Gm‐Pi linkage in 843 French families: effect of the alleles Pi Z and Pi S
Authors: BABRON M.‐C. , CONSTANS J. , DUGOUJON J. M. , CAMBON‐THOMSEN A. , BONAÏTI‐PELLIÉ C.
Published: September 2007

Linkage analysis was performed between Gm and Pi in 843 French families. The overall recombination fraction is equal to025 with a sex difference ratio of 1–4 (recombination fraction of 020 in males and 0–29 in females), confirming previous results in the literature. Our study does not confirm the existence of a heterogeneity in recombination rate of Pi S versus non‐S alleles, but it confirms the previous finding that the presence of the Pi Z allele tends to decrease the recombination rate between the two loci. This decrease appears to be similar in both sexes, and not uniquely in males as previously noted. This result suggests a possible linkage disequilibrium between the Pi Z allele and a presumably large inversion between the two loci Gm and Pi.
Using age of onset to distinguish between subforms of breast cancer
Authors: CLAUS E. B. , RISCH N. J. , THOMPSON W. D.
Published: September 2007

Information on family history and age of onset of breast cancer is examined in an attempt to distinguish between postulated early and late onset forms of breast cancer and to estimate the familial correlation between any subforms that may exist. Data are taken from the Cancer and Steroid Hormone Study, a multicentre, population‐based, case‐control study conducted by the Centers for Disease Control (CDC). The data set includes 4730 histologically confirmed breast cancer cases aged 20–54 and 4688 controls who were frequency‐matched to cases by geographic region and five‐year categories of age. Data regarding family history of breast cancer for mothers and sisters of cases and controls are used in this analysis. The methods of Smith (1976) are modified to obtain maximum likelihood estimates of heritability and familial correlation using 35, 40, 45, and 50 years of age as the dividing point between early and late onset. The heritabilities for both the early and late onset forms decrease and approach one another in size with increasing age outpoint, although the heritability for the early group is always greater than that for the late group. Irrespective of cutpoint, the familial correlation between the two groups does not differ significantly from one, providing evidence for a single genetic form of breast cancer with familial cases increasingly represented among cases with earlier onset.
Isolation of a cDNA probe for the human intestinal dipeptidylpeptidase IV and assignment of the gene locus DPP4 to chromosome 2
Authors: DARMOUL D. , LACASA M. , CHANTRET I. , SWALLOW D. M. , TRUGNAN G.
Published: September 2007

We report the nucleotide sequence and derived amino‐acid sequence of a cDNA clone encoding the 3′ end of human intestinal dipeptidylpeptidase IV (DPP‐IV). This cDNA probe identifies a 4 kb mRNA in the human colon cancer cell line Caco‐2. We demonstrate here an extensive homology between this human DPP‐IV cDNA and the recently published rat liver DPP‐IV cDNA. Using the human DPP‐IV cDNA to probe genomic DNA from a panel of somatic cell hybrids we have assigned the gene encoding human DPP‐IV to chromosome 2.
A cytogenetic and molecular reappraisal of a series of patients with Turner's syndrome
Authors: JACOBS P. A. , BETTS P. R. , COCKWELL A. E. , CROLLA J. A. , MACKENZIE M. J. , ROBINSON D. O. , YOUINGS S. A.
Published: September 2007

The results of a cytogenetic and molecular reinvestigation of a series of 52 patients with Turner's syndrome are reported. No evidence of Y chromosome material was found among the patients with a 45, X constitution but two patients were found to have a cell line with a r(Y) chromosome which was previously thought to be a r(X). The parental origin of the single X in the 45, X patients was maternal in 69% and paternal in 31%, a similar ratio to that seen among spontaneously aborted 45, X conceptuses. This suggests that X‐chromosome imprinting is not responsible for the two grossly different phenotypes associated with a 45, X chromosome constitution. Approximately half of the structurally abnormal X chromosomes were maternal in origin and half paternal. This observation is consistent with either a meiotic or post‐zygotic mitotic origin and at variance with the predominantly paternal origin reported for autosome structural abnormalities.
On the estimation of the age at onset distribution in Huntington's chorea using the EM algorithm
Authors: BRAMBILLA C. , FRONTALI M. , MALASPINA P. , ROSSI C.
Published: September 2007

Huntington's chorea is a late onset disease of the nervous system whose mode of inheritance conforms to the autosomal dominant model. The present paper shows how the problem of estimating the distribution of age at onset of the disease can be dealt with as an incomplete data problem via the EM algorithm, both in the parametric and non‐parametric setting. In this way it is possible to take into account not only the heterozygotes in the population under study who are manifestly affected, but also those who are apparently unaffected. The estimation of the distribution of age at onset of the disease is required for estimating the posterior probability of heterozygosity of the individual at risk using Bayes' theorem. The proposed approach was applied to data derived from a survey carried out on the population of Latium, Italy.
Standard maps of chromosome 10
Authors: MORTON N. E. , COLLINS A.
Published: September 2007

To achieve consensus more exact definitions of genetical maps are required, of which standard, comprehensive and skeletal might be some. A standard genetic map gives distance from pter in centimorgans (cM), uses the international nomenclature for assigned loci, is sex‐specific, and allows as well as possible for interference and typing errors. A standard physical map gives distance from pter in megabases (Mb). A standard map is called comprehensive if it aims to include all syntenic loci, and skeletal if it is limited to loci whose order is well supported. Loci with established order are called skeletal, and are used to define regional assignments of other loci.

These principles are illustrated using the CEPH data for chromosome 10. Map lengths by multiple 2‐point analysis under supported interference are in good agreement with other evidence, but multipoint mapping gives a substantial overestimate. There are currently 21 loci in the skeletal genetic map and 40 loci in the comprehensive genetic map. From these data, cytogenetic assignments, and partial genetic maps the physical location has been estimated for 85 loci. MEN2A is in a region close to the centromere in which male recombination per megabase is much reduced. Order of DNA markers in this densely mapped region has not been determined, and therefore the exact location of MEN2A is uncertain, although it is likely to lie between D10S34 and D10S30 and close to D10S11.
The linkage detection problem
Authors: EDWARDS J. H.
Published: September 2007

Linkage data in man are usually analysed on families lacking a full set of grandparents on the assumption that there is one locus relating to an abnormal phenotype, the test locus. The basic problems of establishing linkage of this locus to another locus, the marker locus, with a defined likelihood and of estimating the recombination fraction were resolved by Morton(1955). However, the likelihood ratio derived after estimating the most likely recombination fraction is widely misunderstood to be a direct measure of the likelihood of linkage while the bias of estimates conditional on some likelihood criterion derived from the same data is usually ignored. Since data are limited this tolerance of excessive confidence in detecting linkages and a consistent tendency to underestimate recombination fractions is justified but the expected errors are not small and they are readily magnified when multiple loci are involved.

Multiple markers provide further opportunities for detecting false linkages although the corrections required are known. The problems imposed by multiple loci at which mutations lead to a common phenotype have so far had little consideration. As most proteins are multimers whose units are not necessarily coded for by neighbouring loci, and as disturbances to any of several enzymes acting in series may lead to similar consequences, the assumption of a one‐to‐one relationship between a locus and a phenotype will usually be wrong.
Spinocerebellar ataxia (SCA1) in two large Italian kindreds: evidence in favour of a locus position distal to GLO1 and the HLA cluster
Authors: FRONTALI M. , IODICE C. , LULLI P. , SPADARO M. , CAPPELLACCI S. , GIUNTI P. , MALASPINA P. , MORELLINI M. , MOROCUTTI C. , NOVELLETTO A. , PERSICHETTI F. , TRABACE S. , ANASTASI R. , TERRENATO L.
Published: September 2007

Two large Italian pedigrees with HLA‐linked spinocerebellar ataxia (SCA1) were typed for HLA‐A, ‐B and ‐DR as well as for markers either distal (F13A, D6S8) or proximal (D6S29, GLOl) to HLA. Pairwise linkage analyses of SCA1 vs. HLA‐A, ‐B and ‐DR showed peak lodscores of 5‐3, 5‐6 and 3‐3 respectively at 7 % recombination. Negative lodscores significantly excluded linkage with F13A at less than 5% and with GLOl at less than 10%. The lodscores with D6S8 and D6S29 had only low peaks.

Recombination events in the two pedigrees and the estimated genetic distances of SCAl from GLOl and HLA favour the hypothesis of a SCA1 location distal to both of them. An order cen‐GLOl‐HLA‐SCAl‐tel appears therefore most likely with present data. These results are discussed in relation to previous reports placing SCA1 distal to HLA in two families and proximal in another.
Significance of maximal lods
Authors: COLLINS A. , MORTON N. E.
Published: September 2007

A numerical demonstration of the validity of maximal lods is given, showing that P(≤ log A) ≤ 1/A under a null hypothesis that is true in the absence of linkage.
A new genetic polymorphism in human platelet polypeptides detected by two‐dimensional electrophoresis
Authors: KAJII E. , IWAMOTO S. , OMI T. , IKEMOTO S.
Published: September 2007

We describe a new genetic polymorphism of human platelet polypeptide, detected by two‐dimensional polyacrylamide gel electrophoresis followed by silver‐staining. The polymorphism was tentatively designated thrombocyte B (ThB) with a molecular weight of 34 k Da and isoelectric point of 4‐7‐4‐8. In this polypeptide, three different electrophoretic types (1‐1, 1‐2, 2‐2) were identified. Family and population studies indicate that the three phenotypes of the polypeptide are determined by two common alleles at a single autosomal locus. In a Japanese population, the gene frequency of ThB 1/ThB 2 was 0.74/0.26. The ThB polypeptide was not found in other blood cells and decreased or disappeared during the preparation or storage of platelets.
Assignment of the Hepatocyte Growth Factor (HGF) to chromosome 7q22‐qter
Authors: LAGUDA B. , SELDEN C. , JONES M. , HODGSON H. , SPURR N. K.
Published: September 2007

The hepatocyte growth factor (HGF) is thought to be important in the growth of hepatocytes during normal foetal liver growth and following liver damage. The human gene encoding HGF has been mapped to chromosome 7 and shown to be localized in the region q22‐qter.
Chromosomal assignment of human phenol and bilirubin UDP‐glucuronosyltransferase genes (UGT1A‐subfamily)
Authors: MOGHRABI N. , SUTHERLAND L. , WOOSTER R. , POVEY S. , BOXER M. , BURCHELL B.
Published: September 2007

DNA probes were prepared from the 5′ ‐terminal portion of four cDNA clones encoding human phenol and bilirubin UDP‐glucuronosyltransferases (UGTs). An additional sequence common to all four clones was isolated from the 3′ ‐terminal portion of one of the clones (UGT1A1).

The four specific and the one common DNA sequences were used as probes on a panel of 16 human‐rodent somatic cell hybrid DNAs by Southern‐blot analysis. The results obtained indicate that all four cDNA clones are encoded by gene(s) located on human chromosome 2.
Carrier detection of deletions of the Hunter gene by in situ hybridization
Authors: STONE S. , ADINOLFI M.
Published: September 2007

Deficiency of the lysosomal enzyme α‐iduronate sulphate sulphatase (IDS) causes the clinical manifestations of Hunter syndrome, an X‐linked condition. In about 30% of male patients, the disease is due to a major deletion. Using a non‐isotopic in situ hybridization (NISH) method, and a yeast artificial chromosome (YAC) probe, the Hunter gene was mapped to the terminal region of the human X chromosome, close to the Xq28 band.

The NISH procedure was then applied to investigate the carrier status of female relatives of a Hunter patient known to have a deletion of the IDS gene.

Unequivocal evidence that two female relatives were carriers of the deletion was obtained, demonstrating that the NISH method is a valuable diagnostic tool in genetic counselling of families with Hunter patients.
Algorithms for a location database
Authors: MORTON N. E. , COLLINS A. , LAWRENCE S. , SHIELDS D. C.
Published: September 2007

The algorithms that drive the Idb location database are described. The program captures data on genetic and physical maps and combines information from different sources into a summary map. To assure portability it was developed in Fortran on a SUN SPARCStation under Unix. The algorithms, which combine rule‐based seriation with a minimum deviance bootstrap, allow investigators and chromosome committees to produce a composite location in Mb that integrates partial maps. The program and manual are now available from the authors.
The genes coding for phosphoenolpyruvate carboxykinase‐1 (PCK1) and neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) map to human chromosome 20, extending the known region of homology with mouse chromosome 2
Authors: PILZ A. J. , WILLER E. , POVEY S. , ABBOTT C. M.
Published: September 2007

The mouse genes for cytosolic phosphoenolpyruvate carboxykinase‐1 (Pck‐1) and neuronal nicotinic acetylcholine receptor a4 subunit (Acra‐4) both map to distal chromosome 2 (Siracusa et al. 1989; Bessis et al. 1990). We have utilized Southern blot analysis on human/rodent somatic cell hybrids to map the human homologues of both of these genes, PCK1 and CHRNA4, to human chromosome 20.
Mitochondrial DNA polymorphisms in Khoisan populations from Southern Africa
Authors: SOODYALL H. , JENKINS T.
Published: September 2007

Mitochondrial DNA (mtDNA) restriction fragment length polymorphisms (RFLPs) were investigated in 95 individuals, consisting of 49 San (‘Bushmen’) and 46 Nama (‘Hottentot’) individuals from Namibia, using the restriction enzymes HpaI, BamHI, HaeII, MspI, AvaII and HincII. Six of the eleven types found in the pooled Khoisan sample are shared, albeit at varying frequencies, suggesting that both the San and Nama have evolved from a recent common ancestor. However, San and Nama groups differ appreciably, in particular, type 3‐2 (3‐1‐1–2‐2‐2) was found in 7/49 Sekele and 25/46 Nama (χ2[1]= 15·3, P= 9·17 × 10‐5). In addition, type 4 makes up 428 % of the types found in the San, and is not found in the Nama group. This suggests that the San and Nama have evolved along separate lineages, with little gene flow between them, following their proposed separation from a common Khoisan ancestor. Type 7‐2 (3‐1‐1‐1‐1‐2), most common in Negroid populations, is found at a higher frequency in the San (20·4%) than the Nama (6·5%), suggesting that miscegenation involving Negroid females and San males is more common than that between Negroid females and Nama men. The higher frequency of type 21‐2 (2‐1‐1‐1–2‐2) in the Nama (13%) than in the San (4·1%), may be attributable to gene flow from the Dama into the Nama, consistent with the consequences of enslavement of the Dama by the Nama.
Segregation and linkage analysis in five manic depression pedigrees excludes the 5HT1a receptor gene (HTR1A)
Authors: CURTIS D. , BRYNJOLFSSON J. , PETURSSON H. , HOLMES S. , SHERRINGTON R. , BRETT P. , RIFKIN L. , MURPHY P. , MOLONEY E. , MELMER G. , GURLING H. M. D.
Published: September 2007

Five kindreds selected through probands attending an Icelandic hospital were recruited for linkage studies of manic depression. The rates of affection were equal for males and females and the age of onset appeared to be predominantly in early adult life, since prevalence did not rise appreciably with age. A complex segregation analysis was performed using the computer program pointer to obtain maximum likelihood estimates of the contributions to liability from multifactorial transmission and a single major locus. Likelihood ratios between models supported a role for a single major locus which was dominant and had moderately high penetrance with, in the case of unipolar illness, additional multifactorial transmission. The bestfitting parameters were used to devise a transmission model for linkage analysis. Three markers on chromosome 5 were studied, at D5S76, D5S6 and D5S39. Strongly negative lod scores were obtained which were less than ‐2 over a distance of 40 cM, which included the region to which the gene for the 5HT1a receptor has been mapped.
Bayesian inference in multipoint gene mapping
Authors: STEPHENS D. A. , SMITH A. F. M.
Published: September 2007

The problem of rodering and mapping genes on the basis of recombinant data and radiation hybrid data is formulated as a problem of Bayesian inference for an unknown permutation. The challenging computational problems posed by this approach are shown to be resolvable using Markov chain Monte Carlo methods.
Molecular genetic evidence for the delineation of more severe form of familial adenomatous polyposis which results from fresh mutation
Authors: REES M. , LEIGH S. E. A. , DELHANTY J. D. A. , Bowles L. , TALBOT I.C.
Published: September 2007

Familial adenomatous polyposis, an inherited pre‐malignant condition, is caused by mutation in the adenomatous polyposis coli (APC) gene at chromosome 5q22. The lifetime risk of carcinoma approaches loo%, with an average age at death from cancer of 40 years, allowing most patients to complete reproduction. Since there is no evidence for a rising incidence, this is at variance with an apparently high mutation rate. We present evidence for the delineation of a severe form, which hitherto has largely been maintained by fresh mutation. An atypically high frequency of loss of heterozygosity at chromosome 5q22 in small adenomas correlated with an early age of onset or malignancy in two patients, both due to fresh mutation. In both cases, the mutation in APC was shown to be a commonly occurring deletion, leading us to postulate the co‐existence of a modifying gene.
Barriers to gene flow estimated by surname distribution in Italy
Authors: ZEI G. , BARBUJANI G. , LISA A. , FIORANI O. , MENOZZI P. , SIRI E. , CAVALLI‐SFORZA L. L.
Published: September 2007

Surname distributions were studied in order to reconstruct human migration patterns. Zones of sharp change in surname frequencies ‐ presumably barriers to gene flow ‐ were detected by the statistical technique of wombling (Barbujani et al. 1989), using data from consanguineous marriages (1910‐64) collected from 280 Italian dioceses which we grouped into 80 provinces. The 28 observed surname boundaries were compared with physical (geographical) and cultural (linguistic) barriers, and with boundaries detected from distributions of 57 alleles in the same territorial subdivisions. Genetic and surname boundaries had similar locations, as expected given the analogy in the inheritance mechanism of genes and surnames. Physical barriers seemed to be the main cause of gene flow reduction. However, cultural factors alone (e.g. linguistic ones) also determined barriers that delimited areas of homogeneous gene (and surname) frequency probably due to increased endogamy. The observed similarity between spatial patterns of surnames, genes and languages supports the hypothesis of the co‐evolution of genetic and linguistic variation.
Rh null phenotypes are not due to a gross deletion and can occure on different Rh genetic backgrounds
Authors: CARRITT B. , BLUNT T. , AVENT N. , DANIELS G. , STEERS F.
Published: September 2007

Alu element‐primed PCR was performed on genomic clones containing human RH blood group genes. When used as a probe, the Alu PCR product detected a restriction fragment‐length polymorphism which is in complete linkage disequilibrium with the Rh C/c serological polymorphism, irrespective of the Rh D or E serological type it is coupled with. This provides the opportunity to type individuals for their RH C gene directly at the DNA level. RFLP analysis of two individuals with the amorph Rh null phenotype revealed that in one case this phenotype occurred on an RH C background, whereas in the other it was on an RH c background. Taken together these results indicate that the Rh C/c polymorphism has arisen only once, but that the amorph Rh null phenotype, although exceedingly rare, is the result of at least two independent mutations.
Extimating the correlation among siblings
Authors: KEEN K. J.
Published: September 2007

Beginning with Galton, Various authors have proposed non‐iterative estimators of the correlation coefficient that measure the degree of similarity among siblings. However, these extimators lose efficiency appreciable for certain ranges of values of the correlation coefficient. An estimator formed by an algebraic combination of two non‐iterative extimators based on Smith (1957) is shown by simulation to be nearly full efficent for teh full range of values of the coefficent. A new estimator given by the best linear combination of these extimators offers a practical improvement for large values of the coefficent. The discussion conceludes with an example.
Mapping of RXRB to human chromosome 6p21. 3
Authors: FITZGIBBON J. , GILLETT G. T. , WOODWARD K. J. , BOYLE J. M. , WOLFE J. , POVEY S.
Published: September 2007

Retinoid X Receptor beta (RXRB) is a member of the retinoid X receptor (RXR) family of nuclear receptors which are involved in mediating the effects of retinoic acid (RA). We have confirmed the localization of RXRB to chromosome 6 and we have mapped the gene to chromosome 6p21. 3‐p21.1 by PCR amplification of 5′ untranslated sequence in panels of rodent‐human somatic cell hybrids and to 6p21.3 by fluorescent in situ hybridization.
Sex ratio and natural selection in humans: a comparative analysis of two Caucasian populations
Authors: ULIZZI L. , ZONTA L. A.
Published: September 2007

In the course of the last century industrialized countries have experienced significant changes in mortality rates. Since the sex ratio of a population may be considered a function of, among other factors, differential mortality in the two sexes, it is expected to correlate with changes in sex‐specific mortality rates.

In this paper secular changes in the sex ratio at birth and after the action of relevant components of early selection (stillbirth, mortality within the first month and within the first year of life) have been studied in the Italian and in the USA White populations.

The results can be summarized as follows.

(i) In the past, extra male‐specific mortality appeared to reduce the relatively large values of the sex ratio observed at birth, and this held true in both populations.

(ii) In more recent times, male‐specific mortality has been decreasing in all age groups, and the sex ratios before and after the action of early selection now tend to identical values.

Therefore, it can be envisaged that in the near future the sex ratio observed at birth will be maintained up to the reproductive age. If the reproductive value is stabilized by natural selection, as is likely, new relationships between sex ratio and selection may be expected to develop in a relatively short time.
The effect of variation in the apolipoprotein B gene on plasma lipid and apolipoprotein B levels I. A likelihood‐based approach to cladistic analysis
Authors: HALLMAN D. M. , VISVIKIS S. , STEINMETZ J. , BOERWINKLE E.
Published: September 2007

A new method is described for employing family data to test for significant haplotype effects on continuously distributed variables, using likelihood‐ratio tests of linear models in which haplotype effects are parameterized and familial correlations taken into account. The method is applied to the apolipoprotein B (Apo B) gene, using 5 polymorphisms (Insertion/deletion, Bsp1286I,XbaI,MspI,EcoRI) to define haplotypes in 121 French nuclear families. Eleven haplotypes were found, five of which, combined, account for over 95% of the sample. A haplotype phylogeny is proposed, and is used to define a nested set of models for testing the effects of Apo B variation on total‐, low‐density‐lipoprotein (LDL)‐, and high‐density ‐lipoprotein (HDL)‐cholesterol, triglyceride, and Apo B levels. Apo B haplotype effects account for about 10% of the genetic variance and 5% of the total variance in HDL‐cholesterol and triglyceride levels. Clusters of evolutionarily‐related haplotypes with similar phenotypic effects are identified for HDL‐cholesterol and triglycerides. Single haplotypes with statistically significant effects are identified for cholesterol, LDL‐cholesterol, and Apo B levels.
Consanguineous marriage in Turkey and its impact on fertility and mortality
Authors: TUNÇBÍLEK E. , KOC I.
Published: September 2007

Turkey has a high rate of consanguineous marriage (21·1 %), indicating strong preference for this traditional form of marital union. Social and cultural factors are especially important in marriages between first and second cousins. Fertility is high, the closed birth interval is long, and the sterility rate is low among these couples. Post‐neonatal, infant and under‐5 mortalities are high in first cousin unions by comparison with non‐consanguineous marriages. According to the results of the study, first cousin marriage is a significant determinant underlying the high total fertility and infant mortality rates in Turkey.
The two locus problem
Authors: EDWARDS J. H.
Published: September 2007

The problem of detecting linkage between two loci expressed as similar phenotypes and two or more marker loci from a set of families is discussed and a solution advanced. The term amphigenic is suggested for such conditions.
Estimating multipoint recombination fractions
Authors: SMITH C. A. B. , STEPHENS D. A.
Published: September 2007

The likelihood in linkage investigations can be expressed as a polynomial in the relevant recombination fractions. With polymorphic characters, this can be reduced to a product of separate factors for female and male recombinations, with only mild loss of information. With three generation data the polynomials take a specially simple form. Algorithms are given for finding maximum likelihood estimates and their standard errors.
An integrated map of chromosome 9
Authors: COLLINS A. , FORABOSCO P. , LAWRENCE S. , MORTON N. E.
Published: September 2007

An integrated map of 211 loci on chromosome 9 is presented for which 198 loci have genetic locations. The results of the analysis indicate very strong interference for the chromosome and positional variations in recombination rates, most extreme in the male map where there is an excess of recombination near the p telomere and a marked suppression of recombination in a large region that includes the centromere.
Linkage detection under heterogeneity and the mixture problem
Authors: CHIANO M. N. , YATES J. R. W.
Published: September 2007

Linkage analysis has contributed to the localization of many human disease genes. The presence of locus heterogeneity reduces statistical power and can prejudice the detection of linkage if the analysis assumes homogeneity. Nevertheless, mixed genetic models are not routinely used in gene searches. The null distribution of the test statistic is not uniquely defined. In this paper, a transformation is used to determine an approximate asymptotic distribution of the test statistic under a mixture model. The equivalent critical values of the test are computed and the performance of the test under various levels of heterogeneity and family size is investigated. For gene searches, we recommend the routine use of an admixture model with a critical lod score of 3·44.
Estimation of quantitative genetic parameters under non‐normal models
Authors: ANDRADE MARIZA de
Published: September 2007

In traditional quantitative genetics, the relationship between the observed value of a quantitative trait in a set of families and its genetic and environmental contributions can be described as a linear additive relationship. Generally, it is assumed that the genetic and environmental effects are independent and normally distributed. Consequently, the quantitative trait also has a normal distribution. However, there are some situations where the phenotype does not follow the normal distribution. To deal with this problem the author suggests the families of distributions that belong to the Johnson Translation System (JTS). As an example, two dependent quantitative traits, weight and height, are investigated assuming that they have a lognormal and normal distribution, respectively. Computational methods for estimating the genotypic variances and covariances are presented.
Assessing genetic linkage and association with robust components of variance approaches
Authors: AMOS C. I. , ZHU D. K. , BOERWINKLE E.
Published: September 2007

Simulation studies are used to explore the properties of procedures for estimating components of variance and constructing test statistics in genetic linkage studies of quantitative traits. We evaluated the bias and median squared error of estimates of the linked additive genetic variance obtained by regression, maximum likelihood and quasilikelihood estimation procedures. The quasilikelihood and regression procedures provided unbiased estimates of the additive component of variance. Maximum likelihood procedures that assumed multivariate normality were biased for most sample sizes considered but had more precision for most generating models than regression or quasilikelihood methods did. Wald tests derived from quasilikelihood procedures had similar or greater power than Wald tests based upon estimators from maximum likelihood analyses. Quasilikelihood estimation may therefore be preferable whenever there is uncertainty about the generating distribution for the error variance, but the robustness of this approach is offset by its required computational complexity.
Determining approximate estimates of inheritance parameters from sib‐pair IBD proportions
Authors: GREEN J. R. , SHAH S.
Published: September 2007

The use of IBD proportions from a large set of affected sib‐pair data to estimate some or all of the main parameters describing the inheritance of a disease susceptibility gene is here considered. We assume there is no recombination present and neglect ascertainment bias, and assume that there are four distinct parental haplotypes present in each family.
Phylogenetic analysis of mtDNA lineages in South American mummies
Authors: MONSALVE M. V. , CARDENAS F. , GUHL F. , DELANEY A. D. , DEVINE D. V.
Published: September 2007

Some studies of mtDNA propose that contemporary Amerindians have descended from four haplotype groups, each defined by specific sets of polymorphisms. One recent study also found evidence of other potential founder haplotypes. We wanted to determine whether the four haplotypes in modern populations were also present in ancient South American aboriginals. We subjected mtDNA from Colombian mummies (470 to 1849 AD) to PCR amplification and restriction endonuclease analysis. The mtDNA D‐loop region was surveyed for sequence variation by restriction analysis and a segment of this region was sequenced for each mummy to characterize the haplotypes. Our mummies exhibited three of the four major characteristic haplotypes of Amerindian populations denned by four markers. With sequence data obtained in the ancient samples and published data on contemporary Amerindians it was possible to infer the origin of these six mummies.
Genetic diversity in the Iberian Peninsula determined from mitochondrial sequence analysis
Authors: CÔRTE‐REAL H. B. S. M. , MACAULAY V. A. , RICHARDS M. B. , HARITI G. , ISSAD M. S. , CAMBON‐THOMSEN A. , PAPIHA S. , BERTRANPETIT J. , SYKES B. C.
Published: September 2007

We have analysed 302 bp of the first hypervariable region of the mitochondrial D‐loop in 271 individuals from different regions of the Iberian Peninsula and 85 individuals from Algeria. The Basque population is significantly different from neighbouring populations in terms of overall levels of diversity. This is because the majority of sequences in the Basques are restricted to the lineage group defined by the CRS (Cambridge Reference Sequence) and its derivatives although, like other Iberian populations, they showed a unimodal distribution of pairwise sequence differences. The timing of divergence of populations within Iberia points to a shared ancestry of all populations in the Upper Palaeolithic. Further genetic subdivision is apparent in Catalonia and Andalusia, with increased genetic diversity in the latter. Lineage diversity comparisons of Iberian populations with European (Tuscan) and North African (Algerian) populations shows the Iberian Peninsula to be more similar to other European populations, although a small number of Iberian lineages can be traced to North Africa.
European Gene Mapping Project (EUROGEM): Breakpoint panels for human chromosomes based on the CEPH reference families
Authors: COX S. A. , ATTWOOD J. , BRYANT S. P. , BAINS R. , POVEY S. , REBELLO M. , KAPSETAKI M. , MOSCHONAS N. K. , GRZESCHIK K.‐H. , OTTO M. , DIXON M. , SUDWORTH H. E. , KOOY R. F. , WRIGHT A. , TEAGUE P. , TERRENATO L. , VERGNAUD G. , MONFOUILLOUX S. , WEISSENBACH J. , ALIBERT O. , DIB C. , FAURÉ S. , BARKER E. , PEARSON N. M. , VOSSEN R. H. A. M. , GAL A. , MUELLER‐MYHSOK B. , CANN H. M. , SPURR N. K.
Published: September 2007

Meiotic breakpoint panels for human chromosomes 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 17, 18, 20 and X were constructed from genotypes from the CEPH reference families. Each recombinant chromosome included has a breakpoint well‐supported with reference to defined quantitative criteria. The panels were constructed at both a low‐ resolution, useful for a first‐pass localization, and high‐resolution, for a more precise placement. The availability of such panels will reduce the number of genotyping experiments necessary to order new polymorphisms with respect to existing genetic markers. This paper shows only a representative sample of the breakpoints detected. The complete data are available on the World Wide Web URL (http:www.icnet.ukaxphgreurogemHTMLdata.html) or by anonymous ftp (ftp.gene.ucl.ac.uk inpubeurogemmapsbreakpoints).
CROSSFIND: Software for detecting and displaying well‐characterised meiotic breakpoints in human family data
Authors: ATTWOOD J. , POVEY S.
Published: September 2007

An algorithm for detecting well‐characterised breakpoints in human family data has been developed and implemented as a computer program. The well‐established program CRI‐Map is used to perform the necessary likelihood analysis and generate the individual chromosomes, and then a set of user‐defined parameters is used to detect the breakpoints, sort them by their position and classify them according to their support. A further program produces PostScript figures giving a visual representation of the breakpoints. The programs can be applied to data from human chromosomes, and the resulting breakpoint panels used to place new markers rapidly on to the map by typing only a few key individuals and their ancestors. A service has been established on the World Wide Web for chromosome 9, allowing workers to fill in an on‐line form requesting a suitable panel of breakpoints to facilitate the mapping of new markers. A key feature of this approach is that all of the computing is done whilst detecting the breakpoints, after which new markers can be positioned without any need for a computer. CROSSFIND has been used to generate all the meiotic breakpoint panels shown in the preceding paper by members of the Eurogem Collaboration (Cox et al 1996)
Chlorpromazine and Dithioerythritol Protection against Acute Ethanol Toxicity
Authors: Gailis L. , Tourigny A.
Published: September 2007

Our previous work has shown that an increase in body temperature increases the acute toxicity of ethanol in mice. To determine whether a decrease in body temperature would have the opposite effect, we studied the effect of two substances that decrease body temperature (chlorpromazine (CPZ) and dithioerythrrtol (DTE)) on ethanol toxicity. Matched groups of 10 mice were injected sc with CPZ (5 mg/kg), DTE (80 mg/kg), or saline (controls). CPZ and DTE significantly depressed the rectal temperature to 32.8 and 34.5°C, respectively. One hour later, all three groups received a specified dose of ethanol (6.5‐10.7 g/kg, 24% w/v, intraperitoneal). The experiment was repeated 17 times at different ethanol doses. The pretreatments increased the 1 hr LDM from 7.8 ±0.1 g/kg for the controls to 8.6 ± 0.2 g/kg (DTE) and 10.0 ± 0.3 g/kg (CPZ) (p < 0.001). The protective effect of CPZ was maximal around 5 mg/kg, and less at both lower and higher CPZ doses. When the temperature drop was prevented by directly heating the mice, the protective effect of DTE could be eliminated, but the effect of CPZ was only partially prevented. Placing the CPZ‐treated mice in a warmer environment only produced a major reversal of CPZ protection when rectal temperature reached 38°C. In conclusion, CPZ and DTE both decrease body temperature and protect against acute ethanol toxicity. The protection seems to be due at least partially to the decrease in body temperature prior to ethanol injection.