bluuebunny/crossref_metadata_2025 huggingface dataset:
Carrier detection by microsatellite analysis of Duchenne/Becker muscular dystrophy in Hungarian families
Authors: BACHRATI C. Z. , SOMODI Z. , ENDREFFY E. , KALMÁR T. , RASKÓ I.
Published: March 2003

Duchenne and Becker muscular dystrophies are among the most severe and frequent inherited disorders. Being still incurable, medical treatment is concentrated on the carrier diagnosis of the members of the affected families. Here we report the results of the studies of 151 members of 41 Hungarian families, obtained with multiplex PCR amplification of 18 exons as well as the muscle specific promoter region, and haplotype analysis of two polymorphic (CA)n repeat microsatellite loci in introns 45 and 49 of the dystrophin gene. The analysis of 15 deletion‐type families revealed a frequency of new mutations not differing significantly from that in the other regions of Europe. We also compared the allele distributions of the two microsatellites in randomly selected normal individuals and affected family members. The allele distribution of STRP45 shows interesting differences between the two populations.
Genetic linkage analysis using lognormal variance components
Authors: WAN Y. , DE ANDRADE M. , YU L. , COHEN J. , AMOS C. I.
Published: March 2003

Typically genetic studies of continuous traits such as cholesterol levels or blood pressure assume that interindividual variability follows a normal distribution. Here we develop methods to analyze positively skewed data by assuming a lognormal distribution. We develop a variance components approach for identifying such effects from a major gene, residual polygenic factors and nongenetic factors. We compare by a simulation study results from fitting this lognormal model with either applying the log transformation or not transforming the data. We found that the lognormal model provided more precise estimates and more powerful tests than a simple log transformation when analyzing lognormally distributed data. Power varied with sibship size. For the same total number of nonindependent sibpairs, larger sibships were less powerful. However, larger sibships are more economical because they require a smaller sample size to obtain a specified power. To illustrate the application of this lognormal model to real data, we studied evidence for linkage between triglycerides and the lipoprotein lipase gene.
Mitochondrial DNA analysis of Northwest African populations reveals genetic exchanges with European, Near‐Eastern, and sub‐Saharan populations
Authors: RANDO J. C. , PINTO F. , GONZÁLEZ A. M. , HERNÁNDEZ M. , LARRUGA J. M. , CABRERA V. M. , BANDELT H.‐J.
Published: March 2003

Genetic studies have emphasized the contrast between North African and sub‐Saharan populations, but the particular affinities of the North African mtDNA pool to that of Europe, the Near East, and sub‐Saharan Africa have not previously been investigated. We have analysed 268 mtDNA control‐region sequences from various Northwest African populations including several Senegalese groups and compared these with the mtDNA database. We have identified a few mitochondrial motifs that are geographically specific and likely predate the distribution and diversification of modern language families in North and West Africa. A certain mtDNA motif (16172C, 16219G), previously found in Algerian Berbers at high frequency, is apparently omnipresent in Northwest Africa and may reflect regional continuity of more than 20000 years. The majority of the maternal ancestors of the Berbers must have come from Europe and the Near East since the Neolithic. The Mauritanians and West‐Saharans, in contrast, bear substantial though not dominant mtDNA affinity with sub‐Saharans.
Assignment of the human ARNO3 gene (PSCD3) to chromosome 7p21 by radiation hybrid mapping
Authors: KIM HEUI‐SOO
Published: March 2003

The chromosomal localization of the human ARNO3 gene (PSCD3) was determined using monochromosomal somatic cell hybrid and radiation hybrid mapping panel. PCR analysis of a hybrid DNA panel localized the ARNO3 gene to human chromosome 7. The analysis of the Genebridge4 radiation hybrid panel using PCR amplification located the ARNO3 gene between NIB1822 (9.5 cR) and D7S481 (5.5 cR) with a lod score of >3.0. This region is located in the human chromosome band 7p21.
Combined segregation and linkage analysis of nonsyndromic orofacial cleft in two candidate regions
Authors: SCAPOLI C. , COLLINS A. , MARTINELLI M. , PEZZETTI F. , SCAPOLI L. , TOGNON M.
Published: March 2003

We applied a complex segregation analysis to 46 pedigrees with a total of 121 nuclear families and 660 individuals, to verify hypotheses regarding the inheritance of OFC and linkage with markers on chromosomes 6 and 2. The pointer program for segregation analysis strongly rejected the hypothesis of no familial transmission of OFC in these families. When the hypothesis of a two‐locus model was tested with comds, the analysis showed the presence of at least two loci and the model assuming a dominant major gene and a recessive modifier locus was statistically accepted. Given the fitted two‐locus model, we tested for a possible linkage between the major OFC locus and the two markers studied. For D6S259, the estimate of the recombination fraction was θ=0.098, corresponding to a LOD score around 2.1. On the contrary, the data analysis concerning the D2S378 marker showed an estimate of the recombination fraction not significantly different from the independence hypothesis.
Relative efficiencies of the Chi‐square recombination models for gene mapping with human pedigree data
Authors: LIN S. , SPEED T. P.
Published: March 2003

In the paper by Goldstein et al. (Genomics, 1995), the authors carried out a simulation study to investigate the relative efficiencies of a no interference linkage analysis to an analysis with certain models that allow for interference. They showed that, for completely informative and independent recombination data, the analysis with the no interference model was inefficient, in the present of interference. In practice, the assumption of completely informative markers is unrealistic with data from human pedigrees. We report the results of a study investigating whether this conclusion still holds for gametes arising within pedigrees. We consider the same two mapping problems as Goldstein et al.: exclusion mapping and gene ordering. The results obtained were consistent with their findings, although the efficiency gains for analyses using the chi‐square model were not as great in some cases. This is not unexpected with less than fully informative data. These results point to the need for research of developing new statistical and computational methods to incorporate interference into multipoint linkage mapping using pedigree data. This would make efficient use of available, but sometimes scarce data, especially in disease gene mapping.
Identification and characterisation of polymorphisms in human phosphoglucomutase (PGM1)
Authors: YIP S. P. , PUTT W. , HOPKINSON D. A. , WHITEHOUSE D. B.
Published: March 2003

This study is part of our effort to map recombination hotspots in two regions (site A, 18 kb; site B, 40 kb) of the human phosphoglucomutase PGM1 gene. Twenty‐two PCR amplified fragments comprising six groups, covering about 5.2 kb, were screened for single nucleotide polymorphisms (SNPs) using non‐isotopic single stranded conformation polymorphism (SSCP) analysis. Fourteen fragments were variable and seven of these showed common polymorphism. Our strategy for screening for polymorphic sites in the PGM1 gene was based on the results of allelic association analysis between each new marker and the sites of the classical isozyme polymorphism (2/1 in exon 4 and +/− in exon 8). Samples from four populations (Caucasian, Chinese, Vietnamese and New Guinean) were typed for each of the seven polymorphic markers. Between two and four common alleles were found in each case, together with a few rare alleles. Co‐dominant inheritance patterns were demonstrated by family studies. The molecular basis of each new marker was determined by direct sequencing of the PCR products: most were SNPs except two that were small insertions/deletions. Direct sequence analysis of a 2.1 kb segment in sixteen individuals revealed no additional nucleotide variation indicating a very high level of efficiency of the SSCP screening method used in this study. The overall nucleotide diversity (θ) for PGM1 was estimated as 0.9×10−3based on 33 segregating sites in a sequence of 5187 nt and a sample size of 614 individuals.
Common HLA alleles, rather than rare mutants, confer susceptibility to coeliac disease
Authors: BRETT P. M. , YIANNAKOU J. Y. , MORRIS M‐A. , VAUGHAN R. , CURTIS D. , CICLITIRA P. J.
Published: March 2003

Coeliac Disease (CD) is a gluten sensitive enteropathy characterised by villous atrophy and crypt cell hyperplasia. It has a very strong HLA class II association to the DQ locus. The nature of the involvement of the DQ locus in the susceptibility to CD has been examined by tissue culture experiments, association and peptide binding studies. We examined the role of the DQ molecules in the pathogenesis from the perspective of a genetic family study. Using flanking microsatellite markers to the class II region of the MHC to establish the parental origin of the susceptibility DQ alleles, we have evidence suggesting that the HLA association is probably due to the necessity to have these DQ alleles in order to express CD and there is no support for the presence of a rare mutation within the DQ alleles nor any rare HLA‐linked gene nearby in linkage disequilibrium with the DQ locus. This approach is applicable to other diseases demonstrating strong association with common alleles, and can be used to predict whether screening the region for rare mutations is likely to be worthwhile.
Sequence variants in the 5′ flanking region of the leptin gene are associated with obesity in women
Authors: LI W.‐D. , REED D. R. , LEE J. H. , XU W. , KILKER R. L. , SODAM B. R. , ARLEN PRICE R.
Published: March 2003

Few mutations have been found in the human leptin gene and the relationship between leptin gene sequence variation and human overweight is uncertain. To determine whether sequence variation within the leptin gene and its regulatory elements contribute to extreme obesity, we screened ∼3 kb of the 5′ flanking region and the three exons in 125 unrelated extremely obese (BMI ≥ 40 kg/m2) and 86 average weight women (BMI < 27 kg/m2). Within the protein coding regions only one heterozygous silent mutation was found (codon 102; AAC/AAT). Within the 5′ flanking region, six frequent sequence variants were detected (q > 0.10), and the allele frequencies of three of these variants differed between obese and average weight Caucasian women (+19, χ2= 4.46, p= 0.035; −1823, χ2= 4.36, p= 0.037; −2548, χ2= 5.73, p= 0.017). Nine infrequent sequence variants were detected (q < 0.05) but they did not occur more often among obese women compared with those of average‐weight. For extremely obese women, three polymorphisms (+19, −188, and −633) predicted the degree of obesity. Allelic variants may influence the regulation of the leptin gene and thereby influence body weight, particularly among extremely obese women. However, given the low variability in coding regions and the high variability in the 5′ flanking region, discerning the functional significance of each variant is likely to be difficult.
Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele?
Authors: CORBO R. M. , SCACCHI R.
Published: March 2003

Apolipoprotein E (APOE = gene, apoE = protein) plays a central role in plasma lipoprotein metabolism and in lipid transport within tissues. The APOE shows a genetic polymorphism determined by three common alleles, APOE*2, APOE*3, APOE*4 and the product of the three alleles differs in several functional properties. APOE is involved in the development of certain pathological conditions. In particular, the APOE*4 allele is a risk factor for susceptibility to coronary artery disease (CAD) and Alzheimer's Disease (AD). In the present study we analyzed the APOE allele distribution in the world. The APOE*3 is the most frequent in all the human groups, especially in populations with a long‐established agricultural economy like those of the Mediterranean basin (0.849–0.898). The frequency of APOE*4, the ancestral allele, remains higher in populations like Pygmies (0.407) and Khoi San (0.370), aborigines of Malaysia (0.240) and Australia (0.260), Papuans (0.368), some Native Americans (0.280), and Lapps (0.310) where an economy of foraging still exists, or food supply is (or was until the recent past) scarce and sporadically available. The APOE*2frequency fluctuates with no apparent trend (0.145–0.02) and is absent in Native Americans. We suggest that the APOE*4, based on some functional properties it has and on its distribution among human populations, could be identified as a ‘thrifty’ allele. The exposure of APOE*4 to the contemporary environmental conditions (Western diet, longer lifespans) could have rendered it a susceptibility allele for CAD and AD. The absence of the association of APOE*4 with CAD and AD in Sub‐Saharan Africans, and its presence in African Americans, seems to confirm this hypothesis.
Haplotype analysis of three polymorphisms of the COL2A1 gene and associations with generalised radiological osteoarthritis
Authors: MEULENBELT I. , BIJKERK C. , De WILDT S. C. M. , MIEDEMA H. S. , BREEDVELD F. C. , POLS H. A. P. , HOFMAN A. , VAN DUIJN C. M. , SLAGBOOM P. E.
Published: March 2003

It was investigated whether radiographic osteoarthritis (ROA) is associated with specific haplotypes of the COL2A1 gene. Radiographs of knees, hips, hands, and spine were scored for the presence of ROA in subjects of 55–70 years from a population‐based cohort study, the Rotterdam study. Cases had ROA in 3 or more joint groups; controls, from the same population, had ROA in less than 3 joint groups. Allele frequencies of 3 dimorphisms (HaeIII, HindIII, MaeII) and a VNTR polymorphism of the COL2A1 gene were determined. The VNTR allele 14R2 and the HindIII polymorphism showed a significant association. Haplotype analysis of the HaeIII, HindIII and VNTR polymorphisms showed that a specific haplotype (1‐2‐14R2) is strongly associated with ROA in 3 or more joint groups (OR = 5.3, 95% CI 2.3–12.7). Our results suggest that a specific haplotype of the COL2A1 locus may predispose to generalised ROA.
Phylogeographic patterns of mtDNA reflecting the colonization of the Canary Islands
Authors: RANDO J. C. , CABRERA V. M. , LARRUGA J. M. , HERNÁNDEZ M. , GONZÁLEZ A. M. , PINTO F. , BANDELT H.‐J.
Published: March 2003

Although the Canary Islands were settled by humans, possibly of Berber origin, as late as 2500 years ago, the precise course and numbers of early migrations to the archipelago remain controversial. We have therefore analysed mtDNA variation (HVS‐I as well as selected RFLP sites) in 300 individuals from the seven Canary Islands. The distribution and variation across the islands in a specific mtDNA clade of Northwest African ancestry suggest that there was one dominant initial settlement process that affected all the islands, from east to west. This indicates that a certain genetic affinity of present‐day Canary Islanders to Northwest African Berbers mainly stems from the autochthonous population rather than slaves captured on the neighbouring African coast. The slave trade after the European conquest left measurable, though minor, traces in the mtDNA pool of the Canary Islands, which in its majority testifies to the European immigration.
Significance testing for direct identity‐by‐descent mapping
Authors: GRANT G. R. , MANDUCHI E. , CHEUNG V. G. , EWENS W. J.
Published: March 2003

Direct identity‐by‐descent mapping is a technique for narrowing down the location of the gene or genes responsible for a given genetic disease to small segments of the genome. The technique involves DNA comparisons between pairs of affected individuals. The data generated are in the form of matching segments of the genome, representing regions likely to be identical‐by‐descent (IBD). Regions in the genome over which there are significantly more segments aligned than is expected by chance are taken as candidate regions for the disease gene or genes. Due to the complex geometric nature of the data, significance testing involves certain mathematical difficulties. We present here a new method for measuring this significance. This method introduces a novel statistic and is appropriate whether or not the relationships between the paired individuals are known. We give examples that we have calculated by implementing this method, including an application to real data.
Analysis of lipoprotein lipase haplotypes reveals associations not apparent from analysis of the constituent loci
Authors: HALLMAN D. M. , GROENEMEIJER B. E. , JUKEMA J. W. , BOERWINKLE E. , KASTELEIN J. J. P.
Published: March 2003

Simultaneously analysing genotype effects at several closely‐linked loci may be preferable to analysing them separately, but can be difficult, due to multiple genotype classes, small class sizes, and non‐independence induced by associations among loci. Analysis of haplotype effects offers an alternative approach. We studied effects of haplotypes comprising 3 loci (5′ to 3′: PvuII, HindIII, and Ser447‐Stop) in the lipoprotein lipase (LPL) gene on plasma lipid levels and LPL activity, in 807 Dutch males with coronary atherosclerosis. We analysed haplotype effects in individuals for whom haplotypes could either be determined unequivocally or inferred with high probability, using contrasts suggested by likely evolutionary relationships among the haplotypes. One haplotype was associated with significantly higher total cholesterol, while another was associated with significantly lower triglyceride levels. Though these two haplotypes had generally opposite effects on lipids, both were associated with significantly higher LPL activity. In genotype analyses, the HindIII (−) allele was associated with higher LPL activity; however, one haplotype bearing it had no significant effect on LPL activity. Haplotypes thus provided more information than genotypes alone would have. The two haplotypes with consistently different effects on lipid levels despite similar effects on LPL activity, provide further evidence that aspects of LPL biology, apart from its catalytic function in lipolysis, may mediate its effects on plasma lipids at least in coronary artery disease patients.
Power of variance component linkage analysis to detect quantitative trait loci
Authors: WILLIAMS J. T. , BLANGERO J.
Published: March 2003

Expressions are derived for the sample size required to achieve a given power in variance component linkage analysis of a quantitative trait in unascertained samples. For simplicity an additive model, comprising effects due to a single QTL, residual additive genetic factors, and individual‐specific random environmental variation, is considered. Equations are given relating sample size to trait heritability for sibpairs, sib trios, nuclear families having two and three sibs, and arbitrary relative pairs. The effects of nonzero residual additive genetic variance and parental information are discussed, and a scale relationship for sample sizes with sibships and nuclear families is derived. For larger sampling structures such as extended pedigrees the inheritance space is randomly sampled and the relevant equations are solved numerically. Comparative power curves are presented for sibships of size 2–4 and for an extended pedigree of 48 individuals. Simulation results for sibpairs confirm the validity of the theoretical results.
Applications of the estimating equations theory to genetic epidemiology: a review
Authors: TREGOUET D. A. , TIRET L.
Published: March 2003

Unlike monogenic diseases for which considerable progress has been made in past years, the identification of susceptibility genes involved in multifactorial diseases still poses numerous challenges, including the development of new statistical methodologies. Recently, several authors have advocated the use of the estimating equations (EE) approach as an alternative to standard maximum likelihood methods for analysing correlated data. Since most genetic studies rely on family data, the EE found a natural field of application in genetic epidemiology. The objective of this review is to give a brief description of the EE principles, and to outline its applications in the main areas of genetic epidemiology, including familial aggregation analysis, segregation analysis, linkage analysis and association studies.
A two‐locus model for non‐syndromic congenital dysplasia of the hip (CDH)
Authors: SOLLAZZO V. , BERTOLANI G. , CALZOLARI E. , ATTI G. , SCAPOLI C.
Published: March 2003

Complex segregation analysis was conducted in a sample of 171 pedigrees collected through probands affected by non‐syndromic dysplasia of the hip (CDH) treated in Ferrara's CDH Centre in the period 1991–6. The analysis favoured a two‐locus model, in which the accepted segregation model at the major locus was compatible with recessive transmission, with a gene frequency of the deleterious allele of around 0.20. For the other locus, among the Mendelian hypotheses tested, the recessive model turned out to be the most parsimonious. When ultrasonographic level was examined as an indication of severity, a significant improvement in the fit of the model was observed, giving clear evidence that information on the severity of CDH is important for a better definition of the hereditary transmission model.
Probable ancestors of Hungarian ethnic groups: an admixture analysis
Authors: GUGLIELMINO C. R. , DE SILVESTRI A. , BERES J.
Published: March 2003

The history of Hungary starts in the 9th century with the arrival of the Magyars in the Carpathian Basin. They spoke, like modern Hungarians, an Uralic language belonging to the Finno‐Ugric language group. Their original composition probably included Iranian and Turkish people, while other populations were already present in the territory (Avars, Slavs, Germans). Some of the Hungarian ethnic groups claim to be descendants of ancient Magyars settlers (such as the Örség), others of Huns, Turks or Iranians. We collected and compared the previously published gene frequencies of eight ethnic groups and seven hypothetical ancestral populations, including Uralics, applying a model of admixture. The results, most of which confirm historical hypotheses or the oral tradition, show that only one ethnic group (Örség) highly resembles the Uralic population.
Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African‐American populations
Authors: McKEIGUE P. M. , CARPENTER J. R. , PARRA E. J. , SHRIVER M. D.
Published: March 2003

We describe a novel method for analysis of marker genotype data from admixed populations, based on a hybrid of Bayesian and frequentist approaches in which the posterior distribution is generated by Markov chain simulation and score tests are obtained from the missing‐data likelihood. We analysed data on unrelated individuals from eight African‐American populations, genotyped at ten marker loci of which two (FY and AT3) are linked (22 cM apart). Linkage between these two loci was detected by testing for association of ancestry conditional on parental admixture. The strength of this association was consistent with European gene flow into the African‐American population between five and nine generations ago. To mimic the mapping of an unknown gene in an ‘affecteds‐ only’ analysis, a binary trait was constructed from the genotype at the AT3 locus and a score test was shown to detect linkage of this ‘trait’ with the FY locus. Mis‐specification of the ancestry‐specific allele frequencies – the probabilities of each allelic state given the ancestry of the allele – was detected at three of the ten marker loci. The methods described here have wide application to the analysis of data from admixed populations, allowing the effects of linkage and population structure (variation of admixture between individuals) to be distinguished. With more markers and a more complex statistical model, genes underlying ethnic differences in disease risk could be mapped by this approach.
Fine scale association mapping of disease loci using simplex families
Authors: MORRIS A. P. , WHITTAKER J. C.
Published: March 2003

We present a new method for the fine scale mapping of disease loci based on samples of simplex families, each containing an affected child. The method is based on a generalisation of a single locus allele transmission model to multiple marker loci. The model is developed under the assumption of a single ancestral mutation and allows for the calculation of posterior probabilities that each allele at a particular marker was present on the founder chromosome. We illustrate the method using simulated family data for cystic fibrosis and Huntingtons disease, for which the locations of mutations in the disease genes are now known. For both diseases, our new method provides good estimates of the location of the mutations.
A review of Dysgenics: Genetic Deterioration in Modern Populations
Authors: HAMILTON W. D.
Published: March 2003

Editorial Note

This book review arrived here at the beginning of this year with a very apologetic note from the author, Bill Hamilton, about the long delay in producing the review and its ‘rambling essay format’. Sadly, Hamilton died just a few weeks later from complications following malarial infection. Several tributes have been published, such as Science (2000), 287, 2438, and we continue the tributes with a final unedited manuscript from the hand of this unique, colourful and idiosyncratic evolutionary theorist.

Dysgenics: Genetic Deterioration in Modern Populations. Human Evolution, Behaviour, and Intelligence Series. By R. Lynn (Series Editor: S. Itzkoff). Westport, Connecticut and London: Praeger. 1996. Pp. 237. £47.50 (hardback).

In a sense a dominance hierarchy has only one satisfied individual – she or he at the top. If the hierarchy is bottom‐numerous rather than linear, as is the case with most human hierarchies, it is all the more true that the vast majority of people are dissatisfied, wishing they were higher up, a thought which provides a basic reason why democracies (and especially, within democracies, such institutions as their state school systems) have to be unstable. We see a wobbly pyramid, and particularly within that pyramid we see certain side stairs all human examples have by which demagogues skip up a level or two so as to shout down to the restless base that the whole structure is somehow ‘wrong’. Under a different system, the demagogue shouts, ‘You could be higher too’.
The use of long PCR to confirm three common alleles at the CYP2A6 locus and the relationship between genotype and smoking habit
Authors: GU D. F. , HINKS L. J. , MORTON N. E. , DAY I. N. M.
Published: March 2003

Long PCR followed by nested PCR has previously been used to determine CYP2A6 160H alleles, but the method proved unreliable. We have optimized this approach in a DNA bank of 1032 subjects (age range 59–74 years) to give reliable results, yielding indirect molecular evidence and very strong statistical evidence of hitherto unrecognized common alleles (designated O) recalcitrant to the long PCR. Coding three alleles (160L, 160H and O) and an approach to association analysis originally developed to deal with null alleles implicit in ABO blood group phenotyping, the contribution of 160H (functionally null) to reduced smoking habit has been clearly measured for the first time, unconfounded by alleles null to the long PCR. The most significant findings (p < 0.01) are that the possession of a 160H allele, compared with not possessing a 160H allele, is associated with a mean age of starting regular smoking 3 years later (95% CI±1.93 years, average start age 20–21 years rather than 17–18 years); and that the average likelihood of quitting smoking at any time is 1.75 fold (95% CI. 1.17–2.61) for those possessing an 160H allele compared with those who have no 160H allele. This suggests that a smoking subject with a genotype predicted to confer 50% of the ability to eliminate nicotine via the CYP2A6 pathway has almost twice the likelihood of quitting smoking.
Association of the G‐2548A polymorphism in the 5′ region of the LEP gene with overweight
Authors: MAMMÈS O. , BETOULLE D. , AUBERT R. , HERBETH B. , SIEST G. , FUMERON F.
Published: March 2003

Mutations in the translated part of the leptin gene (LEP) have been found in only two families. Nevertheless DNA polymorphisms in the LEP region are linked to extreme obesity. We previously found in the 5′ region of LEP a polymorphism, G‐2548A, associated with a difference in BMI reduction following a low calorie diet in overweight women. Recently, this polymorphism was associated with extreme obesity in women. In this work, we genotyped a new sample from the general population including 314 normal weight (BMI < 27 kg/m2) and 109 overweight subjects (BMI ≥ 27 kg/m2). The genotype and allele frequencies were significantly different between groups, with the G‐2548 allele being more frequent in the overweight subjects (p < 0.01). In men, carriers of this allele had lower leptin concentrations adjusted for fat mass (p= 0.05). Our results indicate that variations at the leptin locus are associated with common obesity phenotypes, and not only with extreme obesity or the rare mendelian obesity syndromes.
A genome‐wide family‐based linkage study of coeliac disease
Authors: KING A. L. , YIANNAKOU J. Y. , BRETT P. M. , CURTIS D. , MORRIS M.‐A. , DEARLOVE A. M. , RHODES M. , ROSEN‐BRONSON S. , MATHEW C. , ELLIS H. J. , CICLITIRA P. J.
Published: March 2003

The susceptibility to develop coeliac disease (CD) has a strong genetic component, which is not entirely explained by HLA associations. Two previous genome wide linkage studies have been performed to identify additional loci outside this region. These studies both used a sib‐pair design and produced conflicting results.

Our aim is to identify non‐MHC genetic loci contributing to coeliac disease using a family based linkage study. We performed a genome wide search in 16 highly informative multiply affected pedigrees using 400 microsatellite markers with an average spacing of 10 cM. Linkage analysis was performed using lod score and model free methods.

We identified two new potential susceptibility loci with lod scores of 1.9, at 10q23.1, and 16q23.3. Significant, but lower lod scores were found for 6q14 (1.2), 11p11 (1.5), and 19q13.4 (0.9), areas implicated in a previous genome wide study. Lod scores of 0.9 were obtained for both D7S507, which lies 1 cM from the γT‐cell receptor gene, and for D2S364, which lies 12 cM from the CTLA4 gene.
Diversity of mtDNA lineages in Portugal: not a genetic edge of European variation
Authors: PEREIRA L. , PRATA M. J. , AMORIM A.
Published: March 2003

The analysis of the hypervariable regions I and II of mitochondrial DNA in Portugal showed that this Iberian population presents a higher level of diversity than some neighbouring populations. The classification of the different sequences into haplogroups revealed the presence of all the most important European haplogroups, including those that expanded through Europe in the Palaeolithic, and those whose expansion has occurred during the Neolithic. Additionally a rather distinct African influence was detected in this Portuguese survey, as signalled by the distributions of haplogroups U6 and L, present at higher frequencies than those usually reported in Iberian populations. The geographical distributions of both haplogroups were quite different, with U6 being restricted to North Portugal whereas L was widespread all over the country. This seems to point to different population movements as the main contributors for the two haplogroup introductions. We hypothesise that the recent Black African slave trade could have been the mediator of most of the L sequence inputs, while the population movement associated with the Muslim rule of Iberia has predominantly introduced U6 lineages.
Haplotype analysis of the human α2‐HS glycoprotein (fetuin) gene
Authors: OSAWA M. , YUASA I. , KITANO T. , HENKE J. , KANEKO M. , UDONO T. , SAITOU N , UMETSU K.
Published: March 2003

Alpha2‐HS glycoprotein (AHSG), which is equivalent to fetuin in other species, is a protein found in human plasma. AHSG is polymorphic with two common alleles and many variants. To examine the intragenic haplotypes and their diversity at this locus, a contiguous genomic DNA sequence (10·3 kb) was analyzed in 20 samples (40 chromosomes), and haplotypes were determined for 309 subjects. Judging from the aligned nucleotide sequences and the conserved amino acid residues comparing human and chimpanzee AHSG, it was concluded that the type 1 allele is probably older and has evolved into four major suballeles. The type 2 allele was generated from one branch of the type 1 allele. AHSG*3 and *5 variants were each found to have a single nucleotide change in exon 7, resulting in the change of an amino acid residue from Arg299 to Cys and from Asp258 to Asn, respectively. It was noted that the AHSG*3 mutation gives rise to an additional cysteine residue, which possibly affects the conformation of the protein. The AHSG gene was found to have a low mutation rate and no apparent recombination events. Furthermore, the detected substitutions were nonhomogeneously distributed at this locus. In particular, four nonsynonymous substitutions were concentrated in the carboxyl‐terminal domain.
Use of an artificial neural network to detect association between a disease and multiple marker genotypes
Authors: CURTIS D. , NORTH B. V. , SHAM P. C.
Published: March 2003

Single nucleotide polymorphisms (SNPs) are very common throughout the genome and hence are potentially valuable for mapping disease susceptibility loci by detecting association between SNP markers and disease. However as SNPs are biallelic they may have relatively little power in association studies compared with the information that would be obtainable if marker haplotypes were available and could be used efficiently. Modelling the evolutionary events leading to linkage disequilibrium is very complex and many methods that seek to use information from multiple markers simultaneously need to make simplifying assumptions and may only be applicable when marker haplotypes, rather than genotypes, are available for analysis. We explore the properties of a simple application of a standard artificial neural network to this problem. The pattern‐recognition properties of the network are used in the hope that marker haplotypes implicit in the genotypes will differ between cases and controls in a way which will lead to the network being able to classify the subjects correctly, according to their marker genotype. This method makes no assumptions at all regarding population history or the marker map, and can be applied to genotypes, as would be available from a simple case‐control sample, without any need to determine haplotypes. Through application to data simulated under a very wide range of assumptions we show that such an analysis produces a useful augmentation in power above that which would be achieved by testing each marker individually, in particular when more than one mutation has occurred in a disease gene at different points in evolution. The application of neural networks to such problems shows considerable promise and further work could usefully be directed towards optimising the design and implementation of such networks.
Distribution of FMR1 and FMR2 alleles in Javanese individuals with developmental disability and confirmation of a specific AGG‐interruption pattern in Asian populations
Authors: FARADZ SULTANA M. H. , LEGGO J. , MURRAY A. , LAM‐PO‐TANG P. R. L. , BUCKLEY M. F. , HOLDEN J. J. A.
Published: March 2003

The number of trinucleotide repeats in the 5′ untranslated regions of the FMR1 and FMR2 genes was determined by PCR in 254 Fragile XA‐negative Javanese male children with developmental disabilities. The distribution of FMR1 and FMR2 trinucleotide repeat alleles was found to be significantly different in the Indonesian population with developmental disability compared to that in developmentally disabled populations in North America and Europe (p < 0.021). Sequence analysis was performed on the trinucleotide repeat arrays of the 27 individuals with FMR1 alleles in the ‘grey zone’ (35–54 repeats). A repeat array structure of 9A9A6A9 was found in 16 unrelated individuals with 36 repeats, confirming earlier observations in intellectually normal Japanese. We propose that this FMR1 array pattern is specific for Asian populations and that Javanese and Japanese populations arose from a single progenitor population.
Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study
Authors: SWERDLOW A. J. , HERMON C. , JACOBS P. A. , ALBERMAN E. , BERAL V. , DAKER M. , FORDYCE A. , YOUINGS S.
Published: March 2003

Mortality and cancer incidence were assessed in a cohort of 1373 patients with numerical sex chromosome abnormalities diagnosed at three cytogenetics centres in Britain during 1959–90, and were compared with expectations from national rates. Four hundred patients with Turner's syndrome were followed, of whom 62 died, with a relative risk (RR) of death of 4.16 (95% confidence interval (CI) 3.22–5.39). Turner's syndrome patients had greatly raised risks of death from diseases of the nervous, cardiovascular, respiratory, digestive and genitourinary systems. One hundred and sixty three deaths occurred among 646 patients with Klinefelter's syndrome with a 47,XXY constitution, giving an RR of 1.63 (1.40–1.91). Mortality in these patients was significantly raised from diabetes and diseases of the cardiovascular, respiratory and digestive systems. There was also significantly increased mortality for patients with X polysomy (RR = 2.11 (1.43–3.02)) and Y polysomy (RR = 1.90 (1.20–2.85)), the former with significantly increased mortality from cardiovascular disease and the latter from respiratory disease. The only significantly raised risks of cancer incidence or mortality in the cohort were for lung cancer and breast cancer in patients with Klinefelter's syndrome with a 47,XXY constitution, and non‐Hodgkin's lymphoma in men with more than three sex chromosomes.
Physical mapping: integrating computational and molecular genetic data
Authors: LE HELLARD S. , SEMPLE C. A. M. , MORRIS S. W. , PORTEOUS D. J. , EVANS K. L.
Published: March 2003

A crucial step beyond the identification of genetic linkage of a disease to a chromosomal region is the production of a physical map that will allow the identification of candidate genes. Although the process of physical map building has been facilitated by the flow of data released by the Human Genome Project, gathering all the information together requires significant effort. In a previous study, we reported linkage between Bipolar Affective Disorder and the chromosomal location 4p15.3–p16.1. In this review we use this example to describe how to collect publicly available sequence, DNA fingerprint, and genetic marker data and integrate these with empirical data to build a large scale high resolution physical map of a region. Methods used to identify new genetic markers and candidate genes within a circumscribed region are also presented.
Y chromosome microsatellite variation in three populations of Jerba Island (Tunisia)
Authors: KHODJET EL KHIL H. , TRIKI MARRAKCHI R. , YACOUBI LOUESLATI B. , LANGANEY A. , FELLOUS M. , BENAMMAR ELGAAIED A.
Published: March 2003

Six Y‐chromosome linked microsatellites were typed in a sample of 135 unrelated males representing three different ethnic groups: Arabs, Berbers and Blacks of Jerba Island (Tunisia). Analysis of variation at the six Y chromosome STRs showed significant differences in allele distributions between the Black group and the two other Islander groups. The Black group revealed the highest level of genetic diversity as compared to Arabs and Berbers, while the latter group was the most homogenous. Allele frequencies obtained for the three islander groups analysed were compared to data available for some European, Mediterranean and African populations. Principal‐coordinate analyses showed genetic differentiation between the three geographically closed groups of Jerba. The absence of the YAP insertion marker and the position of Arabs and Jerban Blacks near the European cluster would suggest their relative ‘admixture’ with European populations.
LOD score exclusion analyses for candidate genes using random population samples
Authors: DENG H.‐W. , LI J. , RECKER R. R.
Published: March 2003

While extensive analyses have been conducted to test for, no formal analyses have been conducted to test against, the importance of candidate genes with random population samples. We develop a LOD score approach for exclusion analyses of candidate genes with random population samples. Under this approach, specific genetic effects and inheritance models at candidate genes can be analysed and if a LOD score is ≤− 2.0, the locus can be excluded from having an effect larger than that specified. Computer simulations show that, with sample sizes often employed in association studies, this approach has high power to exclude a gene from having moderate genetic effects. In contrast to regular association analyses, population admixture will not affect the robustness of our analyses; in fact, it renders our analyses more conservative and thus any significant exclusion result is robust. Our exclusion analysis complements association analysis for candidate genes in random population samples and is parallel to the exclusion mapping analyses that may be conducted in linkage analyses with pedigrees or relative pairs. The usefulness of the approach is demonstrated by an application to test the importance of vitamin D receptor and estrogen receptor genes underlying the differential risk to osteoporotic fractures.
A multistep process for the dispersal of a Y chromosomal lineage in the Mediterranean area
Authors: MALASPINA P. , TSOPANOMICHALOU M. , DUMAN T. , STEFAN M. , SILVESTRI A. , RINALDI B. , GARCIA O. , GIPARAKI M. , PLATA E. , KOZLOV A. I. , BARBUJANI G. , VERNESI C. , PAPOLA F. , CIAVARELLA G. , KOVATCHEV D. , KERIMOVA M. G. , ANAGNOU N. , GAVRILA L. , VENEZIANO L. , AKAR N. , LOUTRADIS A. , MICHALODIMITRAKIS E. N. , TERRENATO L. , NOVELLETTO A.
Published: March 2003

In this work we focus on a microsatellite‐defined Y‐chromosomal lineage (network 1.2) identified by us and reported in previous studies, whose geographic distribution and antiquity appear to be compatible with the Neolithic spread of farmers. Here, we set network 1.2 in the Y‐chromosomal phylogenetic tree, date it with respect to other lineages associated with the same movements by other authors, examine its diversity by means of tri‐ and tetranucleotide loci and discuss the implications in reconstructing the spread of this group of chromosomes in the Mediterranean area. Our results define a tripartite phylogeny within HG 9 (Rosser et al. 2000), with the deepest branching defined by alleles T (Haplogroup Eu10) or G (Haplogroup Eu9) at M172 (Semino et al. 2000), and a subsequent branching within Eu9 defined by network 1.2. Population distributions of HG 9 and network 1.2 show that their occurrence in the surveyed area is not due to the spread of people from a single parental population but, rather, to a process punctuated by at least two phases. Our data identify the wide area of the Balkans, Aegean and Anatolia as the possible homeland harbouring the largest variation within network 1.2. The use of recently proposed tests based on the stepwise mutation model suggests that its spread was associated to a population expansion, with a high rate of male gene flow in the Turkish–Greek area.
Length variability and interspersion patterns of the HRAS1 minisatellite: a new approach for the reconstruction of human population relationships
Authors: VEGA A. , SALAS A. , COSTAS J. , BARROS F. , CARRACEDO A.
Published: March 2003

During recent years the HRAS1 minisatellite has been analysed by several authors because of its putative association with cancer susceptibility. The aim of this report is to test the usefulness of this minisatellite in investigating human population relationships. We have studied 370 chromosomes from two well‐differentiated populations: Galicia (North‐west Iberia) and South‐east Africa, as well as available data on allele length gene frequencies. The fragment analysis results show a strong tendency to differentiate between non‐African and African populations. In spite of the usefulness of fragment analysis, the minisatellite variant repeat (MVR) approach of the HRAS1 minisatellite appears to be a more powerful method for use in human population studies, due to the high level of diversity of its interspersion pattern structures. In addition, this approach has allowed us to define some new structural characteristics of this minisatellite. Four different major groups of human HRAS1 minisatellite alleles could be distinguished following a structural criterion based on the MVR code. Furthermore, the characterisation of the HRAS1 minisatellite in chimpanzees revealed clear differences when compared to humans, not only with respect to the allele size but also to the internal structure.
Grade‐of‐membership sibpair linkage analysis maps IDDM11 to chromosome 14q24.3–q31
Authors: CORDER E. H. , WOODBURY M. A. , MANTON K. G. , FIELD L. L.
Published: March 2003

We demonstrate the use of Grade‐of‐membership (GoM) (Manton et al. 1994) for sibpair linkage analysis: GoM was used to map the IDDM11 locus to the region of chromosome 14q24.3 identified by Field et al. (1996). Haplotype groups were constructed from sib pair information on the number of shared alleles. The sample consisted of 578 sibling pairs found in 246 multiplex IDDM families. Both siblings were diabetic in 53% of the pairs (AA). Pair members could share 0, 1 or 2 alleles IBS at each of eight linked marker loci spanning IDDM11. Three model‐based groups best represented the data on allele sharing: the groups corresponded to ‘No’, ‘One’ and ‘Two’ shared haplotypes for the region. Group ‘Two’ was larger (37% vs. 25%, p<0.0001) and more homogeneous (p<0.0001) than expected by chance consistent with the IDDM11 locus being a determinant of diabetes in multiplex families. Genetic linkage of IDDM to the region was demonstrated by a 19% increase in the proportion of AA pairs over the haplotype groups: ‘No’, 42%; ‘One’, 49%; ‘Two’, 61%, p= 0.0005, representing a 43% relative increase.
Sampling variance and distribution of the D′ measure of overall gametic disequilibrium between multiallelic loci
Authors: ZAPATA C. , CAROLLO C. , RODRIGUEZ S.
Published: March 2003

The development of the theory of estimation of gametic disequilibrium for multiallelic systems is particularly necessary, since a large number of the genetic markers available at present are highly polymorphic multiallelic systems. The D′ coefficient is one of the most commonly used measures of the extent of overall disequilibrium between all possible pairs of alleles at two multiallelic loci. Nevertheless, the sampling properties of this measure of overall disequilibrium, are to date, unknown. In this work, we have derived explicit expressions by large‐sample theory to compute the approximate sampling variance of D^′ between pairs of multiallelic loci, when samples of haplotypes are taken from populations. Formulae for calculating the asymptotic sampling variance were checked by Monte Carlo simulation. In addition, the magnitude of the sampling variance of D^′ was investigated under different scenarios of disequilibrium between multiallelic loci. Extensive simulations were also carried out for describing the sampling distribution of D^′, conditioned on the sample size, number of alleles and their frequencies, and disequilibrium components. It was found that the sampling distribution of D^′ generally approaches well the theoretical normal distribution for experimental sample sizes, particularly when loci have many alleles. Disequilibrium data between microsatellite loci of human chromosome 11p are used for illustration. These investigations increase substantially our knowledge about this widely used measure of overall disequilibrium, which is relevant to evaluate disequilibrium between multiallelic loci in populations.