bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of male‐specific inter‐population divergence in Europe, West Asia and North Africa
Authors: MALASPINA P. , CRUCIANI F. , SANTOLAMAZZA P. , TORRONI A. , PANGRAZIO A. , AKAR N. , BAKALLI V. , BRDICKA R. , JARUZELSKA J. , KOZLOV A. , MALYARCHUK B. , MEHDI S. Q. , MICHALODIMITRAKIS E. , VARESI L. , MEMMI M. M. , VONA G. , VILLEMS R. , PARIK J. , ROMANO V. , STEFAN M. , STENICO M. , TERRENATO L. , NOVELLETTO A. , SCOZZARI R.
Published: March 2003

We typed 1801 males from 55 locations for the Y‐specific binary markers YAP, DYZ3, SRY10831 and the (CA)n microsatellites YCAII and DYS413. Phylogenetic relationships of chromosomes with the same binary haplotype were condensed in seven large one‐step networks, which accounted for 95% of all chromosomes. Their coalescence ages were estimated based on microsatellite diversity. The three largest and oldest networks undergo sharp frequency changes in three areas. The more recent network 3.1A clearly discriminates between Western and Eastern European populations. Pairwise Fst showed an overall increment with increasing geographic distance but with a slope greatly reduced when compared to previous reports. By sectioning the entire data set according to geographic and linguistic criteria, we found higher Fst‐on‐distance slopes within Europe than in West Asia or across the two continents.
Evaluating linkage and linkage disequilibrium: use of excess sharing and transmission disequilibrium methods in affected sib pairs
Authors: WICKS J. , WILSON S. R.
Published: March 2003

Two popular and robust approaches to analysing affected sib pair (ASP) data for linkage are the traditional excess sharing methods and the transmission/disequilibrium test (TDT). Here we derive an overall test of linkage for multi‐allelic ASP marker data which comprises two component tests: one for excess sharing and one for transmission disequilibrium. This method has several advantages. Firstly the overall test of linkage is often more powerful than either of the two component tests. Secondly the method makes it possible to determine the contribution of linkage disequilibrium (LD), in addition to linkage, to an overall positive linkage result. This is useful because the presence of LD in addition to linkage may suggest that the marker locus is in very close proximity to a disease susceptibility gene. Thirdly the method provides estimates of the risk associated with transmission of the different marker alleles.
The triangle test statistic (TTS): a test of genetic homogeneity using departure from the triangle constraints in IBD distribution among affected sib‐pairs
Authors: DIZIER M. H. , QUESNEVILLE H. , PRUM B. , SELINGER‐LENEMAN H. , CLERGET‐DARPOUX F.
Published: March 2003

The proportions of affected sibs sharing 2, 1 or 0 identical by descent parental marker alleles have been shown to conform to the ‘triangle constraints’ (Suarez, 1978; Holmans, 1993). It has also been shown (Dudoit & Speed, 1999) that the constraints are verified provided certain assumptions hold. In this study we explore a realistic situation in which the constraints fail due to the presence of a factor in which the sibs differ, a factor on which penetrance depends. This factor may be a characteristic of the trait (severe vs. mild form), or the presence/absence of an associated trait or an environmental factor. We show that under such situations, using the triangle constraints may lead to important loss of power to detect linkage by the MLS test. We propose here an alternative approach in order to detect both linkage and heterogeneity.
On power and efficiency robust linkage tests for affected sibs
Authors: GASTWIRTH J. L. , FREIDLIN B.
Published: March 2003

For diseases that do not follow a clear Mendelian pattern of inheritance nonparametric tests applied to affected sibs have been shown to be robust to the inherent uncertainty about the precise underlying genetic model. It is known that the weights optimizing the power of tests using IBD alleles shared by affected sib pairs or triples depend on the underlying model. We show how efficiency robustness techniques, used in other areas of statistics, provide a systematic approach for constructing a robust linear combination of the statistics that are optimal for the individual members of a family of plausible genetic models. The method depends on the correlation matrix of the optimal tests as these correlations reflect how different the models are. When the minimal correlation is less than 0.5, an alternate robust procedure is proposed. The methods apply to combining data from sibships of different sizes.
Allelic association between the NRAMP1 gene and susceptibility to tuberculosis in Guinea–Conakry
Authors: CERVINO A. C. L. , LAKISS S. , SOW O. , HILL A. V. S.
Published: March 2003

Forty four families from Guinea–Conakry were analysed to test for association between NRAMP1 (Natural Resistance Associated Macrophage Protein 1) polymorphisms and tuberculosis. Each family included at least one affected sib and one parent. Healthy sibs were also analysed and on average the families included four members. A total of 160 individuals were included in the final dataset. The analysis of association was performed using an extended TDT test, TRANSMIT, to allow for missing information in the parental genotypes. Three polymorphisms in the NRAMP1 gene were typed: a microsatellite (CA) repeat, a 4 bp deletion in the 3′ untranslated region and a single nucleotide change in intron 4. The single base change in intron 4 was significantly associated (p= 0.036) with tuberculosis. Our results therefore confirm, using a family‐based approach on a newly studied population, the previously reported association between this polymorphism and tuberculosis in a population‐based study of West Africans.
Monte Carlo methods for linkage analysis of two‐locus disease models
Authors: LIN S.
Published: March 2003

Parametric linkage analysis of simultaneous mapping of the two disease loci of a qualitative trait governed by a two‐locus model has been shown to provide greater power in detecting linkage than standard lod‐score analysis that maps a single disease locus. Despite its great potential for power gains, two‐locus parametric analysis has not been used routinely in disease gene mapping, due to the computational intensity of currently available methods and programs. In this paper, we propose a Markov chain Monte Carlo (MCMC) method for performing lod‐score analysis of qualitative traits governed by two‐locus models. This method obtains lod‐score estimates that can be arbitrarily close to their corresponding exact values. The algorithm implementing this MCMC method is linear in the number of markers. This feature enables us to perform two‐locus analysis mapping each trait to a set of markers, instead of just to a single marker. We analyzed an alcohol dependence dataset composed of 105 pedigrees with various sizes and various degrees of missingness in the observed marker and disease data. The estimates from our MCMC procedure match up well with the lod scores from exact analysis, but it took much less time for the MCMC procedure to obtain the results. We also performed a simulation study to investigate power gains with additional markers. Our results indicate that an additional marker on each map can provide a great deal more information for linkage measured in terms of the magnitude of lod scores.
Should ambiguous trios for the TDT be discarded?
Authors: SHAM P. C. , ZHAO J. H. , WALDMAN I. , CURTIS D.
Published: March 2003

It is well known that the TDT proposed by Spielman et al. (1993) is potentially anti‐conservative if families with one missing parental genotype are included (Curtis & Sham, 1995). We now bring attention to another situation that could give rise to an inflated rate of false positive results. This occurs when families in which the affected offspring and both parents have the same heterozygous genotype are excluded. If the heterozygous genotype is denoted as AB, then it is clear that one parent must have transmitted allele A and the other allele B. The standard TDT procedure is to increment the counts for transmissions of both A and B by one. It may seem reasonable to disregard such trios because it is ambiguous which parent has transmitted which allele. Although the resulting test statistic would retain all the information concerning preferential transmission of alleles, it can be shown that referring it to a χ2 distribution would lead to an increased type I error rate (see Appendix A).
How selection shapes variation of the human major histocompatibility complex: a review
Authors: MEYER DIOGO , THOMSON GLENYS
Published: March 2003

The nature of polymorphism and molecular sequence variation in the genes of the human major histocompatibility complex (MHC) provides strong support for the idea that these genes are under selection. With the understanding that selection shapes MHC variation new questions have become the focus of study. What is the mode of selection that accounts for MHC polymorphism? Is variation maintained by pathogen pressure or by reproductive mechanisms? Discerning between these requires drawing on information from studies on association between HLA genes and infectious diseases, reproductive success and mating preferences relative to HLA genotypes, and theoretical studies that compare the outcomes of different selection regimes. The pattern that has emerged suggests that several types of selection are plausible for the maintenance of HLA polymorphism.
Existence of a genetic risk factor on chromosome 5q in Italian Coeliac Disease families
Authors: GRECO L. , BABRON M. C. , CORAZZA G. R. , PERCOPO S. , SICA R. , CLOT F. , FULCHIGNONI‐LATAUD M. C. , ZAVATTARI P. , MOMIGLIANO‐RICHIARDI P. , CASARI G. , GASPARINI P. , TOSI R. , MANTOVANI V. , DE VIRGILIIS S. , IACONO G. , D'ALFONSO A. , SELINGER‐LENEMAN H. , LEMAINQUE A. , SERRE J. L. , CLERGET‐DARPOUX F.
Published: March 2003

Coeliac disease (CD) is a malabsorptive disorder of the small intestine resulting from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the whole genetic susceptibility. Several regions of potential linkage on chromosomes 3q, 5q, 10q, 11q, 15q and 19q have already been reported in the literature. These six regions were analyzed with the Maximum Lod Score method on a dense set of markers. A new sample of 89 Italian sibpairs was available for study. There was no evidence for linkage for any of the regions tested, except for chromosome 5q. For this region, our data, as well as a sample of 93 sibpairs from our first genome screen (Greco et al. 1998), are compatible with the presence of a risk factor for CD with a moderate effect.
The phylogeography of Y chromosome binary haplotypes and the origins of modern human populations
Authors: UNDERHILL P. A. , PASSARINO G. , LIN A. A. , SHEN P. , MIRAZÓN LAHR M. , FOLEY R. A. , OEFNER P. J. , CAVALLI‐SFORZA L. L.
Published: March 2003

Although molecular genetic evidence continues to accumulate that is consistent with a recent common African ancestry of modern humans, its ability to illuminate regional histories remains incomplete. A set of unique event polymorphisms associated with the non‐recombining portion of the Y‐chromosome (NRY) addresses this issue by providing evidence concerning successful migrations originating from Africa, which can be interpreted as subsequent colonizations, differentiations and migrations overlaid upon previous population ranges. A total of 205 markers identified by denaturing high performance liquid chromatography (DHPLC), together with 13 taken from the literature, were used to construct a parsimonious genealogy. Ancestral allelic states were deduced from orthologous great ape sequences. A total of 131 unique haplotypes were defined which trace the microevolutionary trajectory of global modern human genetic diversification. The genealogy provides a detailed phylogeographic portrait of contemporary global population structure that is emblematic of human origins, divergence and population history that is consistent with climatic, paleoanthropological and other genetic knowledge.
Genetic crossover interference in the human genome
Authors: LIN S. , CHENG R. , WRIGHT F. A.
Published: March 2003

Positive crossover interference refers to the phenomenon that the occurrence of a crossover reduces the probability of another crossover in its vicinity. There have been studies reporting the presence of positive interference in humans. Some studies have also found evidence suggesting within and between chromosomal interference heterogeneity on some of the chromosomes. However, there has been no systematic study of interference and interference heterogeneity in the whole human genome, using pedigree data without first inferring crossovers. In this paper, we studied the Chi‐square interference model and other models extensively to compare the relative performance of each of these models for accounting for interference and measuring strength of interference. Our results showed that the Chi‐square model consistently fitted the data well and provided easily interpretable estimates of interference strength. The Chi‐square model was then used to study interference and interference heterogeneity within and between chromosomes. We found strong evidence of positive interference in the whole human genome. Our results also indicated that the level of interference was fairly constant in most parts of the genome, but there was some evidence suggesting that the levels of interference for two of the chromosomes were different from the rest. We also found evidence of within chromosomal interference heterogeneity for several of the chromosomes.
Genetics of Parkinsonism: a review
Authors: VAUGHAN J. R. , DAVIS M. B. , WOOD N. W.
Published: March 2003

Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.
Mitochondrial DNA sequence diversity in two groups of Italian Veneto speakers from Veneto
Authors: MOGENTALE‐PROFIZI N. , CHOLLET L. , STÉVANOVITCH A. , DUBUT V. , POGGI C. , PRADIÉ M. P. , SPADONI J. L. , GILLES A. , BÉRAUD‐COLOMB E.
Published: March 2003

Although frequencies of mitochondrial DNA (mtDNA) haplogroups in the different European populations are rather homogenous, there are a few European populations or linguistic isolates that show different mtDNA haplogroup distributions; examples are the Saami and Ladin speakers from the eastern Italian Alps.

MtDNA sequence diversity was analysed from subjects from two villages in Veneto. The first, Posina, is situated in the Venetian Alps near Vicenza. The second, Barco di Pravisdomini is a village on the plains near Venice. In spite of their common Veneto dialect, the two group populations have not preserved a genetic homogeneity; particularly, they show differences in T and J haplogroups frequencies. MtDNA diversity in these two groups seems to depend more on their geographic situation.
A permutation procedure for the haplotype method for identification of disease‐predisposing variants
Authors: LI H.
Published: March 2003

Once a genetic region involved in a complex disease has been localized through linkage or association studies, we need methods to help us identify the actual disease predisposing genetic variant(s) in the region. A large number of single nucleotide polymorphic (SNP) sites may exist in this region. It is important to identify genetic variants directly involved in disease from those in linkage disequilibrium, and thus associated with, the disease predisposing variant(s). A question of great interest is to test whether a SNP, or a combination of SNPs, that influence the trait under investigation have been identified. For many complex HLA‐associated diseases, patterns of amino acid site variability raise the possibility that HLA‐variation association with a disease may not be due to a given allele but rather one or more variable amino acid sites occurring on several alleles. Here the question is whether an amino acid variant or a combination of amino acid variants involved in disease are identified. To address this question, this paper proposes a permutation procedure for the haplotype method, to test whether all the sites involved in the disease have been identified using the haplotypic data of patients and controls. The method is based on the theoretical result of Valdes and Thomson, that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease, but in linkage disequilibrium with the disease‐predisposing sites, are expected to be the same in patients and controls. This procedure takes into account the non‐independence of the sites sampled and is robust to mode of inheritance and penetrance of the disease, and can definitely specify when all the disease predisposing sites have not been identified. Application to both simulated data and real data sets on type 1 diabetes and alcoholism indicates that the proposed procedure works well in testing the important null hypothesis of whether all the predisposing sites are identified.
Comparison of statistical power between 2×2 allele frequency and allele positivity tables in case‐control studies of complex disease genes
Authors: OHASHI J. , YAMAMOTO S. , TSUCHIYA N. , HATTA Y. , KOMATA T. , MATSUSHITA M. , TOKUNAGA K.
Published: March 2003

In case‐control studies of complex disease genes, allele frequencies or allele positivities at candidate loci or markers are compared between cases and controls. Although 2 × 2 contingency tables based on allele frequency and allele positivity are generally used to perform simple statistical tests (e.g. a comparison of two proportions and a χ2 test), little is known about the difference in power between the two tables. In this study, we investigated the number of subjects required to obtain a power of 1 −β with a significance level of α for the allele frequency and allele positivity tables. A large difference in the required number of subjects was found between the two tables. Allele positivity tables were suitable for the detection of susceptibility alleles showing a dominant mode of inheritance (MOI). On the other hand, allele frequency tables were suitable for the identification of susceptibility alleles showing a recessive MOI or a multiplicative MOI. In the case of an additive MOI, a suitable table was determined by combining the frequency of the susceptibility allele and the penetrance. These results imply that there are cases in which true association is detected based on one contingency table and is not detected based on another. A simulation analysis revealed that the type I error rate was not much inflated under the null hypothesis of no association, even when a statistical test was performed twice using both allele frequency and allele positivity tables. In contrast, under the alternative hypothesis, the loss of power was marked when a test was performed once using an unsuitable table. In conclusion, statistical tests should be performed using both tables, without adjustment of multiplicity, in case‐control studies of complex disease genes when the study objective is exploratory.
Fine‐scale mapping using Hardy–Weinberg disequilibrium
Authors: JIANG R. , DONG J. , WANG D. , SUN F. Z.
Published: March 2003

Hardy–Weinberg disequilibrium (HWD) among affected individuals has recently been proposed for fine‐scale mapping of disease susceptibility genes. We investigate the statistical properties of several available HWD measures and develop a new HWD measure J for fine‐scale mapping. It is shown both theoretically and through simulations that the available HWD measures depend not only on the genetic distance between the marker locus of interest and the disease susceptibility locus, but also on the allele frequencies at the marker locus. On the contrary, the new measure is not affected by the allele frequencies at the marker locus under the following assumptions: (a) there is initial complete linkage disequilibrium between the marker and the disease loci, (b) there are no new mutations at the marker and the disease loci, and (c) the population under study is large. We develop a novel method to estimate the location of the disease susceptibility gene based on the HWD measure J. The estimator is robust to low mutation rates at the marker and the disease loci. We compare the standard error of the estimated disease gene loci using Pexcess for case‐control studies with the standard error using J for case‐only studies under various disease models. The newly developed method is successfully applied to a data set on hereditary haemochromatosis (HH).
HLA molecular markers in Tuvinians: a population with both Oriental and Caucasoid characteristics
Authors: MARTINEZ‐LASO J. , SARTAKOVA M. , ALLENDE L. , KONENKOV V. , MOSCOSO J. , SILVERA‐REDONDO C. , PACHO A. , TRAPAGA J. , GOMEZ‐CASADO E. , ARNAIZ‐VILLENA A.
Published: March 2003

HLA class I and class II alleles have been studied for the first time in the Turkish‐speaking Tuvinian population, which lives in Russia, North of Mongolia and close to the Altai mountains. Comparisons have been done with about 11000 chromosomes from other worldwide populations, and extended haplotypes, genetic distances, neighbor joining dendrograms and correspondence analyses have been calculated. Tuvinians show an admixture of Mongoloid and Caucasoid characters, the latter probably coming from the ancient Kyrgyz background or, less feasibly, more recent Russian Caucasoid admixture. However, Siberian population traits are not found and thus Tuvinians are closer to Central Asian populations. Siberians are more related to Na‐Dene and Eskimo American Indians; Amerindians (from nowadays Iberian–America) are not related to any other group, including Pacific Islanders, Siberians or other American Indians. The ‘more than one wave’ model for the peopling of the Americas is supported.
Molecular characterisation of four human Y‐specific microsatellites (DYS434, DYS437, DYS438, DYS439) for population and forensic studies
Authors: GUSMÃO L. , ALVES C. , AMORIM A.
Published: March 2003

In this work we present results on DYS434, DYS437, DYS438 and DYS439 loci studied in three population samples from North Portugal (N: 69), Macao (N: 59) and Mozambique (N: 64). Gene and haplotype diversity values are presented and compared. Gene diversity values ranged from 0.0290 to 0.0620 for DYS434; 0.0615 to 0.5959 for DYS437; 0.4906 to 0.6424 for DYS438; 0.5873 to 0.7038 for DYS439. The highest average gene diversity was found in Macao and the lowest in Mozambique. Haplotype diversity in North Portugal, Macao and Mozambique was calculated to be 0.925, 0.928 and 0.787, respectively.

Allele and haplotype frequency distributions for all markers were compared between the three populations. At the haplotype level all the differences between pairs of samples were significant. Sequencing analysis was performed for all alleles found in the four loci. Identical flanking sequences were observed with most of the alleles differing only by the repeat number. However, two variations were found in allele 10 of DYS438: one in a Macao sample presenting a TTTTA before the last TTTTC repetition and one in a Portuguese sample showing a base substitution (A/C) at position 7 downstream from the tandem repeat. A base substitution (C/T) at position 3 upstream from the repeat motif was also found in allele 14 of DYS437 in a sample from Mozambique.
Family‐based tests of association and/or linkage
Authors: WHITTAKER J. C. , MORRIS A. P.
Published: March 2003

The large literature on family‐based tests of association and/or linkage is reviewed, concentrating on the underlying principles and on recent methodological developments. We explain the distinction between testing for association and testing for linkage, and give our views on the circumstances in which each is the appropriate null hypothesis.
Polymorphism of the human ABO‐Secretor locus (FUT2) in four populations in Asia: indication of distinct Asian subpopulations
Authors: PANG H. , KODA Y. , SOEJIMA M. , FUJITANI N. , OGAKI T. , SAITO A. , KAWASAKI T. , KIMURA H.
Published: March 2003

The polymorphic alleles of the human ABO‐Secretor locus (FUT2 or Se) show high heterogeneity and overt ethnic specificity. To provide additional data for analysis to elucidate the origins of populations, we have investigated the allelic polymorphism of FUT2 in 40 unrelated Tibetan and 53 Tamang individuals from Nepal, 42 Indonesian individuals from Surabaya, and 55 Uygur individuals from Urumqi, using DNA sequencing. In Tibetan, Tamang and Indonesian populations, the frequency of a nonfunctional allele, se357,385, which is found only in Asian populations, was 0·638, 0·509 and 0·631, respectively. In Uygur, the se428, which is common in Caucasian populations, and the se357,385 consisting of two common nonfunctional FUT2 alleles, had frequencies of 0·3 and 0·145, respectively. The fixation index (FST) based on genetic differentiation was obtained pairwise among the four populations in this study and six populations in our previous studies. The results suggested that genetic differentiation among Tibetan, Tamang, Indonesian and East Asian populations is very low, while the distribution feature of the FUT2 alleles in the Uygur population implied an admixture of European with Asian. The distribution of nonfunctional alleles at the FUT2 locus provided further evidence of human migration among the Asian populations.
Estimate of the frequency of Wilson's disease in the US Caucasian population: a mutation analysis approach
Authors: OLIVAREZ L. , CAGGANA M. , PASS K. A. , FERGUSON P. , BREWER G. J.
Published: March 2003

The frequency of Wilson's disease in many populations is thought to be about one in 40000 persons, based on case and autopsy studies. Although the Wilson's disease gene has been identified, there is such a large number of mutations already known that it is not currently feasible to determine disease gene frequency by mutation analysis of a population. We have used a novel approach to obtain an estimate of the number of cases of Wilson's disease expected at birth in the US Caucasian population. We used data from four studies to determine that approximately one‐third of Wilson's disease mutations in US Caucasian Wilson's disease patients are due to His→Gln at the 1069 position. We then determined the frequency of this mutation in random DNA samples from 2601 US Caucasian newborns to be 0·285%. Multiplying by three gives an expected Wilson's disease heterozygote frequency of 0·855% and an allele frequency of 0·428%, or 0·00428. These data translate into a Wilson's disease frequency of about one in 55000 births. The 95% confidence interval is rather broad, ranging from about one in 18000 to one in 700000 births, but will be reduced as more data are added.
A novel method of two‐locus linkage analysis applied to a genome scan for late onset Alzheimer's disease
Authors: CURTIS D. , NORTH B. V. , SHAM P. C.
Published: March 2003

A number of methods have previously been described which carry out linkage analysis considering information for two or more loci simultaneously. Apart from some ad hoc methods such as analysing subsamples, these methods use information regarding linkage at all loci under consideration. However, if the actual genotype‐specific effects are known for some loci then it would be preferable to consider the genotypes of these loci directly, rather than the amount of allele‐sharing they demonstrate. Here we present an extension to our likelihood‐based method of model‐free linkage analysis as implemented in the MFLINK program. This allows the incorporation of liability classes. The genotypes of a locus known to affect risk can be used to assign subjects to liability classes prior to carrying out linkage tests at other loci. An example application is presented for genome scan data on Alzheimer's disease with analysis conditional on Apoliprotein E (APOE) genotypes. The results provide support for the existence of additional susceptibility loci linked to D10S1211 and to D12S358.
SNPs and snails and puppy dogs' tails: analysis of SNP haplotype data using the gamete competition model
Authors: SINSHEIMER J. S. , MCKENZIE C. A. , KEAVNEY B. , LANGE K.
Published: March 2003

The gamete competition model is a likelihood version of the transmission disequilibrium test (TDT) that is inspired by conditional logistic regression and the Bradley–Terry ranking procedure. In family‐based association studies, both the TDT and the gamete competition model apply directly to data on a single nucleotide polymorphism (SNP). Because any given SNP has limited polymorphism, it is tempting to collect several SNPs within a gene into a single super marker whose alleles are haplotypes. Unfortunately, this tactic wreaks havoc with the traditional TDT, which requires codominant markers (Spielman et al. 1993; Terwilliger & Ott, 1992). Eliminating phase ambiguities by assigning haplotypes to individuals before conducting the TDT may give misleading results because only the most probable haplotypes are then considered. Because pedigree implementations of the gamete competition model can accommodate dominant as well as codominant markers, they circumvent the phase problem by including all possible phases weighted by their estimated frequencies.
Sample size requirements to control for stochastic variation in magnitude and location of allele‐sharing linkage statistics in affected sibling pairs
Authors: CORDELL H. J.
Published: March 2003

Typically, genome scans for complex disease have produced linkage peaks which have proved difficult to replicate in additional independent studies. Here we confirm that this may be due to the large variance in magnitude and position of the linkage statistics when maximized across a region. Simulations suggest that for genes of moderate effect (locus‐specific sibling relative risks λsin the range 1.23–1.39), sample sizes of less than 500 affected sib pairs will give unacceptably large standard errors in the magnitudes and locations of significant linkage results. For genes of small effect (λs≤ 1.13), sample sizes in the region of 1000–2000 pairs may be required to achieve consistency of results between different studies. These figures have important implications for our confidence in location estimates for disease genes obtained from linkage studies of modest size. In particular, collection of larger data sets and/or analysis strategies such as conditioning or narrowing the phenotype definition, in order to increase the relative effect size, may be required before embarking on positional cloning.
Epistasis and its possible effects on transmission disequilibrium tests
Authors: WILSON S. R.
Published: March 2003

Most approaches to analysing complex genetic disorders are based on an underlying model that assumes that the probability of being affected is mainly due to the effect of a major, single disease locus. Where the penetrance (the conditional probability of being affected) is hypothesised to be influenced by known covariates, methods have been developed to accommodate these covariates appropriately in the analysis. Unexplained variation in the incomplete penetrance is then attributed to either unspecified environmental effects or to other genes of small effect that might act epistatically with the ‘disease gene’. Recently, there have been some proposals to incorporate two (or more) possibly epistatic identified loci as major effects in the analysis. However, the effect of two (or more) major epistatic disease genes on the analysis of data that assumes a single ‘disease gene’, and so ignores any other major gene, does not seem to have been explored. This investigation is undertaken here for triad data consisting of affected singletons and their parents. Following development of a quite general underlying genetic model, a global approach to analysing two marker loci for triad data is developed. This approach is the appropriate one for such data where two, possibly epistatic, loci have been identified a priori. The motivation for the development of this methodology is to evaluate the possible effect a second epistatic disease locus might be having on the results for triad data collected and analysed in different population studies, where the underlying analysis is based on an underlying major, single disease locus model. It is shown that, dependent on the population parameters associated with the other unidentified major disease gene, results concerning the single ‘disease gene’ can vary markedly. So, finding that conclusions differ from study to study may be indicative of the ‘disease gene’ under investigation acting epistatically with other major disease genes.
Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease
Authors: POPAT S. , HEARLE N. , HOGBERG L. , BRAEGGER C. P. , O'DONOGHUE D. , FALTH‐MAGNUSSON K. , HOLMES G. K. T. , HOWDLE P. D. , JENKINS H. , JOHNSTON S. , KENNEDY N. P. , KUMAR P. J. , LOGAN R. F. A. , MARSH M. N. , MULDER C. J. , TORINSSON NALUAI A. , SJOBERG K. , STENHAMMAR L. , WALTERS J. R. F. , JEWELL D. P. , HOULSTON R. S.
Published: March 2003

Susceptibility to coeliac disease involves HLA and non‐HLA‐linked genes. The CTLA4/CD28 gene region encodes immune regulatory T‐cell surface molecules and is a strong candidate as a susceptibility locus. We evaluated CTLA4/CD28 in coeliac disease by genetic linkage and association and combined our findings with published studies through a meta‐analysis. 116 multiplex families were genotyped across CTLA4/CD28 using eight markers. The contribution of CTLA4/CD28 to coeliac disease was assessed by non‐parametric linkage and association analyses. Seven studies were identified that had evaluated the relationship between CTLA4/CD28 and coeliac disease and a pooled analysis of data undertaken. In our study there was evidence for a relationship between variation in the CTLA4/CD28 region and coeliac disease by linkage and association analyses. However, the findings did not attain formal statistical significance (p = 0·004 and 0·039, respectively). Pooling findings with published results showed significant evidence for linkage (504 families) and association (940 families): p values, 0·0001 and 0·0014 at D2S2214, respectively, and 0·0008 and 0·0006 at D2S116, respectively. These findings suggest that variation in the CD28/CTLA4 gene region is a determinant of coeliac disease susceptibility. Dissecting the sequence variation underlying this relationship will depend on further analyses utilising denser sets of markers.
The probability that similar haplotypes are identical by descent
Authors: NOLTE I. M. , TE MEERMAN G. J.
Published: March 2003

The logic of gene mapping in highly penetrant diseases is to find the minimal overlap of haplotypes that are identical by descent (IBD). If the pedigree is unknown, identity by descent of haplotype overlap cannot be established with certainty. In many cases, it is intuitively clear that similar haplotypes are indeed IBD. The logical and statistical evaluation of haplotype overlap requires that probabilities of IBD are substantial. It is, therefore, important to estimate these probabilities. In this paper, we derive a recursive formula for the probability of IBD. Simulations are used to validate the expected values and to study the variability around the expected value. We demonstrate that for populations 1000 generations of age – without bottlenecks – haplotypes of 1 cM consisting of at least five microsatellite markers have a significant probability to be IBD. Likewise, SNP haplotypes of 1 cM should consist of at least nine identical SNP alleles for a similar probability of IBD. Without considering bottlenecks, haplotypes consisting of as few as three SNPs spanning a region of less than 0.01 cM are likely IBD in populations that are 10000 generations of age.
Identification of two SNPs in the 5′ flanking region of the ACP1 gene and evaluation of disequilibrium among polymorphic sites
Authors: FAGGIONI G. , BORGIANI P. , BOTTINI N. , GLORIA‐BOTTINI F. , TONTOLI F. , CONTREAS V. , BOTTINI E. , LISTA F.
Published: March 2003

We have studied the 5′ flanking region of the ACP1 gene looking for new polymorphisms. Two SNPs, DdeI and FokI restricted, have been found in this region. We determined the genotype of DdeI and FokI SNPs, as well as of three other known SNPs, codon 43 (CfoI restricted), codon 41 and codon 105 (TaqI restricted), located respectively in exons 3, 4 and 6 in 62 unrelated subjects from the Italian population. Haplotype distribution for the ten possible pairs of loci were determined by a maximum likelihood procedure. Overall, statistically significant deviations from expected frequencies assuming equilibrium have been observed for the following pairs: FokI/codon 41, FokI/TaqI, codon 41/TaqI (complete association), DdeI/FokI, DdeI/codon 41 and DdeI/TaqI. The data suggest that the FokI area could include sequences operating in strict functional association with sequences included in the codon 41/TaqI area, possibly in order to regulate the F/S isoforms ratio of the A* and *B alleles. Since the ratio between the concentration of the two F and S isoforms is different for the three ACP1 alleles, we suggest that the ACP1 locus has been subjected to strong selective pressure to obtain an optimal alternative splicing mechanism of the *A and *B alleles. The *C variant, on the other hand, seems completely independent from sequences in the FokI/codon 41/TaqI areas, resulting in an inverted F/S ratio compared to that found for *A and *B alleles.
Y‐chromosome biallelic polymorphisms and Native American population structure
Authors: BORTOLINI M.‐C. , SALZANO F. M. , BAU C. H. D. , LAYRISSE Z. , PETZL‐ERLER M. L. , TSUNETO L. T. , HILL K. , HURTADO A. M. , CASTRO‐DE‐GUERRA D. , BEDOYA G. , RUIZ‐LINARES A.
Published: March 2003

It has been proposed that women had a higher migration rate than men throughout human evolutionary history. However, in a recent study of South American natives using mtDNA restriction fragment polymorphisms and Y‐chromosome microsatellites we failed to detect a significant difference in estimates of migration rates between the sexes. As the high mutation rate of microsatellites might affect estimates of population structure, we now examine biallelic polymorphisms in both mtDNA and the Y‐chromosome. Analyses of these markers in Amerinds from North, Central and South America agree with our previous findings in not supporting a higher migration rate for women in these populations. Furthermore, they underline the importance of genetic drift in the evolution of Amerinds and suggest the existence of a North to South gradient of increasing drift in the Americas.
Distribution of HLA alleles in Portugal and Cabo Verde. Relationships with the slave trade route
Authors: SPÍNOLA H. , BREHM A. , WILLIAMS F. , JESUS J. , MIDDLETON D.
Published: March 2003

HLA‐A, ‐B, and ‐DR frequencies were analysed in populations from Portugal and the Madeira and Cabo Verde Archipelagos, aiming to characterize their genetic composition. Portuguese settlers colonized both Archipelagos in the 15th and 16th centuries. Madeira received many sub‐Saharan slaves to work in the sugar plantations, and Cabo Verde served as a pivotal market in the Atlantic slave trade and was populated by individuals coming from the Senegambia region of the West African coast. The population of Madeira shows the highest genetic diversity and the presence of alleles and haplotypes usually linked to sub‐Saharan populations, the haplotypes accounting for 3.5% of the total. Cabo Verde presents typical markers acknowledged to be of European or Ibero‐Mediterranean origin, thus revealing the admixture of European settlers with Sub‐Saharan slaves. Altogether the number of European haplotypes reaches 15% of the total. The Portuguese population shows a perceivable and significant heterogeneity both in allele and haplotype frequencies, unveiling a differential input of peoples from different origins. A PCA of the populations studied, plus other relevant ones, clearly shows gene heterogeneity in mainland Portugal as well as the differences and relationships between these populations and Madeira and Cabo Verde.
Nijmegen breakage syndrome gene (NBS1) alterations and its protein (nibrin) expression in human ovarian tumours
Authors: PLISIECKA‐HAŁASA J. , DANSONKA‐MIESZKOWSKA A. , REMBISZEWSKA A. , BIDZIŃSKI M. , STEFFEN J. , KUPRYJAŃCZYK J.
Published: March 2003

We looked for NBS1 gene (602667) alterations and changes in nibrin expression in 162 human gynaecological tumours, mostly ovarian. Exons 6–8 and 10 of the NBS1 gene were evaluated by the SSCP and direct sequencing method. Nibrin expression was detected immunohistochemically with the use of the p95NBS1 (Ab‐1) antibody. The 657del5 mutation (Slavic mutation) was found in two of 117 carcinomas studied (1.7%) – in both cases it was present in the germline; one of these tumours showed loss of heterozygosity (LOH) for the 657del5 mutation and loss of nibrin expression. We have found three types of novel germline intron variants: (1) two concomitant transitions (G to A) at bases 14009 and 14256; (2) C to T transition at base 13998; (3) G to C transversion at base 20035. Among the carcinomas studied, the intron variants were associated with a clear cell histological type (p = 0.004). Our results may suggest that NBS1 gene alterations contribute to the development of rare ovarian carcinomas. LOH for 657del5 in tumour tissue may support the hypothesis that the NBS1 gene functions as a tumour suppressor.
Power of a simplified multivariate test for genetic linkage
Authors: GORLOVA O. Y. , AMOS C. I. , ZHU D. K. , WANG W. , TURNER S. , BOERWINKLE E.
Published: March 2003

In this paper we compare the power of the multivariate Haseman–Elston (MHE) test proposed earlier by Amos et al. (1990) and a computationally rapid new version of the multivariate Haseman–Elston test (NMHE) (Elston et al. 2000). We show that the power of NMHE was, for different simulation setups, identical or higher than that of MHE. In the bivariate case, the power of the NMHE method was somewhat less than that of the computationally intensive maximum likelihood variance components method (Amos et al. 2001). We present comparisons of the empirical distributions of the NMHE test to its limiting distributions for a range of numbers of traits. The distribution of the NMHE test appeared to conform satisfactorily to its limiting asymptotic distribution in large samples. Otherwise, empirical critical values for NMHE are somewhat higher than predicted, i.e. the test proposed by Elston et al. (2000) is non‐conservative. The use of empirical critical values is therefore recommended for limited sample sizes (less than several hundred families). We also present the results of a linkage analysis performed by the NMHE method on a set of 4 body size‐related traits. The method identified meaningful combinations of traits that showed significant linkage on chromosome 2 and suggestive linkage to regions on chromosomes 16 and 17.
Linkage mapping of quantitative trait loci in humans: an overview
Authors: GHOSH S. , REICH T. , MAJUMDER P. P.
Published: March 2003

In this article, we provide an overview of the different statistical procedures that have been developed for linkage mapping of quantitative trait loci. We outline the model assumptions, the data requirements and the underlying tests for linkage for the different methods.
Identification of the sources of error in allele frequency estimations from pooled DNA indicates an optimal experimental design
Authors: BARRATT B. J. , PAYNE F. , RANCE H. E. , NUTLAND S. , TODD J. A. , CLAYTON D. G.
Published: March 2003

Genotyping costs still preclude analysis of a comprehensive SNP map in thousands of individual subjects in the search for disease susceptibility loci. Allele frequency estimation in DNA pools from cases and controls offers a partial solution, but variance in these estimates will result in some loss of statistical power. However, there has been no systematic attempt to quantify the several sources of error in previous studies. We report an analysis of the magnitude of variance components of each experimental stage in DNA pooling studies, and find that a design based on the formation of numerous small pools of approximately 50 individuals is superior to the formation of fewer, larger pools and the replication of any of the experimental stages. We conclude that this approach may retain an effective sample size greater than 68% of the true sample size, whilst offering a 60‐fold reduction in DNA usage and a greater than 30‐fold saving in cost, compared to individual genotyping. The possibility of combining pooling with informed selection of haplotype tag SNPs is also considered. In this way further savings in efficiency may be possible by using pooled allele frequency estimates to infer haplotype frequencies and hence, allele frequencies at untyped markers.
Genetic dissection between coeliac disease and dermatitis herpetiformis in sib pairs
Authors: KARELL K. , KORPONAY‐SZABO I. , SZALAI Zs. , HOLOPAINEN P. , MUSTALAHTI K. , COLLIN P. , MÄKI M. , PARTANEN J.
Published: March 2003

Gluten sensitive enteropathy has various manifestations, of which the two major forms are classical coeliac disease (cCD) and dermatitis herpetiformis (DH). In cCD predominantly the small intestine is affected, whereas in DH also the skin is affected showing typical rash and IgA deposits. The symptoms in both forms are dependent on gluten intake. The factors diversifying these two clinical outcomes are unknown. In the present report we evaluated the role of the major genetic susceptibility locus, HLA DQ, in 25 families, in which both forms of the disease, cCD and DH, occurred in siblings. By using the family‐based approach it can be assumed that within each family variation in environmental factors is substantially lower than in the standard case‐control setting, and also the problems related to population stratification can be avoided. Results from the Finnish family material with 25 discordant and 85 concordant sib pairs, and from additional case‐control material comprising 71 unrelated Hungarian DH and 68 cCD patients, together indicated that the HLA DQ locus did not differ between the two major outcomes of gluten sensitive enteropathy. The non‐HLA DR;DQ factors are critical for the different clinical manifestations of gluten sensitivity.