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In a Workshop sponsored by the United States National Institutes of Health in 1983 it was pointed out (51) that "Since 1974, theoretical population genetics has treated increasingly complex models, but sometimes with decreasing biological relevance." With the increasing emphasis and interest in molecular studies, the character of population genetics has changed considerably. "The subject has changed from one that is rich in theory and poor in data to one that is almost the opposite" (13). There has also been a shift from the bitter debates over the selective/neutral dichotomy. With the increasing availability of DNA sequence data, there is unequivocal evidence in favor of the neutral theory. The observed rates and patterns of DNA base substitutions are generally in concordance with the predictions of the neutral theory (35, 36, 42). This, of course, does not imply that all mutations are neutral; evidence for positive Darwinian selection at the molecular level has also recently been found (92). The theoretical and empirical studies of the last two decades have made it abundantly clear that the forces of mutation and random genetic drift are much more important in the creation and maintenance of genetic variability in populations than had previously been envisaged. Many important theoretical population genetic results, incorporating mutation and drift, on ages of alleles, sampling distributions of functions of allele frequencies, statistics for

Data pertaining to abdominal aortic aneurysm among first-degree relatives of 91 patients with abdominal aortic aneurysm are presented. The percentage of families with at least one affected first-degree relative of the proband (multiplex families) was 15.4%. In 21.4% of multiplex families parent-offspring transmission of abdominal aortic aneurysm was noted; in the remaining families only siblings were affected. The mean age at onset among probands was 67.3 years; that among all affected was 67.4 years. No statistically significant difference in the mean ages at onset between genders was noted. Among affected siblings of probands, the sex ratio, male:female, was 1.33:1, which is not significantly different from 1:1. The relative risk of developing an abdominal aortic aneurysm was 3.97 for fathers, 4.03 for mothers, 9.92 for brothers, and 22.93 for sisters.

Peroxisome proliferator-activated receptor-gamma2 (PPARG2) is a nuclear hormone receptor of ligand-dependent transcription factor involved in adipogenesis and a molecular target of the insulin sensitizers thiazolidinediones. We addressed the question of whether the 3 variants (-1279G/A, Pro12Ala, and His478His) in the PPARG2 gene are associated with type 2 diabetes mellitus and its related traits in a South Indian population. The study subjects (1000 type 2 diabetes mellitus and 1000 normal-glucose-tolerant subjects) were chosen randomly from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The variants were screened by single-stranded conformational variant, direct sequencing, and restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotypic frequencies. The -1279G/A, Pro12Ala, and His478His variants of the PPARG2 gene were not associated with type 2 diabetes mellitus. However, the 2-loci analyses showed that, in the presence of Pro/Pro genotype of the Pro12Ala variant, the -1279G/A promoter variant showed increased susceptibility to type 2 diabetes mellitus (odds ratio, 2.092; 95% confidence interval, 1.22-3.59; P = .008), whereas in the presence of 12Ala allele, the -1279G/A showed a protective effect against type 2 diabetes mellitus (odds ratio, 0.270; 95% confidence interval, 0.15-0.49; P < .0001). The 3-loci haplotype analysis showed that the A-Ala-T (-1279G/A-Pro12Ala-His478His) haplotype was associated with a reduced risk of type 2 diabetes mellitus (P < .0001). Although our data indicate that the PPARG2 gene variants, independently, have no association with type 2 diabetes mellitus, the 2-loci genotype analysis involving -1279G/A and Pro12Ala variants and the 3-loci haplotype analysis have shown a significant association with type 2 diabetes mellitus in this South Indian population.

Analyses of frequency profiles of markers on disease or drug-response related genes in diverse populations are important for the dissection of common diseases. We report the results of analyses of data on 405 SNPs from 75 such genes and a 5.2 Mb chromosome, 22 genomic region in 1871 individuals from diverse 55 endogamous Indian populations. These include 32 large (>10 million individuals) and 23 isolated populations, representing a large fraction of the people of India. We observe high levels of genetic divergence between groups of populations that cluster largely on the basis of ethnicity and language. Indian populations not only overlap with the diversity of HapMap populations, but also contain population groups that are genetically distinct. These data and results are useful for addressing stratification and study design issues in complex traits especially for heterogeneous populations.

South Asia has been a major corridor for the geographic dispersal of modern human from out-of-Africa to other regions of the world. Genomic markers have provided key information for tracing trails of human migration. An overall view of these trails has emerged, though there are still many contentious issues. The nature of genomic differentiation in south Asia is high, resulting from a combination of admixture and isolation.

Adiponectin is an adipose tissue specific protein that is decreased in subjects with obesity and type 2 diabetes. The objective of the present study was to examine whether variants in the regulatory regions of the adiponectin gene contribute to type 2 diabetes in Asian Indians. The study comprised of 2,000 normal glucose tolerant (NGT) and 2,000 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. We identified two proximal promoter SNPs (-11377C--G and -11282T--C), one intronic SNP (+10211T--G) and one exonic SNP (+45T--G) by SSCP and direct sequencing in a pilot study (n = 500). The +10211T--G SNP alone was genotyped using PCR-RFLP in 4,000 study subjects. Logistic regression analysis revealed that subjects with TG genotype of +10211T--G had significantly higher risk for diabetes compared to TT genotype [Odds ratio 1.28; 95% Confidence Interval (CI) 1.07-1.54; P = 0.008]. However, no association with diabetes was observed with GG genotype (P = 0.22). Stratification of the study subjects based on BMI showed that the odds ratio for obesity for the TG genotype was 1.53 (95%CI 1.3-1.8; P10(-7)) and that for GG genotype, 2.10 (95% CI 1.3-3.3; P = 0.002). Among NGT subjects, the mean serum adiponectin levels were significantly lower among the GG (P = 0.007) and TG (P = 0.001) genotypes compared to TT genotype. Among Asian Indians there is an association of +10211T--G polymorphism in the first intron of the adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia.

This study reports results of an extensive and comprehensive study of genetic diversity in 12 genes of the innate immune system in a population of eastern India. Genomic variation was assayed in 171 individuals by resequencing approximately 75kb of DNA comprising these genes in each individual. Almost half of the 548 DNA variants discovered was novel. DNA sequence comparisons with human and chimpanzee reference sequences revealed evolutionary features indicative of natural selection operating among individuals, who are residents of an area with a high load of microbial and other pathogens. Significant differences in allele and haplotype frequencies of the study population were observed with the HapMap populations. Gene and haplotype diversities were observed to be high. The genetic positioning of the study population among the HapMap populations based on data of the innate immunity genes substantially differed from what has been observed for Indian populations based on data of other genes. The reported range of variation in SNP density in the human genome is one SNP per 1.19kb (chromosome 22) to one SNP per 2.18kb (chromosome 19). The SNP density in innate immunity genes observed in this study (>3SNPskb(-1)) exceeds the highest density observed for any autosomal chromosome in the human genome. The extensive genomic variation and the distinct haplotype structure of innate immunity genes observed among individuals have possibly resulted from the impact of natural selection.

Parametric linkage methods for quantitative trait locus mapping require explicit specification of the probability model of the quantitative trait and hence can lead to misleading linkage inferences when the model assumptions are not valid. Ghosh and Majumder developed a nonparametric regression method based on kernel-smoothing for linkage mapping of quantitative trait locus using squared differences in trait values of independent sib pairs, which is relatively more robust than parametric methods with respect to violations in distributional assumptions. In this study, we modify the above mentioned nonparametric regression method by considering local linear polynomials instead of the Nadaraya-Watson estimator and squared sums of sib-pair trait values in addition to squared differences to perform a genome-wide scan of rheumatoid factor-IgM levels on sib pairs in the Genetic Analysis Workshop 15 simulated data set. We obtain significant evidence of linkage very close to the quantitative trait locus controlling for RF-IgM. We find that the simultaneous use of squared differences and squared sums increases the power to detect linkage compared to using only squared differences. However, because of all the sib pairs are selected for rheumatoid arthritis, there is reduced variance of RF-IgM values, and empirical power to detect linkage is not very high. We also compare the performance of our method with two linear regression approaches: the classical Haseman-Elston method using squared sib-pair trait differences and its extension proposed by Elston et al. using mean-corrected sib-pair cross-products. We find that the proposed nonparametric method yields more power than the linear regression approaches.

Isolated population groups are useful in conducting association studies of complex diseases to avoid various pitfalls, including those arising from population stratification. Since DNA resequencing is expensive, it is recommended that genotyping be carried out at tagSNP (tSNP) loci. For this, tSNPs identified in one isolated population need to be used in another. Unless tSNPs are highly portable across populations this strategy may result in loss of information in association studies. We examined the issue of tSNP portability by sampling individuals from 10 isolated ethnic groups from India. We generated DNA resequencing data pertaining to 3 genomic regions and identified tSNPs in each population. We defined an index of tSNP portability and showed that portability is low across isolated Indian ethnic groups. The extent of portability did not significantly correlate with genetic similarity among the populations studied here. We also analyzed our data with sequence data from individuals of African and European descent. Our results indicated that it may be necessary to carry out resequencing in a small number of individuals to discover SNPs and identify tSNPs in the specific isolated population in which a disease association study is to be conducted.

The aim of the study was to investigate the association of serum adiponectin levels with the Pro12Ala polymorphism of the peroxisome proliferator activated receptor-gamma (PPARG) gene in Asian Indians.We selected 400 diabetic subjects, 200 with the Pro12Pro genotype (100 male and 100 female) and 200 with the Pro12Ala genotype (100 male and 100 female) and 400 age- and sex-matched normal glucose tolerance subjects with similar genotype profiles from the Chennai Urban Rural Epidemiology Study. Fasting serum adiponection levels were measured using radioimmunoassay. The Pro12Ala polymorphism was genotyped by PCR-restriction fragment length polymorphism using BstUI.All clinical and biochemical parameters were similar in the subjects with the Pro12Pro and Pro12Ala genotypes. There was no significant difference in serum adiponectin values between subjects with the Pro12Pro and Pro12Ala genotypes (males 5.4 vs. 5.8 microg/ml, P = 0.546; females 6.9 vs. 7.2 microg/ml, P = 0.748). Adiponectin values did not differ among these two genotypes even when categorized based on their diabetes status (normal glucose tolerance Pro12Pro 7.9 vs. Pro12Ala 7.7 microg/ml, P = 0.994; diabetes Pro12Pro 4.7 vs. Pro12Ala 5.4 microg/ml, P = 0.622).The Pro12Ala polymorphism of the PPARG gene is not associated with serum adiponectin levels in Asian Indians.

Hemophilia B, an X-linked recessive bleeding disorder, is caused by heterogeneous mutations in the factor IX (F9) gene. Hence, carriers of the disease are usually detected by F9 gene linked RFLP analysis. We aimed to test a set of RFLP markers (DdeI, XmnI, MnlI, TaqI & HhaI), used worldwide for carrier detection, to estimate its heterozygosity in different population groups of India, and identify additional single nucleotide polymorphisms (SNPs) if necessary. A total of 8 population groups encompassing different regions of India, consisting of 107 unrelated normal females without any history of hemophilia B in the family and 13 unrelated obligate carriers were recruited in the study. Regions of F9 gene were amplified by PCR from genomic DNA of the donors followed by restriction enzyme digestion and/or sequencing as appropriate. Combined informativeness for the markers varied between 52–86% among normal females belonging to different geographical locations of India. Haplotype analysis revealed that the most prevalent haplotype lacked the restriction sites for all five RFLP markers. Screening regions of F9 gene that harbor 10 SNPs reported in dbSNP yielded only two SNPs, which increased the overall informativeness in each population group and heterozygosity in the obligate carriers for the disease from 38% to 69%. Our data show that heterozygosity of commonly used RFLP markers is remarkably variable across different regions of India. Thus prudent selection of the markers based on specific population groups including usage of additional markers is recommended for efficient carrier detection.

Considerable variation in antibody response (AR) was observed among recipients of an injectable typhoid vaccine and an oral cholera vaccine. We sought to find whether polymorphisms in genes of the immune system, both innate and adaptive, were associated with the observed variation in response. For both vaccines, we were able to discover and validate several polymorphisms that were significantly associated with immune response. For the typhoid vaccines, these polymorphisms were on genes that belonged to pathways of polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signalling and eventual production of antimicrobial peptides. For the cholera vaccine, the pathways included epithelial barrier integrity, intestinal homeostasis and leucocyte recruitment. Even though traditional wisdom indicates that both vaccines should act as T-cell-independent antigens, our findings reveal that the vaccines induce AR using different pathways.

Genes move as people move. Therefore, it is possible to reconstruct trails of human migration by studying genetic characteristics of people from different regions of the world. Humankind evolved out of Africa and moved out of Africa to populate different parts of the world. One of the earliest waves of human migration from out-of-Africa came into India. Genetic data have been helpful in reconstructing the processes of peopling of India and the relationships among contemporary ethnic groups of India. This article provides an overview of these findings. Keywords: Indian; DNA polymorphism; tribe; caste; migration; admixture

To determine whether the peroxisome proliferator-activated receptor (PPAR)-gamma Pro12ala polymorphism modulates susceptibility to diabetes in South Asians.South Asians (n = 697) and Caucasians (n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India (n = 1,619), were enrolled for this study. PPAR-gamma Pro12Ala was determined using restriction fragment-length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects.The Caucasian diabetic subjects had significantly lower prevalence of PPAR-gamma 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-gamma Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 +/- 68 and 54 +/- 33 microU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-gamma Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas.Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-gamma Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

To identify the variants in UDP-glucuronosyltransferase 1 (UGT1A1) gene in Gilbert's syndrome (GS) and to estimate the association between homozygosity for TA insertion and GS in India, as well as the frequency of TA insertion and its impact among normal controls in India.Ninety-five GS cases and 95 normal controls were selected. Liver function and other tests were done. The promoter and all 5 exons of UGT1A1 gene were resequenced. Functional assessment of a novel trinucleotide insertion was done by in silico analysis and by estimating UGT1A1 promoter activity carried out by luciferase reporter assay of appropriate constructs in Hep G2 cell line.Among the GS patients, 80% were homozygous for the TA insertion, which was several-fold higher than reports from other ethnic groups. The mean UCB level was elevated among individuals with only one copy of this insertion, which was not significantly different from those with two copies. Many new DNA variants in UGT1A1 gene were discovered, including a trinucleotide (CAT) insertion in the promoter found in a subset (10%) of GS patients, but not among normal controls. In-silico analysis showed marked changes in the DNA-folding of the promoter and functional analysis showed a 20-fold reduction in transcription efficiency of UGT1A1 gene resulting from this insertion, thereby significantly elevating the UCB level.The genetic epidemiology of GS is variable across ethnic groups and the epistatic interactions among UGT1A1 promoter variants modulate bilirubin glucuronidation.

The main objective of this study was to evaluate if the −429T/C, −374T/A and 63 bp deletion polymorphisms in the RAGE gene are associated with diabetic retinopathy (DR) among Type 2 diabetic subjects in a clinic-based population from South India. We screened 149 normal glucose tolerant subjects (NGT), 189 Type 2 diabetes subjects without retinopathy (DM) and 190 subjects with DR for these polymorphisms using the PCR-RFLP method. DR was diagnosed by grading color fundus photography. Logistic regression models were used to evaluate the association of individual polymorphisms with DR. Expectation–maximization algorithms were implemented in haplotype tests of association to examine the combined effects of −429T/C and −374T/A polymorphisms on DR. The allelic frequencies of −429T are 0.83 in NGT, 0.84 in DM and 0.85 in DR subjects, and that of −374T are 0.93 in NGT, 0.92 in DM and 0.88 in DR subjects. The −374 polymorphism was found to be associated with non-proliferative retinopathy when this subgroup was compared to the DM group (OR=1.814, 95% CI=1.005–3.273). However, this association was not obvious when both the subphenotypes of DR (the nonproliferative and proliferative DR groups) were studied jointly. We found no evidence for associations between the −429T/C polymorphism and the DR phenotype. Finally, extension to a 2-SNP haplotype did not reveal any significant statistical difference between the groups (P=0.668). In this study, we found a modest association with the −374T/A polymorphism in the nonproliferative DR subgroup.

Purpose To obtain a global perspective on the distribution and evolution of CYP1B1 mutations in primary congenital glaucoma (PCG) worldwide. Methods Five intragenic single-nucleotide polymorphisms in CYP1B1-R48G, A119S, V432L, D449D, and N453S-were used to generate haplotype data from 138 Indian patients with PCG and 132 ethnically matched normal controls, which were then analyzed in conjunction with data from other populations. Maximum-likelihood estimates of haplotype frequencies were estimated from the genotype data. Subsets of patients and normal control subjects were also genotyped with respect to eight short tandem repeat (STR) markers around the CYP1B1 locus (D2S305, D2S165, D2S367, D2S2259, D2S391, D2S3337, D2S23678, and D2S286), to gain evolutionary insights. Results Common mutations in CYP1B1 that are causal of PCG occurred on a uniform haplotype background among Indian patients, which is completely distinct from the modal haplotype background found among unaffected control subjects. Comparison of these data with data from other global regions reveals strong clustering of CYP1B1 mutations by geographic and haplotype backgrounds. The two distinct modal haplotypes found among Indian patients with PCG and control subjects are both ancient with ages of similar magnitudes, as indicated by large variances in the number of repeats at eight STR loci. Together with data from chimpanzee and normal control subjects from India and other global regions, it was possible to make a parsimonious reconstruction of the evolution of these haplotypes. Conclusions The strong association of specific haplotypes with some predominant CYP1B1 mutations underlying PCG and the observed geographical clustering, probably due to founder effects, may be useful for predictive testing.

Multivariate phenotypes underlie complex traits. Thus, instead of using the end-point trait, it may be statistically more powerful to use a multivariate phenotype correlated to the end-point trait for detecting linkage. In this study, we develop a reverse regression method to analyze linkage of Kofendrerd Personality Disorder affection status in the New York population of the Genetic Analysis Workshop 14 (GAW14) simulated dataset. When we used the multivariate phenotype, we obtained significant evidence of linkage near four of the six putative loci in at least 25% of the replicates. On the other hand, the linkage analysis based on Kofendrerd Personality Disorder status as a phenotype produced significant findings only near two of the loci and in a smaller proportion of replicates.

This study was undertaken to estimate prevalence of metabolic syndrome in traditional societies in the sub-Himalayan region and to assess the impact of modernization on the risk to the syndrome. Two tribal populations—Toto and Bhutia—with a shared ancestry and habitat were selected. Some Bhutians have adopted a modern lifestyle. The study design permitted assessment of the relative roles of lifestyle and genetic factors in influencing the prevalence of metabolic syndrome. Our study has revealed that metabolic syndrome (or its contributing variables) can be a major health problem, even in traditional rural ethnic groups, indicating that this syndrome is not necessarily a result of modernization or urbanization. Dyslipidemia seems to be the major contributor to metabolic syndrome. Further, our study indicates that genetic factors that adversely affect the levels of such variables have long antiquities in Indian ethnic groups. We find that there is an additional adverse impact of adoption of urban lifestyles (perhaps primarily mediated through dietary changes) on metabolic syndrome. Am. J. Hum. Biol. 17:814–817, 2005. © 2005 Wiley-Liss, Inc.

Indian population, comprising of more than a billion people, consists of 4693 communities with several thousands of endogamous groups, 325 functioning languages and 25 scripts. To address the questions related to ethnic diversity, migrations, founder populations, predisposition to complex disorders or pharmacogenomics, one needs to understand the diversity and relatedness at the genetic level in such a diverse population. In this backdrop, six constituent laboratories of the Council of Scientific and Industrial Research (CSIR), with funding from the Government of India, initiated a network program on predictive medicine using repeats and single nucleotide polymorphisms. The Indian Genome Variation (IGV) consortium aims to provide data on validated SNPs and repeats, both novel and reported, along with gene duplications, in over a thousand genes, in 15,000 individuals drawn from Indian subpopulations. These genes have been selected on the basis of their relevance as functional and positional candidates in many common diseases including genes relevant to pharmacogenomics. This is the first large-scale comprehensive study of the structure of the Indian population with wide-reaching implications. A comprehensive platform for Indian Genome Variation (IGV) data management, analysis and creation of IGVdb portal has also been developed. The samples are being collected following ethical guidelines of Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT), India. This paper reveals the structure of the IGV project highlighting its various aspects like genesis, objectives, strategies for selection of genes, identification of the Indian subpopulations, collection of samples and discovery and validation of genetic markers, data analysis and monitoring as well as the project's data release policy.

When parental populations give rise to a hybrid population, it is possible to estimate the proportions of admixture from each parental population on the basis of known marker allele frequencies if there has been no genetic drift. Methods include generalized least squares and maximum likelihood. It is also possible to use a measure of genetic similarity. All these methods assume that the admixture is a static, one-time phenomenon, whereas in reality there is usually a continued, long-term exchange of genes among populations. Keywords: generalized least squares; maximum likelihood; genetic distance; population genetics

The problem of identifying motifs comprising nucleotides at a set of polymorphic DNA sites, not necessarily contiguous, arises in many human genetic problems. However, when the sites are not contiguous, no efficient algorithm exists for polymorphic motif identification. A search based on complete enumeration is computationally inefficient. We have developed probabilistic search algorithms to discover motifs of known or unknown lengths. We have developed statistical tests of significance for assessing a motif discovery, and a statistical criterion for simultaneously estimating motif length and discovering it. We have tested these algorithms on various synthetic data sets and have shown that they are very efficient, in the sense that the “true” motifs can be detected in the vast majority of replications and in a small number of iterations. Additionally, we have applied them to some real data sets and have shown that they are able to identify known motifs. In certain applications, it is pertinent to find motifs that contain contrasting nucleotides at the sites included in the motif (e.g., motifs identified in case-control association studies). For this, we have suggested appropriate modifications. Using simulations, we have discovered that the success rate of identification of the correct motif is high in case-control studies except when relative risks are small. Our analyses of evolutionary data sets resulted in the identification of some motifs that appear to have important implications on human evolutionary inference. These algorithms can easily be implemented to discover motifs from multilocus genotype data by simple numerical recoding of genotypes.

Summary We describe the genetic structure and affinities of five Dravidian-speaking tribal populations inhabiting the Nilgiri hills of Tamil Nadu, in south India, using 24 autosomal DNA markers. Our goals were: (i) to examine what evolutionary forces have most significantly impacted south Indian tribal genetic variation, and (ii) to test whether the phenotypic similarities of some south Indian tribal groups to Africans represent a signature of close relationship to Africans or are due to convergence. All loci were polymorphic and average heterozygosities were substantial (range: 0.347‐0.423). Genetic differentiation was high (Gst = 6.7%) and genetic distances were not significantly correlated with geographic distances. Genetic drift therefore probably played a significant role in shaping the patterns of genetic variation observed in southern Indian tribal populations. Otherwise, analyses of population relationships showed that Indian populations are closely related to one another, regardless of phenotypic characteristics, and do not show particular affinities to Africans. We conclude that the phenotypic similarities of some Indian groups to Africans do not reflect a close relationship between these groups, but are better explained by convergence.

We have compared two statistical methods of estimating the time to most recent common ancestor (TMRCA) from a sample of DNA sequences, which have been proposed by Templeton (1993) and Bandelt et al. (1995). Monte-Carlo simulations were used for generating DNA sequence data. Different evolutionary scenarios were simulated and the estimation procedures were evaluated. We have found that for both methods (i) the estimates are insensitive to demographic parameters and (ii) the standard deviations of the estimates are too high for these methods to be reliably used in practice.

Arriere-plan: Les polymorphismes de l'ADN mitochondrial ont fait la preuve de leur utilite pour l'etude des origines et des parentes genetiques. Les origines des populations castees de l'Inde sont restees enigmatiques et les apparentements genetiques des castes ne sont pas uniformes d'une region geographique a une autre. But: Cette etude a ete entreprises pour analyser la nature et l'etendue des variations d'ADNmt ainsi que les relations des groupes castes de l'etat indien occidental du Maharashtra et pour examiner ce que les resultats impliquent quant a leurs origines. Sujets et methodes: Une population a ete selectionnee dans chacune des trois castes et des echantillons sanguins ont ete obtenus de sujets non apparentes pleinement informes du but de l'etude. Les populations ordonnees en castes etaient : le rang superieur (Brahmane; n = 31), rang moyen (Maratha; n = 41) et le rang inferieur (Nava Baudh; n = 40). On a etudie les polymorphismes de dix sites de restriction (RSPs) et d'un locus d'insertion/deletion (InDel). Le segment hypervariable 1 (SHV1) a ete sequence a partir d'un sous-ensemble des individus echantillonnes. Resultats: Quatre loci RSPs ont ete trouves monomorphiques dans les trois populations. Le locus InDel est monomorphique dans deux d'entre-elles (Brahmane et Maratha). Un haplotype construit sur la base des RSPs est predominant dans les trois groupes. La diversite haplotypique est de magnitude similaire chez les Maratha et les Nava Baudh (respectivement 68% et 64%), nettement plus elevee que chez les brahmanes (49%). La frequence de l'haplogroupe M est elevee dans les trois groupes, mais contrairement a ce qui etait attendu, elle est plus haute chez les brahmanes. Pres de 10% des brahmanes cependant portent l'haplogroupe C. Une large variation a ete trouvee dans la region du SHV1. Les diversites nucleotidiques et le nombre moyen de non appariements, ont une magnitude semblable dans les trois groupes. Conclusions: La caste superieure Brahmane est genetiquement distincte des castes moyenne et inferieure; cependant, sa frequence plus elevee de l'haplogroupe M, laisse penser qu'elle aurait pu recevoir des apports de population externes.

The origins and genomic affinities of various tribal populations of India are of considerable contemporary interest. In this study, we have investigated relationships among five tribal groups inhabiting the north-eastern, eastern and sub-Himalayan regions of India. DNA samples have been analysed in respect of 25 polymorphic loci, based on which genetic affinities have been estimated. The interesting findings of this study are (i) the Tibeto-Burman speaking, morphologically Mongoloid, tribal groups of India are not genetically very homogeneous, and (ii) the Tharu, a group inhabiting the sub-Himalayan region, may indeed have undergone considerable admixture as has been postulated by some anthropologists.

Linguistic evidence suggests that West Asia and Central Asia have been the two major geographical sources of genes in the contemporary Indian gene pool. To test the nature and extent of similarities in the gene pools of these regions we have collected DNA samples from four ethnic populations of northern India, and have screened these samples for a set of 18 Y-chromosome polymorphic markers (12 unique event polymorphisms and six short tandem repeats). These data from Indian populations have been analysed in conjunction with published data from several West Asian and Central Asian populations. Our analyses have revealed traces of population movement from Central Asia and West Asia into India. Two haplogroups, HG-3 and HG-9, which are known to have arisen in the Central Asian region, are found in reasonably high frequencies (41.7% and 14.3% respectively) in the study populations. The ages estimated for these two haplogroups are less in the Indian populations than those estimated from data on Middle Eastern populations. A neighbour-joining tree based on Y-haplogroup frequencies shows that the North Indians are genetically placed between the West Asian and Central Asian populations. This is consistent with gene flow from West Asia and Central Asia into India.

Background: Pathogenesis and genetic factors influencing predisposition to antituberculosis drug (ATD)-induced hepatotoxicity are not clear. Polymorphism at the genetic locus of a drug and xenobiotic compound metabolizing enzyme, N-acetyltransferase type 2 (NAT2), is reported to be associated with the excess generation of toxic reactive metabolites. Polymorphisms at the glutathione S-transferase (GST) loci (GSTM1 and GSTT1) are involved in the detoxification of these toxic metabolites in the human body to a lesser extent. We have examined whether polymorphisms at these loci are associated with the risk of ATD-induced hepatotoxicity. Methods: In this case-control study, 33 pulmonary tuberculosis patients with ATD-induced hepatotoxicity and 33 pulmonary tuberculosis patients receiving ATD drugs without any evidence of hepatotoxicity were considered as cases and controls, respectively. Point mutations at NAT2 and homozygous ‘null’ mutations at GSTM1 and GSTT1 genes were looked into genomic DNA, isolated from peripheral blood mononuclear cells by using polymerase chain reaction (PCR). Results: The frequency of homozygous ‘null’ mutation at the GSTM1 gene was significantly higher among cases (n = 17, 52%) than controls (n = 8, 24%) (P < 0.05, relative risk 2.13, 95% CI: 1.25–3.10). Frequencies of mutations at GSTT1 and NAT2 genes did not differ significantly between cases and controls. Conclusion: Homozygous ‘null’ mutation at the GSTM1 gene might predispose an individual to ATD-induced hepatotoxicity.

The International Genetic Epidemiology Society (IGES) has examined the charges against James V. Neel and his colleagues contained in the recently published book by Patrick Tierney entitled Darkness in El Dorado: How Scientists and Journalists Devastated the Amazon (W.W. Norton, 2000). The book implicates Neel in causing or promoting an epidemic of measles among the Yanomamo Indians of Venezuela in 1968 leading to "hundreds if not thousands" of deaths by using a "dinosaur" vaccine (Edmonston B) as a deliberate "experiment" to test his "eugenic" theories. Tierney also attempts to link this research, funded by the Atomic Energy Commission (AEC), with a broader tapestry of human radiation experiments. To investigate these serious charges, the IGES undertook a thorough examination of most source documents referenced in Tierney's book, Neel's field logs, notes, first-hand reports, contemporary writings, film sound tracks, etc., and conducted interviews with many relevant persons. The IGES finds that these allegations are false. Neel was not a eugenicist and was in fact highly critical of both the scientific basis of eugenics and its coercive social policies. In this regard, Tierney has grossly misrepresented Neel's views on a wide range of social implications of modern civilization for the long-term health of the gene pool. Far from causing an epidemic of measles, Neel did his utmost to protect the Yanomamo from the ravages of the impending epidemic by a vaccination program using a vaccine that was widely used at the time and administered in an appropriate manner. There was nothing experimental about the vaccination program, which in fact severely hindered the primary scientific objectives of the expedition. Although the research was funded in large part by the AEC, there was no element of radiation research and the work had no connection with the ethical abuses that have been reported from AEC-sponsored radiation research, such as studies of heavy isotopes. Neel's seminal contributions to a broad range of topics in human genetics have been extensively chronicled elsewhere. His research on the Yanomamo in particular has provided unique insights into the evolutionary biology of our species, the role of sociocultural practices, such as kinship relationships and selective pressures in shaping the genetic diversity of primitive population isolates, as well as the general picture of health in such populations. The IGES decries the damage done to the reputation of one of its founders and its first President and the misperception this book may have caused about the conduct of research in genetic epidemiology. Ethical issues about scientific research in primitive populations deserve serious and wide discussion, but the IGES condemns the gross misrepresentation of the facts and demonization of the principal characters in this book.

We estimated the frequencies of GSTM1 and GSTT1 "null" homozygotes in 10 different ethnic populations of India by a genotyping method based on polymerase chain reaction. These populations, inhabiting diverse geographical locations and occupying various positions in the sociocultural hierarchy, were represented by a sample of 299 unrelated individuals. Frequencies of GSTM1 and GSTT1 "null" homozygotes varied from 20% to 79% and 3% to 39%, respectively, across the study populations. Maximum frequencies of GSTM1 and GSTT1 "null" homozygotes (79% and 39%, respectively) have been observed in the same population (Jamatia). Frequencies of homozygous "null" genotypes at the GSTM1 and GSTT1 loci show a significant positive correlation in these populations, which is contrary to expectations. A possible implication is that the two enzymes are working in tandem, instead of working in a complementary way.

Recent epidemiological data and projections indicate that HIV infection will spread rapidly in India. An allele Delta ccr5 of the beta-chemokine receptor gene CCR5 has been found to confer protection against HIV-1. We find that this protective allele is absent in most ethnic populations of India, except some populations of the northern and western regions where this allele may have been introduced by Caucasian gene flow. The implications of this finding are discussed in the light of increasing HIV prevalence in India.

There are various conflicting hypotheses regarding the origins of the tribal groups of India, who belong to three major language groups – Austro-Asiatic, Dravidian and Tibeto-Burman. To test some of the major hypotheses we designed a genetic study in which we sampled tribal populations belonging to all the three language groups. We used a set of autosomal DNA markers, mtDNA restriction-site polymorphisms (RSPs) and mtDNA hypervariable segment-1 (HVS-1) sequence polymorphisms in this study. Using the unlinked autosomal markers we found that there is a fair correspondence between linguistic and genomic affinities among the Indian tribal groups. We reconstructed mtDNA RSP haplotypes and found that there is extensive haplotype sharing among all tribal populations. However, there is very little sharing of mtDNA HVS-1 sequences across populations, and none across language groups. Haplogroup M is ubiquitous, and the subcluster U2i of haplogroup U occurs in a high frequency. Our analyses of haplogroup and HVS-1 sequence data provides evidence in support of the hypothesis that the Austro-Asiatic speakers are the most ancient inhabitants of India. Our data also support the earlier finding that some of the western Eurasian haplogroups found in India may have been present in India prior to the entry of Aryan speakers. However, we do not find compelling evidence to support the theory that haplogroup M was brought into India on an "out of Africa" wave of migration through a southern exit route from Ethiopia. On the contrary, our data raise the possibility that this haplogroup arose in India and was later carried to East Africa from India.

Obesity is a major health concern throughout the world (e.g., Bouchard, 1994). Body fat is variously measured through under water weighing or through bioelectric impedance. While these measures provide accurate direct measurements of total body fat or percent body fat, often highly correlated surrogates are used in epidemiological studies, such as the sum of skinfolds measured at multiple sites or the body mass index (BMI), computed as the weight (kilograms) over the squared height (meters). Several indices of fat patterning are in wide use: Trunk-to-Extremity Ratio (TER, computed as the sum of skinfolds measured close to the trunk area over the sum of skinfolds measured in distal areas) provides a measure of relative fat patterning. Waist-to-hip ratio and abdominal obesity (visceral plus subcutaneous fat) are also commonly used. Ironically, the BMI is highly correlated with both total body fat as well as measures of fat patterning. Accordingly, BMI tends to be used in most studies because of its simplicity of measurement. Several large family studies are currently involved in an evaluation of the genes underlying adiposity (e.g., Bouchard et al., 1995). Since most family studies include BMI, it provides a good example for investigating the genetics of fat patterning. Like most quantitative traits and disease-related risk factors, BMI is a complex trait that involves the action of multiple genes and environmental effects. In this paper, we will review the general problems involved in genetic studies of complex traits in general, and review some of the known results for BMI in particular.

A heritable multivariate quantitative phenotype comprises several correlated component phenotypes that are usually pleiotropically controlled by a set of major loci and environmental factors. One approach to decipher the genetic architecture of a multivariate phenotype, in particular to map the underlying loci, is to reduce the dimensionality of the data by means of a data reduction technique, such as principal component analysis. The extracted principal components are then analyzed in conjunction with marker data to map the underlying loci. We have examined the efficiency of this approach with and without taking into account the correlation structure of the multivariate phenotype when extracting principal components. We have assumed that genome-wide scan data on sibpairs are available for low-density (widely spaced) and high-density markers. Using extensive simulations, based on three models of the multivariate phenotype, we have shown that although ignoring the correlation structure of the multivariate phenotype does not have any serious impact on the efficiency of mapping the underlying trait loci in wide marker intervals, there is a significant adverse effect of this practice for fine-mapping. We, therefore, recommend that the correlation structure of the multivariate phenotype be carefully examined to decide on the strategy of extracting principal components for deciphering the genetic architecture of the multivariate phenotype.

Gingivo-buccal oral cancer (GBOC), an anatomical and clinical sub-type of head and neck squamous cell carcinoma (HNSCC), is prevalent in regions where tobacco-chewing is common. Exome sequencing and other data on 50 GBOC tumor/normal DNA pairs revealed (a) significantly and recurrently mutated genes that are (i) specific (USP9X, MLL4, ARID2, UNC13C and TRPM3), and (ii) shared with HNSCC (e.g., TP53, CDKN2A, PIK3CA, HRAS, NOTCH1); (b) new genes with recurrent amplifications (e.g., DROSHA, YAP1) or homozygous deletions (e.g., DDX3X); (c) existence of molecular sub-types, with distinctive mutational profiles; (d) high proportion of C>G transversions, not noted earlier in HNSCC, among tobacco users with high numbers of mutations; and, (e) enrichment of alterations of pathways specific to GBOC, including Neurotrophin signaling, Wnt signaling, dorso-ventral axis formation and axon guidance. Recurrently mutated genes were validated on an independent set of 30 GBOC patients. These findings open new vistas for biological characterization and exploration of therapies.

Because microsatellite loci are abundant in the human genome and are highly polymorphic in most global populations, such loci have become very popular in studies on reconstructing evolutionary relationships among contemporary human populations. We have made an assessment of the efficiency of recovery of true evolutionary relationships using simulated data of microsatellite loci and a variety of distance measures. We find that allele frequency data on about 30 microsatellite loci and the use ofD A (Neiet al. 1983) orD c (Cavalli-Sforza and Edwards 1967) distance measures with UPGMA clustering algorithm can recover true short-term evolutionary relationships with a high degree of accuracy, unless the effective sizes of the populations or mutation rates or both are very small.

Vitiligo is a depigmenting disorder of the skin caused by destruction of melanocytes. The depigmented skin has several abnormal functions, including some autonomic nervous functions. The inflammatory response in the depigmented skin is muted. Recent genetic and epidemiologic studies indicate that vitiligo affects men and women equally. The prevalence in the population is about one in 200. Vitiligo seems to be transmitted as a polygenic trait. New data suggest that it is not associated with autoimmune endocrine disorders, but more comprehensive studies are required.

Artículo científico -- Instituto de Investigaciones en Salud. 1996 We have analyzed the CTG repeat length and the neighboring Alu insertion/deletion (+/-) polymorphism in DNA samples from 16 ethnically and geographically diverse human populations to understand the evolutionary dynamics of the myotonic dystrophy-associated CTG repeat. Our results show that the CTG repeat length is variable in human populations. Although the (CTG)5 repeat is the most common allele in the majority of populations, this allele is absent among Costa Ricans and New Guinea highlanders. We have detected a (CTG)4 repeat allele, the smallest CTG known allele, in an American Samoan individual. (CTG) > or = 19 alleles are the most frequent in Europeans followed by the populations of Asian origin and are absent or rare in Africans. To understand the evolution of CTG repeats, we have used haplotype data from the CTG repeat and Alu(+/-) locus. Our results are consistent with previous studies, which show that among individuals of Caucasian and Japanese origin, the association of the Alu(+) allele with CTG repeats of 5 and > or = 19 is complete, whereas the Alu(-) allele is associated with (CTG)11-16 repeats. However, these associations are not exclusive in non-Caucasian populations. Most significantly, we have detected the (CTG)5 repeat allele on an Alu(-) background in several populations including Native Africans. As no (CTG)5 repeat allele on an Alu(-) background was observed thus far, it was proposed that the Alu(-) allele arose on a (CTG)11-13 background. Our data now suggest that the most parsimonious evolutionary model is (1) (CTG)5-Alu(+) is the ancestral haplotype; (2) (CTG)5-Alu(-) arose from a (CTG)5-Alu(+) chromosome later in evolution; and (3) expansion of CTG alleles occurred from (CTG)5 alleles on both Alu(+) and Alu(-) backgrounds. Universidad de Costa Rica, Instituto de Investigaciones en Salud UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)

In DNA fingerprinting work, it is well known that, although fragment lengths of a sample are uncorrelated, measurement errors of fragment lengths are correlated. Unless the fragment length is very large, the measurement errors are directly proportional to fragment lengths. In the currently practiced matching procedures for forensic identification, these facts are ignored or inadequately used. Some of these issues are addressed in this study. Based on available empirical observations, an appropriate statistical model and techniques are proposed. These techniques lead to the definition and construction of elliptical match windows, instead of independent interval (linear) windows currently used. Simulation experiments indicate that the performance of the proposed procedure is superior to the current procedures. Further, the proposed procedure does not make use of some assumptions underlying the current procedures. Extensions of the procedure to utilize replicate measurements of crime-scene and/or suspect's samples are indicated.

(1993). P.C. Mahalanobis’ Contributions to Biometry. Journal of Human Ecology: Vol. 4, No. 3, pp. 233-235.

In comparison with a genetic disorder which has no environmental contribution, which expresses itself at birth and which is determined by a completely penetrant allele at a single autosomal diallelic locus, genetics of many human disorders are more complex. The complexity can arise in a variety of ways. Although no claim is made that the following list is exhaustive, some of the more common causes of complexity of a disorder are