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NorthEast India, with its unique geographic location in the midst of the Himalayas and Bay of Bengal, has served as a passage for the movement of modern humans across the Indian subcontinent and East/Southeast Asia. In this study we look into the population genetics of a unique population called the Khasi, speaking a language (also known as the Khasi language) belonging to the Austroasiatic language family and residing amidst the Tibeto-Burman speakers as an isolated population. The Khasi language belongs to one of the three major broad classifications or phyla of the Austroasiatic language and the speakers of the three sub-groups are separated from each other by large geographical distances. The Khasi speakers are separated from their nearest Austroasiatic language-speaking sub-groups: the “Mundari” sub-family from East and peninsular India and the “Mon-Khmers” in Mainland Southeast Asia. We found the Khasi population to be genetically distinct from other Austroasiatic speakers, i.e. Mundaris and Mon-Khmers, but relatively similar to the geographically proximal Tibeto Burmans. The possible reasons for this genetic-linguistic discordance lie in the admixture history of different migration events that originated from East Asia and proceeded possibly towards Southeast Asia. We found at least two distinct migration events from East Asia. While the ancestors of today’s Tibeto-Burman speakers were affected by both, the ancestors of Khasis were insulated from the second migration event. Correlating the linguistic similarity of Tibeto-Burman and Sino-Tibetan languages of today’s East Asians, we infer that the second wave of migration resulted in a linguistic transition while the Khasis could preserve their linguistic identity.

Oral squamous cell carcinoma of the gingivo-buccal region (OSCC-GB) accounts for the highest cancer morbidity and mortality among men in India. It has been observed that about one-third of individuals with oral leukoplakia, a dysplastic precancerous lesion in the oral cavity, progress to oral cancer. We aimed to identify systematic transcriptomic changes as a normal tissue in the oral cavity progresses to frank OSCC-GB. Seventy-two OSCC-GB patients, from multiple hospitals, were recruited, and transcriptome analysis of tumor and adjacent normal tissue (of all patients) and adjacent leukoplakia tissue (of a subset of 25 unselected patients with concomitant leukoplakia) was performed. We have identified many differences in the transcriptomic profiles between OSCC-GB and squamous cell carcinoma of the head and neck regions. Compared to the normal/precancerous tissue, significant enrichment of ECM−receptor interaction, PI3K-Akt signaling, cytokine−cytokine receptor interaction, focal adhesion, and cell cycle pathways were observed in OSCC-GB. Using gene set enrichment analysis, we identified a profound role of interferon receptor signaling in tumor growth by activating immune evasion mechanisms. The role of tumor-infiltrating immune cells further supported the growth and immunosuppressive mechanism of tumor tissues. Some immune evasion genes—CD274, CD80, and IDO1—were found to be activated even in the precancerous tissue. Taken together, our findings provide a clear insight into the sequential genetic dysregulation associated with progression to oral cancer. This insight provides a window to the development of predictive biomarkers and therapeutic targets for gingivo-buccal oral cancer.

Many variants with low frequencies or with low to modest effects likely remain unidentified in genome-wide association studies (GWAS) because of stringent genome-wide thresholds for detection. To improve the power of detection, variant prioritization based on their functional annotations and epigenetic landmarks has been used successfully. Here, we propose a novel method of prioritization of a GWAS by exploiting gene-level knowledge (e.g., annotations to pathways and ontologies) and show that it further improves power. Often, disease associated variants are found near genes that are coinvolved in specific biological pathways relevant to disease process. Utilization of this knowledge to conduct a prioritized scan increases the power to detect loci that map to genes clustered in a few specific pathways. We have developed a computationally scalable framework based on penalized logistic regression (termed GKnowMTest-Genomic Knowledge-guided Multiplte Testing) to enable a prioritized pathway-guided GWAS scan with a very large number of gene-level annotations. We demonstrate that the proposed strategy improves overall power and maintains the Type 1 error globally. Our method works on genome-wide summary level data and a user-specified list of pathways (e.g., those extracted from large pathway databases without reference to biology of a specific disease). It automatically reweights the input p values by incorporating the pathway enrichments as "adaptively learned" from the data using a cross-validation technique to avoid overfitting. We used whole-genome simulations and some publicly available GWAS data sets to illustrate the application of our method. The GKnowMTest framework has been implemented as a user-friendly open-source R package.

Recent work has demonstrated that two archaic human groups (Neanderthals and Denisovans) interbred with modern humans and contributed to the contemporary human gene pool. These findings relied on the availability of high-coverage genomes from both Neanderthals and Denisovans. Here we search for evidence of archaic admixture from a worldwide panel of 1,667 individuals using an approach that does not require the presence of an archaic human reference genome. We find no evidence for archaic admixture in the Andaman Islands, as previously claimed, or on the island of Flores, where Homo floresiensis fossils have been found. However, we do find evidence for at least one archaic admixture event in sub-Saharan Africa, with the strongest signal in Khoesan and Pygmy individuals from Southern and Central Africa. The locations of these putative archaic admixture tracts are weighted against functional regions of the genome, consistent with the long-term effects of purifying selection against introgressed genetic material.

Background Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the most common cancer among men in India and is associated with high mortality. Although OSCC-GB is known to be quite different from tongue cancer in its genomic presentation and its clinical behavior, it is treated identically as tongue cancer. Predictive markers of prognosis and therapy that are specific to OSCC-GB are, therefore, required. Although genomic drivers of OSCC-GB have been identified by whole exome and whole genome sequencing, no epigenome-wide study has been conducted in OSCC-GB; our study has filled this gap, and has discovered and validated epigenomic hallmarks of gingivobuccal oral cancer. Methods We have carried out integrative analysis of epigenomic (n = 87) and transcriptomic (n = 72) profiles of paired tumor-normal tissues collected from OSCC-GB patients from India. Genome-wide DNA methylation assays and RNA-sequencing were performed on high-throughput platforms (Illumina) using a half-sample of randomly selected patients to discover significantly differentially methylated probes (DMPs), which were validated on the remaining half-sample of patients. Results About 200 genes showed significant inverse correlation between promoter methylation and expression, of which the most significant genes included genes that act as transcription factors and genes associated with other cancer types. Novel findings of this study include identification of (a) potential immunosuppressive effect in OSCC-GB due to significant promoter hypomethylation driven upregulation of CD274 and CD80, (b) significant dysregulation by epigenetic modification of DNMT3B (upregulation) and TET1 (downregulation); and (c) known drugs that can reverse the direction of dysregulation of gene expression caused by promoter methylation. Conclusions In OSCC-GB patients, there are significant alterations in expression of key genes that (a) regulate normal cell division by maintenance of balanced DNA methylation and transcription process, (b) maintain normal physiological signaling (PPAR, B cell receptor) and metabolism (arachidonic acid) pathways, and (c) provide immune protection against antigens, including tumor cells. These findings indicate novel therapeutic targets, including immunotherapeutic, for treatment of OSCC-GB.

We present 42 new Y-chromosomal sequences from diverse Indian tribal and non-tribal populations, including the Jarawa and Onge from the Andaman Islands, which are analysed within a calibrated Y-chromosomal phylogeny incorporating South Asian (in total 305 individuals) and worldwide (in total 1286 individuals) data from the 1000 Genomes Project. In contrast to the more ancient ancestry in the South than in the North that has been claimed, we detected very similar coalescence times within Northern and Southern non-tribal Indian populations. A closest neighbour analysis in the phylogeny showed that Indian populations have an affinity towards Southern European populations and that the time of divergence from these populations substantially predated the Indo-European migration into India, probably reflecting ancient shared ancestry rather than the Indo-European migration, which had little effect on Indian male lineages. Among the tribal populations, the Birhor (Austro-Asiatic-speaking) and Irula (Dravidian-speaking) are the nearest neighbours of South Asian non-tribal populations, with a common origin in the last few millennia. In contrast, the Riang (Tibeto-Burman-speaking) and Andamanese have their nearest neighbour lineages in East Asia. The Jarawa and Onge shared haplogroup D lineages with each other within the last ~7000 years, but had diverged from Japanese haplogroup D Y-chromosomes ~53000 years ago, most likely by a split from a shared ancestral population. This analysis suggests that Indian populations have complex ancestry which cannot be explained by a single expansion model. Funding was provided by the joint Spain–India bilateral grant PRI-PIBIN-2011-0942 and BFU2016-77961-P (AEI/ FEDER, UE) both awarded by the Ministerio de Economía y Competitividad (Spain) and with the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2014 SGR 866). Anders Bergström, YaliXue and Chris Tyler-Smith were supported by The Wellcome Trust (Grant 098051)

Summary Variants in the UGT1A1 gene and its promoter are known to determine levels of unconjugated bilirubin (UCB), but do not explain all cases of unconjugated hyperbilirubinemia. To discover associations with variants in genes other than UGT1A1, we undertook a genome-wide association study. We recruited 200 participants to cover the entire range of quantitative variation in UCB level. The data set – after data curation, including analyses for population stratification and cryptic relatedness – comprised genotypes at 512,349 SNP loci on 182 individuals. Quantitative trait locus (QTL) association analyses were performed, after adjusting the UCB level for effects of age, gender, and genotype at the dinucleotide (TA) insertion locus in UGT1A1 that is known to significantly modulate UCB level. A significant association of a polymorphic marker (rs2328136) near the NUP153 gene (which produces a 153 kDa nucleoporin) was obtained (p = 0.002, after multiple-testing correction). The frequency of the variant allele (A) at the rs2328136 locus in our study population is 40%, higher than most global populations. NUP153, whose product is a major regulatory factor in bidirectional transport of biomolecules across nucleus to cytosol, is associated with the transport of biliverdin reductase, which is important for bilirubin conjugation.

Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/Gypsy founder population. Comprehensive sequencing analysis revealed a level of heterogeneity unusual for this population, with five CYP1B1 and one ancestral LTBP2 mutation accounting for ∼70% of patients (25 out of 37) and the remainder still unexplained. Homozygosity for the founder LTBP2 p.R299X mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of p.R299X homozygotes showed variable phenotypes (presumably also underlying pathogenetic mechanisms), wherein PCG proper with primary dysgenesis of the trabecular meshwork, and Marfan syndrome-like zonular disease with ectopia lentis and later onset secondary glaucoma are two extremes. The spectrum manifestations may occur in different combinations and have a different evolution even within the same sibship or a single patient. Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. We provide a population genetics perspective to explain the allelic heterogeneity, comparing the history and geographic distribution of the two major founder mutations – p.R299X/LTBP2 and p.E387K/CYP1B1.

Primary congenital glaucoma (PCG) is a childhood autosomal-recessive disorder caused by developmental defects in the trabecular meshwork and anterior chamber angle. These defects cause raised intraocular pressure (IOP) that damages the optic nerve and if left untreated, results in irreversible blindness. Mutations in CYP1B1 gene at the GLC3A locus (2p21) are associated with PCG. However, there has been very limited exploration of its promoter region. We resequenced the CYP1B1 promoter in a large cohort (n = 835) that included patients with PCG (n = 301), other primary glaucomas (primary open-angle glaucoma: n = 115 and primary angle closure glaucoma: n = 100) and unaffected controls (n = 319). We functionally characterized one associated variant by luciferase reporter assay using the trabecular meshwork (TM3) cell line. We found evidence of strong (P = 6.01 × 10(-4)) association of rs2567206 (T2805C) SNP in PCG and not in other primary glaucomas. Luciferase assay indicated a ∼90% reduction in CYP1B1 promoter activity in the risk-allele (C) compared to the other allele (T). The association of the risk allele was stronger in cases harboring homozygous CYP1B1 mutations (P = 3.42 × 10(-12)). The risk haplotype 'C-C-G' in the promoter had a strong non-random association to the previously characterized risk haplotype 'C-G-G-T-A' in the coding region. The independent effect of genotype at the promoter T2805C locus (P = 0.001), and the interaction effect of genotypes at the promoter and coding region mutations loci (P = 0.001) were significant for the presenting IOP of the worst affected eye. This is the first study that unequivocally shows the functional involvement of a CYP1B1 promoter variant in PCG.

Human Y chromosome haplogroup structure is largely circumscribed by continental boundaries. One notable exception to this general pattern is the young haplogroup R1a that exhibits post-Glacial coalescent times and relates the paternal ancestry of more than 10% of men in a wide geographic area extending from South Asia to Central-East Europe and South Siberia. Its origin and dispersal patterns are poorly understood as no marker has yet been described that would distinguish European R1a chromosomes from Asian. Here we present frequency and haplotype diversity estimates for more than 2, 000 R1a chromosomes assessed for several newly discovered SNP markers that introduce the onset of informative R1a subdivisions by geography. Marker M434 has a low frequency and a late origin in West Asia bearing witness to recent gene flow over the Arabian Sea. Conversely, marker M458 has a significant frequency in Europe, exceeding 30% in its core area in Eastern Europe and comprising up to 70% of all M17 chromosomes present there. The diversity and frequency profiles of M458 suggest its origin during the early Holocene and a subsequent expansion likely related to a number of prehistoric cultural developments in the region. Its primary frequency and diversity distribution correlates well with some of the major Central and East European river basins where settled farming was established before its spread further eastwards. Importantly, the virtual absence of M458 chromosomes outside Europe speaks against substantial patrilineal gene flow from East Europe to Asia, including to India, at least since the mid-Holocene.

Alu insertion/deletion polymorphisms (Alu ACE, Alu PV92 and Alu APO) were studied in three Telugu - speaking immigrants of Tamil Nadu, to understand their affinities with Andhra Pradesh population. Gene frequencies and average heterozygosity were calculated. All the three loci are polymorphic in nature and showed high levels of heterozygosity. Phylogenetic analysis of the present data with the available data of two Tamil Nadu caste population and Yadavar of Andhra Pradesh revealed that all the three immigrant populations did not show closeness with the Andhra Yadavar.

Genomic affinity based on eight human - specific polymorphic insertion/ deletion loci was studied in an early immigrant population, Thevar group, of Tamil Nadu, South India. They are traditionally agriculturists, culturally homogenous and endogamous. The seven Alu elements (Alu APO, Alu CD4, Alu PV92, Alu FXIIIB, Alu ACE, Alu PLAT, Alu D1) and one nuclear insertion of mitochondrial DNA segment (mtNUC) were analyzed for all the DNA samples. All these loci showed high levels of polymorphism in caste populations of Tamil Nadu, thereby reflecting their common ancestry. The significant greater inter-individual variation and the moderate population differentiation probably indicate genetic closeness of these populations. The present study populations were also compared with six other caste populations of Tamil Nadu for which the data were available. Phylogenetic analysis of these populations broadly corresponds to their known ethno-historical affinities.

The HapMap data are being widely used in human genetic studies. We show by direct resequencing of a approximately 6-kb region of chromosome 1 that the HapMap data are unreliable for this region. This region contains a recent mitochondrial (mt) DNA insertion. The HapMap data report the corresponding mtDNA variation and not the nuclear DNA variation. In view of mtDNA insertions of varying lengths throughout the human genome and considerable segmental duplications, it is necessary to use the HapMap data cautiously.

Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders characterized by an abnormally low amount of melanin in the eyes, skin and hair, and associated with common developmental abnormalities of the eye. Defects in the tyrosinase gene (TYR) cause a common type of OCA, known as oculocutaneous albinism type 1 (OCA1). The molecular basis of OCA has been studied extensively in different population groups, but very little information is available on Indian patients. Our investigation covering thirteen ethnic groups of India, some representing >20 million people, revealed that among 25 OCA families 12 were affected with OCA1, and that these cases were primarily due to founder mutations in TYR. We detected nine mutations and eight SNPs in TYR, of which six mutations (five point mutations & one gross deletion) were novel. In contrast to most reports describing compound heterozygotes, the presence of homozygotes in 10 out of the 12 pedigrees underscores the lack of intermixing between these ethnic groups in India. Haplotype analysis suggested a few founder chromosomes causing the disease in the majority of the patients. Direct detection of the mutations prevalent in specific ethnic groups could be used for carrier detection and genetic counselling.

Although considerable cultural impact on social hierarchy and language in South Asia is attributable to the arrival of nomadic Central Asian pastoralists, genetic data (mitochondrial and Y chromosomal) have yielded dramatically conflicting inferences on the genetic origins of tribes and castes of South Asia. We sought to resolve this conflict, using high-resolution data on 69 informative Y-chromosome binary markers and 10 microsatellite markers from a large set of geographically, socially, and linguistically representative ethnic groups of South Asia. We found that the influence of Central Asia on the pre-existing gene pool was minor. The ages of accumulated microsatellite variation in the majority of Indian haplogroups exceed 10,000-15,000 years, which attests to the antiquity of regional differentiation. Therefore, our data do not support models that invoke a pronounced recent genetic input from Central Asia to explain the observed genetic variation in South Asia. R1a1 and R2 haplogroups indicate demographic complexity that is inconsistent with a recent single history. Associated microsatellite analyses of the high-frequency R1a1 haplogroup chromosomes indicate independent recent histories of the Indus Valley and the peninsular Indian region. Our data are also more consistent with a peninsular origin of Dravidian speakers than a source with proximity to the Indus and with significant genetic input resulting from demic diffusion associated with agriculture. Our results underscore the importance of marker ascertainment for distinguishing phylogenetic terminal branches from basal nodes when attributing ancestral composition and temporality to either indigenous or exogenous sources. Our reappraisal indicates that pre-Holocene and Holocene-era--not Indo-European--expansions have shaped the distinctive South Asian Y-chromosome landscape.

The genetic basis of bipolar disorder (BPD) and schizophrenia (SCZ) has been established through numerous clinical and molecular studies. Although often considered separate nosological entities, evidence now suggests that the two syndromes may share some genetic liability. Recent studies have used a composite phenotype (psychosis) that includes BPD, SCZ, psychosis not otherwise specified, and schizoaffective disorder, to identify shared susceptibility loci. Several chromosomal regions are reported to be shared between these syndromes (18p, 6q, 10p, 13q, 22q). As a part of our endeavor to scan these regions, we report a positive linkage and association finding at 18p11.2 for psychosis. Two-point linkage analysis performed on a series of 52 multiplex pedigrees with 23 polymorphic markers yielded a LOD score of 2.02 at D18S37. An independent set of 159 parent offspring trios was used to confirm this suggestive finding. The TDT analysis yielded support for association between the marker D18S453 and the disease allele (X 2 =4.829, P

We have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non-synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF-376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between-population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case-control association studies.

We report a comprehensive statistical analysis of data on 58 DNA markers (mitochondrial [mt], Y-chromosomal, and autosomal) and sequence data of the mtHVS1 from a large number of ethnically diverse populations of India. Our results provide genomic evidence that (1) there is an underlying unity of female lineages in India, indicating that the initial number of female settlers may have been small; (2) the tribal and the caste populations are highly differentiated; (3) the Austro-Asiatic tribals are the earliest settlers in India, providing support to one anthropological hypothesis while refuting some others; (4) a major wave of humans entered India through the northeast; (5) the Tibeto-Burman tribals share considerable genetic commonalities with the Austro-Asiatic tribals, supporting the hypothesis that they may have shared a common habitat in southern China, but the two groups of tribals can be differentiated on the basis of Y-chromosomal haplotypes; (6) the Dravidian tribals were possibly widespread throughout India before the arrival of the Indo-European-speaking nomads, but retreated to southern India to avoid dominance; (7) formation of populations by fission that resulted in founder and drift effects have left their imprints on the genetic structures of contemporary populations; (8) the upper castes show closer genetic affinities with Central Asian populations, although those of southern India are more distant than those of northern India; (9) historical gene flow into India has contributed to a considerable obliteration of genetic histories of contemporary populations so that there is at present no clear congruence of genetic and geographical or sociocultural affinities.

India has the unique distinction of having perhaps the largest diversities, both biological and cultural. The Nilgiri Hills of southern India, a home for several tribal pockets representing different genetic isolates, provides a genetic wealth to understand human evolution. We have analyzed eight widely distributed polymorphic insertion/deletion loci (AluAPO, AluACE, AluDI, AluPLAT, AluPV92, AluFXIIIB, CD4 del and mtNUC) in 250 unrelated individuals from five tribal populations (Badaga, Irula, Kota, Kurumba, and Toda). All loci were highly polymorphic except the CD4 del locus, at which the deletion allele was fixed in Kotas and Kurumbas. The levels of average heterozygosities were found to be high in all the populations. In most populations, they were also higher than those predicted by the island model of population structure. The gene diversity (GST = 8.3%) was found to be higher than that in populations of most global regions with the exception of Africa. It is clear from the present study that drift effects could have accentuated the process of genetic differentiation of the tribal populations. The possibility of an early demographic expansion of modern humans within south India also cannot be ruled out.

DNA samples from 123 unrelated individu- als belonging to 2 endogamous tribal populations, namely, the Koya Doras and Konda Reddis, of East Godavari Dis- trict, Andhra Pradesh, South India were analysed for 8 hu- man specific polymorphic insertion/deletion loci. Except Alu CD4, all the loci are polymorphic in both the popula- tions. Most of the loci showed high levels of heterozygos- ity in both the populations. The average heterozygosity is higher in Konda Reddis than in Koya Doras. The results were compared with available Indian data on four other tribal populations, namely, Lodha, Munda, Santal and Tipperah.

The frequencies of haplotypes based upon the (CTG)n repeat and three other biallelic markers in and around the myotonic dystrophy (DM) locus were estimated in 13 ethnically, linguistically and geographically diverse sub-populations of India. The range of CTG repeats in caste populations was 5-31, while in tribal populations the range was shorter (5-23). Extensive variation in frequencies of large (CTG)n alleles (or =18 repeats) was found in Indian populations. The implications of this finding on DM epidemiology are discussed. Haplotype diversity was found to be very high in most populations. The majority of the Indian DM patients carried a haplotype that is commonly found among DM patients globally; this is the most common haplotype in the class of large (or =18 repeats) CTG alleles. However, one haplotype was found to be present in particularly high frequency in Indian populations; this haplotype was also found among Indian DM patients. This haplotype may be a characteristic of Indian and possibly of other East Asian populations.

We have analysed the distribution of CAG and adjacent polymorphic CCG repeats in the Huntingtin gene in 28 clinically diagnosed unrelated Huntington's disease (HD) patients and in normal individuals belonging to different ethnic groups of India. The range of expanded CAG repeats in HD patients varied from 41 to 56 repeats, whereas in normal individuals this number varied between 11 and 31 repeats. We identified six CCG alleles from a total of 380 normal chromosomes that were pooled across different ethnic populations of India. There were two predominant alleles: (CCG)7 (72.6%) and (CCG)10 (20%). We report here for the first time one four-repeat CCG allele which has not been found in any population so far. We found 30 haplotypes (two loci CAG-CCG) for 380 normal chromosomes. In the present study, no statistically significant preponderance of expanded HD alleles was found on either (CCG)7 or (CCG)10 backgrounds. Our studies suggest that the overall prevalence of HD in Indian populations may not be as high as in Western populations. Further studies are necessary to identify the origin of HD mutation in these populations.

To identify various subtypes of spinocerebellar ataxias (SCAs) among 57 unrelated individuals clinically diagnosed as ataxia patients we analysed the SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci for expansion of CAG repeats. We detected CAG repeat expansion in 6 patients (10.5%) at the SCA1 locus. Ten of the 57 patients (17.5%) had CAG repeat expansion at the SCA2 locus, while four had CAG expansion at the SCA3/MJD locus (7%). At the SCA6 locus there was a single patient (1.8%) with 21 CAG repeats. We have not detected any patient with expansion in the SCA7 and DRPLA loci. To test whether the frequencies of the large normal alleles in SCA1, SCA2 and SCA6 loci can reflect some light on prevalence of the subtypes of SCAs we studied the CAG repeat variation in these loci in nine ethnic sub-populations of eastern India from which the patients originated. We report here that the frequency of large normal alleles (>31 CAG repeats) in SCA1 locus to be 0.211 of 394 chromosomes studied. We also report that the frequency of large normal alleles (>22 CAG repeats) at the SCA2 locus is 0.038 while at the SCA6 locus frequency of large normal alleles (>13 repeats) is 0.032. We discussed our data in light of the distribution of normal alleles and prevalence of SCAs in the Japanese and white populations.

Mapping a locus controlling a quantitative genetic trait (e.g., blood pressure) to a specific genomic region is of considerable interest. Data on the quantitative trait under consideration and several codominant genetic markers with known genomic locations are collected from members of families and statistically analyzed to draw inferences on the genomic position of the trait locus. The vector of parameters of interest comprises the pairwise recombination fractions, θ, between the putative quantitative trait locus and the marker loci. One of the major complications in estimating θ for a quantitative trait in humans is the lack of haplotype information on members of families. The purpose of this study was to devise a computationally simple and efficient method of estimation of θ in the absence of haplotype information. We have proposed a two-stage estimation procedure using the expectation-maximization (EM) algorithm. In the first stage, parameters of the QTL are estimated based on data of a sample of unrelated individuals. From estimates thus obtained, we have used a Bayes' rule to infer QTL genotypes of parents in families. Finally, in the second stage of the procedure, we have proposed an EM algorithm for obtaining the maximum likelihood estimate of θ based on data of informative families (which are identified upon inferring parental QTL genotypes performed in the first stage). We have shown, using simulated data, that the proposed procedure is cost-effective, computationally simple, and statistically efficient. As expected, analysis of data on multiple markers jointly is more efficient than the analysis based on single markers. Genet. Epidemiol. 19:97–126, 2000. © 2000 Wiley-Liss, Inc.

Bipolar affective disorder and schizophrenia are severe behavioral disorders with a lifetime risk of \sim 1% in the population worldwide. There is evidence that these diseases may manifest the phenomenon of anticipation similar to that seen in diseases caused by trinucleotide repeat expansions. A recent report has implicated a potassium channel-coding gene, KCNN3, which contains a polymorphic CAG repeat in its coding region, in schizophrenia and bipolar disorder. We have tried to confirm these findings in Indian patients suffering from bipolar disorder and schizophrenia. No statistically significant evidence for the presence of an excess of longer alleles in the patient population, as compared to ethnically matched controls, was found. However, an analysis of the difference of allele sizes revealed a significantly greater number of patients with schizophrenia having differences of allele sizes \geq 5 when compared to normal controls. This finding may be of functional significance as the KCNN3 protein is thought to act as a tetramer, and a large difference in allele sizes would result in an asymmetric molecule with a different number of glutamine residues in each monomer.

Genome-wide screening for localization of disease genes necessitates the efficient reconstruction of haplotypes of members of a pedigree from genotype data at multiple loci. We propose a genetic algorithmic approach to haplotyping and show that it works fast, efficiently and reliably. This algorithm uses certain principles of biological evolution to find optimal solutions to complex problems. The optimality criterion used in the present problem is the minimum number of recombinations over possible haplotype configurations of members of a pedigree. The proposed algorithm is much less demanding in terms of data and assumption requirements compared to the currently used likelihood-based methods of haplotype reconstruction. It also provides multiple optimal haplotype configurations of a pedigree, if such multiple optima exist.

DNA samples from 396 unrelated individuals belonging to 14 ethnic populations of India, inhabiting various geographical locations and occupying various positions in the socio-cultural hierarchy, were analysed in respect of 8 human-specific polymorphic insertion/deletion loci. All loci, except Alu CD4, were found to be highly polymorphic in all populations. The levels of average heterozygosities were found to be very high in all populations and, in most populations, also higher than those predicted by the island model of population structure. The coefficient of gene differentiation among Indian populations was found to be higher than populations in most other global regions, except Africa. These results are discussed in the light of two possible scenarios of evolution of Indian populations in the broader context of human evolution.

Differences in immunological response among vaccine recipients are determined both by their genetic differences and environmental factors. Knowledge of genetic determinants of immunological response to a vaccine can be used to design a vaccine that circumvents immunogenetic restrictions. The currently available vaccine for typhoid is a pure polysaccharide vaccine, immune response to which is T-cell independent. Little is known about whether genetic variation among vaccinees associates with variation in their antibody response to a polysaccharide vaccine. We conducted a study on 1,000 individuals resident in an area at high-risk for typhoid; vaccinated them with the typhoid vaccine, measured their antibody response to the vaccine, assayed >2,000 curated SNPs chosen from 283 genes that are known to participate in immune-response; and analyzed these data using a strategy to (a) minimize the statistical problems associated with testing of multiple hypotheses, and (b) internally cross-validate inferences, using a half-sample design, with little loss of statistical power. The first stage analysis, using the first half-sample, identified 54 SNPs in 43 genes to be significantly associated with immune response. In the second-stage, these inferences were cross-validated using the second half-sample. First-stage results of only 8 SNPs (out of 54) in 7 genes (out of 43) were cross-validated. We tested additional SNPs in these 7 genes, and found 8 more SNPs to be significantly associated. Haplotypes constructed with these SNPs in these 7 genes also showed significant association. These 7 genes areDEFB1,TLR1,IL1RL1,CTLA4,MAPK8,CD86andIL17D. The overall picture that has emerged from this study is that (a) immune response to polysaccharide antigens is qualitatively different from that to protein antigens, and (b) polymorphisms in genes involved in polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signaling and eventual production of antimicrobial peptides are associated with antibody response to the polysaccharide vaccine for typhoid.

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.

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.

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.

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.

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.

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.

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.

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.

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)

The main feature of Indian society, seen at its strongest in the rural areas, is caste. A caste is a collection of people who share similar cultural and religious values and practices. Members within a caste generally marry among themselves; intercaste marriages are a cultural taboo. These social regulations governing the institution of marriage have resulted in a substructuring of the Indian gene pool. There are also elaborate social regulations of avoidance of marriages within castes, and thus there is genomic substructuring even within a caste. The origins of the castes in India remain an enigma. Many castes are known to have tribal origins, as evidenced from various totemic features that manifest themselves in these caste groups (Kosambi 1964). The caste system in northern India may have developed as a class structure from within tribes: As agriculture spread from the Indus River valley to the Gangetic basin, knowledge and ownership of the means of food production may have created hierarchical divisions within tribal societies (Kosambi 1964). Karve (1961) has also argued that “something very like castes were in India” even before Aryan speakers entered India. The Aryan world comprised three classes (varnas): priests, nobles, and commoners. Aryans as the conquering people possibly placed their three classes on the indigenous Indian society. The varna organization is hierarchical. Initially, the system had names for two ranks, Brahma (Brahmin) and Kshatra (Kshatriya), Brahmin being of a socially higher rank than Kshatriya. The third rank was made up of Vis, that is, all the subjects. To this society, a fourth rank was added: Shudra, who had no rights to Aryan ritual. In southern India, the menial workers, the so-called “untouchables”, were placed in a new varna, Panchama (meaning fifth). It is conceivable that the Aryan speakers had greater contact, including genetic admixture, with the Brahmins, who were professionally the torchbearers and promoters of Aryan rituals. The Aryan contact should have been progressively less as one descended the varna ladder. The genetic expectation, therefore, is that the proportions of those genes (or genomic features, such as haplotypes or haplogroups) that “characterized” the Aryan speakers should progressively decline from the highest varna to the lowest and a reverse trend should be observed with respect to those genes that “characterized” the indigenous Indians. Although some previous studies have sought to test this expectation, the observed trends were equivocal. The primary reason was the lack of data on a large uniform set of markers from populations of India and central/west Asia (the region from which the Aryans speakers who entered India originated). The study by Bamshad et al. (2001), who have also sought to test the above expectation, is clearly a landmark. Using a very large battery of genomic markers and DNA sequences, spanning autosomal, mitochondrial, and Y-chromosomal genomic regions, they have shown that the observed trend of genetic admixture estimated from castes belonging to different varnas is congruent with expectations. This trend was observed in each of the three data subsets. The only exception was in respect of mtDNA restriction site haplotypes, which was also noted in a recent study conducted by us (Roychoudhury et al. 2000). However, after combining these haplotype data with DNA sequence data, Bamshad and colleagues were able to capture the expected trend. Thus, this study not only provides a wonderful genomic view of the castes and of their origins, but also underscores the need for careful statistical analysis of genomic data for drawing appropriate inferences. The use of “upper”, “middle”, and “lower” to designate caste hierarchy is muchmore recent than the use of varna. Whereas varnas are traditionally defined, different anthropologists have used different definitions of upper, middle, and lower castes, in terms of the castes that they included in each of these clusters. Sometimes these differences in definitions have stemmed from socio-cultural similarities or differences as noted or perceived by different anthropologists, and sometimes ranked caste-cluster compositions were altered for convenience, such as pooling to adjust for small sample sizes. As noted earlier, in studies such as Bamshad et al.’s, the most appropriate classification is by varna. As the reader will note, the authors have analyzed their data using different compositions of hierarchical caste-clusters and have obtained homologous results. However, it needs to be emphasized that traditional varna system is the only unequivocally accepted hierarchical system. In studies pertaining to the origins of castes, one is liable to draw incorrect inferences by inE-MAIL ppm@isical.ac.in; FAX 91-33-577 3049. Article and publication are at www.genome.org/cgi/ doi/10.1101/gr.192401. Insight/Outlook

When nonrandom segregation of marker haplotypes from parents to offspring is detected, leading to an increased parental haplotype sharing by affected offspring, an association between the disease and the marker loci is often inferred. In this paper, we provide the uniformly most powerful test for testing nonrandom segregation, and compare the power of this test with another test that is available in the literature. Other statistical properties of the two tests are also discussed. Further, since nonrandom segregation can result from linkage of the disease and marker loci, when the hypothesis of random segregation is rejected, it is of interest to estimate the underlying parameter assuming linkage. We provide an estimation procedure.

An epidemiological profile of vitiligo in Calcutta is presented. Prevalence data were gathered from 15,685 individuals drawn from the general population; pedigree data were collected through 293 vitiligo patients. The overall prevalence of vitiligo is about 5 per 1,000 individuals. There are no significant sex or age differences in prevalence rates. About a 4.5-fold increase in prevalence is observed among close biological relatives of affected individuals. There is, however, no clearcut correspondence between relative risks and kinship coefficients. There are no significant differences in the frequencies of various types of vitiligo between probands with and without positive family history. The overall mean and modal ages of onset are about 22 years and 15 years, respectively. The mean ages among males (24.8 years) and females (19.3 years) are significantly different.

It is often of interest to know whether there is increased occurrence of a trait in a pedigree or other structured set of epidemiological data. In answering such questions most current methods use aggregate measures, such as relative risk, that may not relate the outcome for each individual to that individual's risk. In this paper we present a simple method, and its computational algorithm, to overcome this limitation. This new method also permits one to identify high-risk families or subsets of a collection of data, which is not always possible using other approaches. In a study of cancer risk among relatives of retinoblastoma patients, by applying this new method it was found that 11 of 33 families each obtained through a unilateral retinoblastoma patient are at statistically high risk of cancer at all sites combined, while there are 15 of 47 such families obtained through a bilaterally affected proband. These results are unlikely to have occured by chance, indicating an overall excess risk in the ancestors of these retinoblastoma cases. The proposed test procedure does not specify the cause of elevated risk; however, a method is proposed that provides some indication regarding possible causal mechanisms under some circumstances.