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Background: The Brokpas are an isolated tribal population of the Dah-Hanu villages of the Leh district of India. They speak Dardic, a sub-branch of the Indo-European language family, and are putatively identified as "pure Aryan," a hegemonic impression perpetuated by foreign tourism.Aim: To determine if the above is true by looking for an appreciable frequency of NRY-HG-R1a1(M17) signatures which are common to Indo-European language speakers of mainland India and elsewhere.Subjects and methods: We studied 75 random Brokpa males from the Dah-Hanu region, on the northern bank of the Indus river.Results: Interestingly, the Brokpa males possessed a high proportion of NRY-HG-L1a2(M357) (62.7%) that are found sporadically in India and her neighbourhood. A global analysis of this clade (present study, 214 of 3327 men from 63 populations; from the literature 56 of 873) suggested that they originated from southern India.Conclusion: The Y chromosomal studies suggest the Brokpa to be pre-Vedic settlers of the Himalayas, 9000 ybp, with an isolated evolution. The mtDNA profile shows a predominance of mtDNA HG A4 that must have arrived from outside the Indian subcontinent.

Among the various candidate genes predisposing for cardiovascular diseases, HLA-DRB1* and IL-1β +3953C/T alleles have been implicated repeatedly. To test these in South India, we carried out a case control study of 323 Coronary Artery Disease (CAD) patients, 56 Rheumatic Heart Disease (RHD) patients and 254 endemic controls. The polymorphisms were studied by PCR – SSP and ARMS-PCR methods and results analyzed for various clinical and demographic parameters. In CAD, HLA-DRB1*14 allele showed significant predisposition (OR: 2.19; 95% CI: 1.04–4.58; p value = 0.023), particularly in male patients (OR: 4.07; 95% CI: 1.20–13.81; p value = 0.01) and further in males with Triple Vessel Disease (OR: 5.49; 95% CI: 1.45–20.60; p value = 0.007). On the other hand, HLA-DRB1*15 predisposed for RHD (OR: 3.56; 95% CI: 1.87–6.78; p value = 0.001) in both the genders. Population stratification showed this higher risk association in Vanniyar caste (OR: 5.00; 95% CI: 1.27–19.59; p value = 0.022). Among the IL1-β +3953C/T polymorphism, the ancestral allele ‘C’ showed a significant high risk association with CAD (OR: 1.83; 95% CI: 1.24–2.70; p value = 0.001), particularly in Mudaliar (OR: 6.07; 95% CI: 1.77–20.74; p value = 0.003; AF = 0.7) and Vanniyar castes (OR: 3.67; 95% CI: 0.92–14.57; p value = 0.05; AF = 0.660). Two different cardiac ailments studied, RHD & CAD thus showed varied associations in this South Indian cohorts. RHD having an infectious aetiology shared a HLA-DRB1*15 high risk association, while HLA-DRB1*14 and IL-1β +3953C predisposed for CAD, an inflammatory disorder, reiterating the diverse genetic predisposition of the two cardiac ailments studied.

Multiple questions relating to contributions of cultural and demographical factors in the process of human geographical dispersal remain largely unanswered. India, a land of early human settlement and the resulting diversity is a good place to look for some of the answers. In this study, we explored the genetic structure of India using a diverse panel of 78 males genotyped using the GenoChip. Their genome-wide single-nucleotide polymorphism (SNP) diversity was examined in the context of various covariates that influence Indian gene pool. Admixture analysis of genome-wide SNP data showed high proportion of the Southwest Asian component in all of the Indian samples. Hierarchical clustering based on admixture proportions revealed seven distinct clusters correlating to geographical and linguistic affiliations. Convex hull overlay of Y-chromosomal haplogroups on the genome-wide SNP principal component analysis brought out distinct non-overlapping polygons of F*-M89, H*-M69, L1-M27, O2a-M95 and O3a3c1-M117, suggesting a male-mediated migration and expansion of the Indian gene pool. Lack of similar correlation with mitochondrial DNA clades indicated a shared genetic ancestry of females. We suggest that ancient male-mediated migratory events and settlement in various regional niches led to the present day scenario and peopling of India.

South Asia harbors one of the highest levels genetic diversity in Eurasia, which could be interpreted as a result of its long-term large effective population size and of admixture during its complex demographic history. In contrast to Pakistani populations, populations of Indian origin have been underrepresented in previous genomic scans of positive selection and population structure. Here we report data for more than 600,000 SNP markers genotyped in 142 samples from 30 ethnic groups in India. Combining our results with other available genome-wide data, we show that Indian populations are characterized by two major ancestry components, one of which is spread at comparable frequency and haplotype diversity in populations of South and West Asia and the Caucasus. The second component is more restricted to South Asia and accounts for more than 50% of the ancestry in Indian populations. Haplotype diversity associated with these South Asian ancestry components is significantly higher than that of the components dominating the West Eurasian ancestry palette. Modeling of the observed haplotype diversities suggests that both Indian ancestry components are older than the purported Indo-Aryan invasion 3,500 YBP. Consistent with the results of pairwise genetic distances among world regions, Indians share more ancestry signals with West than with East Eurasians. However, compared to Pakistani populations, a higher proportion of their genes show regionally specific signals of high haplotype homozygosity. Among such candidates of positive selection in India are MSTN and DOK5, both of which have potential implications in lipid metabolism and the etiology of type 2 diabetes.

By interacting with polymorphic HLA class I molecules, the killer cell immunoglobulin-like receptors (KIR) influence the innate and adaptive immune response to infection. The KIR family varies in gene content and sequence polymorphism, thereby, distinguishing individuals and populations. To investigate KIR diversity in the earliest settlers of India, we have characterized the KIR gene content in three Dravidian-speaking populations (Mollukurumba, Kanikar, and Paravar) from the state of Tamil Nadu, southern India. The activating KIR genes and putative group-B KIR haplotypes were frequent in Paravar and Kanikar, a scenario analogous to those seen previously in other populations of Indian origin, indicating that predominance of group-B KIR haplotypes is the characteristic feature of Indian populations. In contrast, the KIR gene profile of Mollukurumba was more related to Caucasian type. It is not clear whether a local-specific selection or a recent admixture from Iran is responsible for such discrete profile in Mollukurumba. Each southern Indian population had distinct KIR genotype profile. Comparative analyses with world populations revealed that group-B KIR haplotypes were frequent in the natives of India, Australia, and America, the populations associated with those involved in extensive prehistoric human migrations. Whether or not natural selection has acted to enrich group-B KIR haplotypes in these migratory descendants is an issue that requires objective testing.

Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.

The immunogenetic dictum "not all the infected develop the disease" can best be explained by a "Lotus and Cactus" model. Lotuses grow in ponds and cacti in deserts: analogously, we can say that tubercle patient's lung (genetic makeup) functions as an ideal 'broth' for Mycobacterium tuberculosis (M.tb) germs to grow, but not the lungs of an endemic control. HLA association studies from Europe to Asia since 1983 till date, have shown a persistent HLA DR2 (15) association. Further, HLA DR2 and non-DR2 endemic controls showed disparate patterns of immune responses and gene expressions. The host and pathogen MHC diversities, Th1-Th2 paradigm and cytokine circuits all may play a crucial role in TB susceptibility. It is possible to decipher the protective immunity by controlling the known confounders - epidemiological, demographic, socio-biological and also host and pathogen diversities. This has become significant with our understanding on the 'out of Africa' migration and neolithic co-dispersal of M.tb with modern human. Divergence and expansion of various MHCs (eg HLA-DRB1*15, HLA-B*57) and non-MHC alleles in various continents might be responsible for the skewed transmission and distribution of the infectious diseases around the globe. The 'Lotus and Cactus' model proposed here exemplifies this. A holistic genetic epidemiology approach employing modern tools is the need of the hour to better understand infectious disease susceptibility.

In a study of mainly paucibacillary leprosy-affected sib-pair families from South India, in addition to the expected associations with the HLA-DRB1 locus, we have identified significant association with a functional variant of the MICA gene as well as a microsatellite in the flanking region of the MICB gene. The associations with MICA and MICB cannot be accounted for by linkage disequilibrium with the HLA class II locus indicating a role in genetic susceptibility to leprosy that is independent of HLA-DRB1. Previous studies have shown that MICA and MICB are expressed on the surface of cells in response to infection, where they are recognized by the NKG2D receptor on gammadelta T cells, CD8+ alphabeta T cells and natural killer cells, all of which contribute to defense against mycobacteria. The MICA*5A5.1 allele, associated here with leprosy susceptibility, encodes a protein lacking a cytoplasmic tail providing a possible mechanism for defective immune surveillance against mycobacteria.

Purified protein derivative (PPD) RT23-recalled T-cell receptor (TCR) Vβ expression was studied in the peripheral blood of 42 pulmonary tuberculosis patients and 44 healthy controls from southern India, a region where tuberculosis is endemic. Forty-eight-hour whole-blood cultures in the presence or absence of PPD-RT23 were set up, and at the end of the culture period total RNA was extracted and cDNA was synthesized. Expression of various TCR Vβ families was assessed by using family-specific primers. PPD-specific expression (usage) of TCR Vβ families 4, 6, 8 to 12, and 14 was found in more controls than patients. Among the responders (individuals who showed PPD-specific expression), endemic controls had significantly higher responses than the patients had for TCR Vβ families 2, 3, 7, 13, and 17. The majority of the patients did not show usage of most of the TCR Vβ families, and this was attributed to T-cell downregulation. A four-way nested classification analysis revealed that TCR Vβ family 1, 5, 9, 12, and 13 usage in the context of HLA class II high-risk alleles (DRB1*1501, DRB1*08, and DQB1*0601) andMycobacterium bovisBCG scar status were the determining factors in susceptibility and resistance to tuberculosis. The healthier status of controls was attributed to the wider usage of many TCR Vβ families readily recalled by PPD, while the disease status of the patients was attributed to TCR Vβ downregulation and the resultant T-cell (memory cell?) unresponsiveness. Host genetics (HLA status) and BCG vaccination (scar status) seem to play important roles in skewing the immune response in adult susceptibility to pulmonary tuberculosis through TCR Vβ usage.

A major susceptibility locus for leprosy has recently been mapped on chromosome 10 (10p13) by genome-wide linkage analysis. Microsatellite markers from this genome screen that showed suggestive evidence of linkage to leprosy were evaluated in an additional 140 families with affected sib pairs. A second region of linkage has thus been identified on chromosome 20 (20p12). The peak of linkage lies at marker D20S115, which has a significant single-point maximum logarithm of odds score of 3.48 (P=.00003). Transmission disequilibrium testing of the microsatellite markers in 20p12 showed that the marker D20S835 is associated with protection against leprosy (P=.021), which suggests that a locus controlling susceptibility lies close to this marker.

HLA DRB1*02 and its subtypes predispose individuals for a far-advanced sputum-positive pulmonary tuberculosis transcending ethnic boundaries.Mycobacterium bovisBCG does not afford the desired protection against adult pulmonary tuberculosis, and a spectrum of immune reactivity exists in controls and hospital contacts. All of these findings have been identified and demonstrated in areas of endemicity. Skewing of immunity from protective to pathogenic may involve a shift in the Th1-Th2 paradigm. To elaborate these ideas, we studied gamma interferon (IFN-γ), interleukin-4 (IL-4), and IL-10 cytokine expression in 71 adult pulmonary tuberculosis patients and 74 controls from areas of endemicity in south India by 48-h microculture and reverse transcription-PCR. Most of the patients and controls expressed IFN-γ de novo, and in the presence of purified protein derivative (PPD), all of them expressed significantly higher levels of IFN-γ, suggesting a PPD-specific recall memory. HLA DRB1* allele-dependent IFN-γ expression was identified only in controls, suggesting a skewing of the immune response in patients. In contrast to the case for IFN-γ, only some patients and controls expressed IL-4 or IL-10 (Th2 profile); thus, the Th1 profile was identifiable only by a nonexpression of IL-4 or IL-10 in this area of endemicity. The Th2 profile was associated with HLA non-DRB1*02 and BCG scar-negative status in patients, attributing a significant risk (odds ratio = 2.074; 95% confidence interval = 0.612 to 7.07). It is possible thatMycobacterium tuberculosis(PPD)-specific IL-10 is expressed preemptively in unvaccinated (BCG scar-negative) individuals with a non-DR2 genetic background by chronic exposure in this area of endemicity and leads to pulmonary tuberculosis of adults.

Setting : Tuberculosis is endemic in south India: sputum positive, pulmonary tuberculosis is predisposed by HLA-DR2 in South India and few other populations of the world. Objective : To study HLA-DRB1, DQB1, DQA1 and DPB1 allelic polymorphism in pulmonary tuberculosis patients and endemic controls from South India. Design: One hundred and twenty-six, sputum positive pulmonary tuberculosis patients and 87, endemic controls, from Madurai were studied for MHC class II allelic polymorphism by PCR-SSOP method. XI IHWC primers and probes and non-radioactive probing methods were employed. Results : HLA DRB1*1501and DQB1*0601 predisposed for pulmonary tuberculosis (DRB1*1501:odds ratio (OR) = 2.68, 95% confidence interval (CI) = 1.30 - 5.89, P value (P) = 0.013, aetiological fraction (EF) = 0.17; DQB1*0601: OR=2.32, CI=1.29-4.27, P=0.008, EF=0.26). Haplotype DRB1*1501-DQB1&0601 was higher in patients (1324 per 10,000, X2 = 27.07) than controls (F=404/10000, X2=8.84). In a subset of 63 caste cmatched samples, DPB1*04 was preventive (OR=0.45, CI=0.21-0.95, P=0.036, PF=0.26): the distributions of DRB1*1501-DQB1*0601-DPB1*04 phenotypes were different between patients and controls (P=0.0092). These alleles were predominant in patients and controls of T5SU caste. Conclusion : HLA-DRB1*1501 and DQB1*0601 predisposed to sputum positive pulmonary tuberculosis, and DPB1*04 was preventive and epistatic to this risk. Caste T5SU is an ideal model to study immunology of tuberculosis

Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22–28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India., Author Summary Human skin color is one of the most visible aspects of human diversity. The genetic basis of pigmentation in Europeans has been understood to some extent, but our knowledge about South Asians has been restricted to a handful of studies. It has been suggested that a single nucleotide difference in SLC24A5 accounts for 25–38% European-African pigmentation differences and correlates with lighter skin. This genetic variant has also been associated with skin color variation among South Asians living in the UK. Here, we report a study based on a homogenous cohort of South India. Our results confirm that SLC24A5 plays a key role in pigmentation diversity of South Asians. Country-wide screening of the variant reveals that the light skin associated allele is widespread in the Indian subcontinent and its complex patterning is shaped by a combination of processes involving selection and demographic history of the populations. By studying the variation of SLC24A5 sequences among a diverse set of individuals, we show that the light skin associated allele in South Asians is identical by descent to that found in Europeans. Our study also provides new insights into positive selection acting on the gene and the evolutionary history of light skin in humans.

ArunKumar, GaneshPrasad et al.--The Genographic Consortium, Previous studies that pooled Indian populations from a wide variety of geographical locations, have obtained contradictory conclusions about the processes of the establishment of the Varna caste system and its genetic impact on the origins and demographic histories of Indian populations. To further investigate these questions we took advantage that both Y chromosome and caste designation are paternally inherited, and genotyped 1,680 Y chromosomes representing 12 tribal and 19 non-tribal (caste) endogamous populations from the predominantly Dravidian-speaking Tamil Nadu state in the southernmost part of India. Tribes and castes were both characterized by an overwhelming proportion of putatively Indian autochthonous Y-chromosomal haplogroups (H-M69, F-M89, R1a1-M17, L1-M27, R2-M124, and C5-M356; 81% combined) with a shared genetic heritage dating back to the late Pleistocene (10-30 Kya), suggesting that more recent Holocene migrations from western Eurasia contributed, The study is supported by “The Genographic Project” funded by The National Geographic Society, IBM and Waitt Family Foundation. CTS was supported by The Wellcome Trust (Grant number 098051).

13 páginas.-- Javed, Asif et al., We have analyzed human genetic diversity in 33 Old World populations including 23 populations obtained through Genographic Project studies. A set of 1,536 SNPs in five X chromosome regions were genotyped in 1,288 individuals (mostly males). We use a novel analysis employing subARG network construction with recombining chromosomal segments. Here, a subARG is constructed independently for each of five gene-free regions across the X chromosome, and the results are aggregated across them. For PCA, MDS and ancestry inference with STRUCTURE, the subARG is processed to obtain feature vectors of samples and pairwise distances between samples. The observed population structure, estimated from the five short X chromosomal segments, supports genome-wide frequency-based analyses: African populations show higher genetic diversity, and the general trend of shared variation is seen across the globe from Africa through Middle East, Europe, Central Asia, Southeast Asia, and East Asia in broad patterns. The recombinational analysis was also compared with established methods based on SNPs and haplotypes. For haplotypes, we also employed a fixed-length approach based on information-content optimization. Our recombinational analysis suggested a southern migration route out of Africa, and it also supports a single, rapid human expansion from Africa to East Asia through South Asia., This research is part of the Genographic Project, funded by National Geographic and IBM. Additional funding was provided by the Spanish Ministry of Science and Innovation projects BFU2007-63657, BFU2007-63171, and BFU2010-19443; MM was supported by grant AP2006-03268, Generalitat de Catalunya; OB was supported by Russian Foundation for Basic Research (grants 10-06-00451, 10-04-01603) and by the Presidium RAS Programme “Molecular and Cell Biology”.

Milk consumption and lactose digestion after weaning are exclusively human traits made possible by the continued production of the enzyme lactase in adulthood. Multiple independent mutations in a 100-bp region—part of an enhancer—approximately 14-kb upstream of the LCT gene are associated with this trait in Europeans and pastoralists from Saudi Arabia and Africa. However, a single mutation of purported western Eurasian origin accounts for much of observed lactase persistence outside Africa. Given the high levels of present-day milk consumption in India, together with archaeological and genetic evidence for the independent domestication of cattle in the Indus valley roughly 7,000 years ago, we sought to determine whether lactase persistence has evolved independently in the subcontinent. Here, we present the results of the first comprehensive survey of the LCT enhancer region in south Asia. Having genotyped 2,284 DNA samples from across the Indian subcontinent, we find that the previously described west Eurasian -13910 C.T mutation accounts for nearly all the genetic variation we observed in the 400- to 700-bp LCT regulatory region that we sequenced. Geography is a significant predictor of -13910*T allele frequency, and consistent with other genomic loci, its distribution in India follows a general northwest to southeast declining pattern, although frequencies among certain neighboring populations vary substantially. We confirm that the mutation is identical by descent to the European allele and is associated with the same .1 Mb extended haplotype in both populations.

Y-chromosome Haplogroup O is the dominant lineage of East Asians, comprising more than a quarter of all males on the world; however, its internal phylogeny remains insufficiently investigated. In this study, we determined the phylogenetic position of recently defined markers (L127, KL1, KL2, P164, and PK4) in the background of Haplogroup O. In the revised tree, subgroup O3a-M324 is divided into two main subclades, O3a1-L127 and O3a2-P201, covering about 20 and 35% of Han Chinese people, respectively. The marker P164 is corrected from a downstream site of M7 to upstream of M134 and parallel to M7 and M159. The marker PK4 is also relocated from downstream of M88 to upstream of M95, separating the former O2(*) into two parts. This revision evidently improved the resolving power of Y-chromosome phylogeny in East Asia.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7×10−8, OR = 0.31, 95% CI = 0.20–0.48, and HLA-DQA1 rs1071630, case-control P = 4.9×10−14, OR = 0.43, 95% CI = 0.35–0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases., Author Summary Mycobacterium leprae is an obligate intracellular pathogen that causes leprosy, a disease that shares a long history with the human population but which remains endemic in many parts of the world. Despite the fact that the genome of M. leprae has been sequenced, our understanding of its pathogenesis and interaction with the human host is limited, in part due to the inability to culture the bacterium in vitro. In this gene-centric microarray study, we have genotyped SNPs in over 2,000 genes and identified TLR1 and HLA-DRB1/DQA1 as major leprosy susceptibility genes. Studying the geographical distribution of this hypo-functional TLR1 variant demonstrated extreme population differentiation at this locus. These results suggest that leprosy may have contributed to the evolution of this genomic region, and provide insight into the long history of the host-pathogen relationship between humans and M. leprae.

Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize the major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate NK cells, the killer-cell immunoglobulin-like receptors (KIR) are a variable and rapidly evolving family of MHC Class I receptors. Studied here isKIR3DL1/S1, which encodes receptors for highly polymorphic human HLA-A and -B and comprises three ancient allelic lineages that have been preserved by balancing selection throughout human evolution. While the 3DS1 lineage of activating receptors has been conserved, the two 3DL1 lineages of inhibitory receptors were diversified through inter-lineage recombination with each other and with 3DS1. Prominent targets for recombination were D0-domain polymorphisms, which modulate enhancer function, and dimorphism at position 283 in the D2 domain, which influences inhibitory function. In African populations, unequal crossing over between the3DL1and3DL2genes produced a deletedKIRhaplotype in which the telomeric “half” was reduced to a single fusion gene with functional properties distinct from its3DL1and3DL2parents. Conversely, in Eurasian populations, duplication of theKIR3DL1/S1locus by unequal crossing over has enabled individuals to carry and express alleles of all threeKIR3DL1/S1lineages. These results demonstrate how meiotic recombination combines with an ancient, preserved diversity to create new KIR phenotypes upon which natural selection acts. A consequence of such recombination is to blur the distinction between alleles and loci in the rapidly evolving humanKIRgene family.

Hypertrophic cardiomyopathy is characterized by massive ventricular hypertrophy, reduced diastolic function, and excessive ventricular contraction. The human leukocyte antigens HLA-A, HLA-B, and HLA-DR were studied in 14 hypertrophic cardiomyopathy patients with left ventricular obstruction from South India. They were compared with 81 normal age- and sex-matched individuals from the same ethnic background. The human leucocyte antigens were identified using the standard serological assay with a longer incubation for DR antigens. The odds ratio, frequency, chi-squared value, p-value, etiological fraction, preventive fraction, and haplotype frequency estimates were calculated. The HLA-B51 and HLA-DR2 levels were significantly increased in hypertrophic cardiomyopathy patients compared to controls, whereas HLA-A19, HLA-B7, and HLA-DR4 were decreased when compared to the controls. It was noticed that haplotype B51-DR2-DQ3 was significantly associated with hypertrophic cardiomyopathy patients from South India. Hypertrophic cardiomyopathy may be associated with genes in the human leukocyte antigen region, and immunogenetic factors linked to human leukocyte antigens appear to play a major role in the pathogenesis.

South India is one of the oldest geophysical regions mainly occupied by Dravidian language-speaking people. Here a random panel of 61 unrelated Nadar healthy individual from Tamil Nadu State were analyzed and compared with other populations of India and the world. HLA-A, B and C alleles frequencies and their haplotype frequencies were determined by high-resolution typing of genomic DNA. The analysis revealed that the Nadar caste of South India have several characters shared with East Asian populations consistent with the demographic history of South India, as well as specific features including several unique alleles such as A*03011, A*31011, B*15011, B*3501, B*51011, Cw*02022. In addition, haplotypes such as A*31011-Cw*02022-B*3501, A*03011-Cw*04011-B*4406 and A*2402101-Cw*04011-B*51011 are of high frequency in both these populations but are rare or absent in other populations of India and the world. The study suggests that a comparatively lesser degree of genetic admixture occurred between the South Indian and North Indian racial groups than that between South Indian and East Asian groups.

An enzyme-linked immunosorbant assay (ELISA) in a Terasaki plate (Micro-Platelet ELISA), using 30000 platelets per well, 2 microL primary antibody (anti HLA antiserum) and 5 microL of secondary antibody (1:2000) are described. Platelets from 30 selected HLA tissue typed cell panel individuals were used to characterize anti HLA A and B antibodies. The first half of the Terasaki tray had platelets in sequence to characterize anti HLA antibodies, while the second half contained anti HLA B antibodies. Results revealed that the HLA specificities of the sera identified by micro-platelet ELISA and microlymphocytotoxicity were concordant. Moreover, split antigens of broader specificities were identified in the Platelet ELISA technique. The advantages of micro-platelet ELISA technique were: (i) it does not require viable/frozen lymphocytes, (ii) reading is very simple and macroscopic, (iii) specificity of the serum is identified with accuracy within the same day, (iv) avoids inter-cell, inter-day variations, (v) complement is not required, (vi) requires only 1/50 volume of the reagents required by conventional ELISA in microtitre plates, and (vii) using platelets isolated from 5 mL of peripheral blood, fifteen thousand sera can be tested. This technique is, thus, very simple, cost effective, and very much suitable for any developing HLA laboratory, which is in the process of developing indigenous HLA reagents.

The nonrecombining portion of the human Y chromosome has proven to be a valuable tool for the study of population history. The maintenance of extended haplotypes characteristic of particular geographic regions, despite extensive admixture, allows complex demographic events to be deconstructed. In this study we report the frequencies of 23 Y-chromosome biallelic polymorphism haplotypes in 1,935 men from 49 Eurasian populations, with a particular focus on Central Asia. These haplotypes reveal traces of historical migrations, and provide an insight into the earliest patterns of settlement of anatomically modern humans on the Eurasian continent. Central Asia is revealed to be an important reservoir of genetic diversity, and the source of at least three major waves of migration leading into Europe, the Americas, and India. The genetic results are interpreted in the context of Eurasian linguistic patterns.

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is prevalent in India, where about half of the world's estimated 800,000 cases occur. A role for the genetics of the host in variable susceptibility to leprosy has been indicated by familial clustering, twin studies, complex segregation analyses and human leukocyte antigen (HLA) association studies. We report here a genetic linkage scan of the genomes of 224 families from South India, containing 245 independent affected sibpairs with leprosy, mainly of the paucibacillary type. In a two-stage genome screen using 396 microsatellite markers, we found significant linkage (maximum lod score (MLS) = 4.09, P < 2x10-5) on chromosome 10p13 for a series of neighboring microsatellite markers, providing evidence for a major locus for this prevalent infectious disease. Thus, despite the polygenic nature of infectious disease susceptibility, some major, non-HLA-linked loci exist that may be mapped through obtainable numbers of affected sibling pairs.

In an effort to study the immunological responses to antigens of tubercle bacilli, 49 tuberculin positive and 41 tuberculin negative hospital contacts aged 20-29 years (staff nurses and students working in Government Rajaji Hospital, Madurai, South India) were studied for serum antibodies (IgG, IgM and IgA classes) to BCG by ELISA and diameter of induration to PPD by Mantoux procedures. The two immunological parameters were correlated in regression analysis. The results have revealed higher anti-BCG serum antibody levels in hospital contacts than in non-contacts, significantly higher antibodies in tuberculin negative hospital contacts than in tuberculin positive hospital contacts, an inverse correlation of tuberculin reactivity and antibodies and a bimodal decline (regression) of antibodies against the increase in skin test induration. This study has thus suggested the existence of an immunological spectrum in hospital contacts from south India; persons at one pole of the spectrum were tuberculin negative and possessed significantly elevated antibody levels and those at the other pole of the spectrum were tuberculin positive and possessed low antibody levels. Thus the spectrum of immune reactivity may be due to an inherent susceptibility/resistance of an individual to Mycobacterium tuberculosis.

HLA-A, B profile of 385 normal healthy individuals living in Tamil Nadu, India was studied by microlymphocytotoxicity testing. Antigen, gene and haplotype frequencies of this population were calculated and compared to those already available in the literature. The sample was further divided into four major groups and the frequencies calculated. Genetic distances between the various major groups were also calculated: the analyses suggest that these different groups may differ by origin. The study further reveals that in any HLA genetic and disease association studies in India, one should give due consideration to the caste system of the sample studied.

Eighty-three south Indian patients with psoriasis vulgaris were studied for HLA antigen frequencies and compared with 77 controls studied simultaneously. HLA Bw57, a split of B17 was found elevated in the patients. The two sexes differed in their age-at-onset curves: females had a preponderance to early onset of the disease, while the males had late onset. Among these patients, major group 3, a Western Brachycephal Armenoid group, revealed the highest risk for B17 & Bw57 but not major group 2, a Mediterranean one.

HLA-A, B antigen and haplotype frequencies were studied in four different caste groups of Tamil Nadu living in Madurai. A total number of 101 Nadars, 36 Kallars, 54 Iyers and 57 Telugu-speaking Naidus were studied. HLA A3 and B15 were significantly higher in Nadars; A10 & B8 in Kallars and Aw19, B12 & B35 in Iyers. HLA A-B haplotypes A10-B7, A28-B17 & A24-B- were characteristic of Nadars; A10-B8 & A1-B-, Kallars; Aw19-B12 & A1-B15, Iyers and A2-B-, Naidus. Negative linkage disequilibria for Aw19-B7, A28-B15 & A9-B51 were significant in Nadars; A1-B5, A1-B12 & Aw19-B- in Iyers and A2-B17 in Naidus. Heterogeneity chi-square based on antigen frequency and genetic distance also suggest the heterogeneous nature of the population of South India. Will these caste groups with such diverse haplotypic combinations differ from one another in their immune response and susceptibility to a given epidemic or infection?

Behar, Doron M. et al.-- The Genographic Consortium, Different lines of evidence point to the resettlement of much of western and central Europe by populations from the Franco-Cantabrian region during the Late Glacial and Postglacial periods. In this context, the study of the genetic diversity of contemporary Basques, a population located at the epicenter of the Franco-Cantabrian region, is particularly useful because they speak a non-Indo-European language that is considered to be a linguistic isolate. In contrast with genome-wide analysis and Y chromosome data, where the problem of poor time estimates remains, a new timescale has been established for the human mtDNA and makes this genome the most informative marker for studying European prehistory. Here, we aim to increase knowledge of the origins of the Basque people and, more generally, of the role of the Franco-Cantabrian refuge in the postglacial repopulation of Europe. We thus characterize the maternal ancestry of 908 Basque and non-Basque individuals from the Basque Country and immediate adjacent regions and, by sequencing 420 complete mtDNA genomes, we focused on haplogroup H. We identified six mtDNA haplogroups, H1j1, H1t1, H2a5a1, H1av1, H3c2a, and H1e1a1, which are autochthonous to the Franco-Cantabrian region and, more specifically, to Basque-speaking populations. We detected signals of the expansion of these haplogroups at ∼4,000 years before present (YBP) and estimated their separation from the pan-European gene pool at ∼8,000 YBP, antedating the Indo-European arrival to the region. Our results clearly support the hypothesis of a partial genetic continuity of contemporary Basques with the preceding Paleolithic/Mesolithic settlers of their homeland., This work was supported by the Institut Pasteur, National Geographic, and the Histoire des populations et variation linguistique dans les Pyrénées de l'Ouest project, which received funding from the Conseil Régional d'Aquitaine, the Conseil Général des Pyrénées-Atlantiques, the Conseil des Elus du Pays-Basque, and the Centre National de la Recherche Scientifique interdisciplinary program Origine de l'Homme, des Langues et du Langage. This study also benefited from the support of Department of Hematology, Centre Hospitalier de la Côte Basque, in Bayonne, and Association Sang 64.