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Migration and admixture history of populations have always been curious and an interesting theme. The West Coast of India harbours a rich diversity, bestowing various ethno-linguistic groups, with many of them having well-documented history of migrations. The Roman Catholic is one such distinct group, whose origin was much debated. While some historians and anthropologists relating them to ancient group of Gaud Saraswat Brahmins, others relating them for being members of the Jews Lost Tribes in the first Century migration to India. Historical records suggests that this community was later forcibly converted to Christianity by the Portuguese in Goa during the Sixteenth Century. Till date, no genetic study was done on this group to infer their origin and genetic affinity. Hence, we analysed 110 Roman Catholics from three different locations of West Coast of India including Goa, Kumta and Mangalore using both uniparental and autosomal markers to understand their genetic history. We found that the Roman Catholics have close affinity with the Indo-European linguistic groups, particularly Brahmins. Additionally, we detected genetic signal of Jews in the linkage disequilibrium-based admixture analysis, which was absent in other Indo-European populations, who are inhabited in the same geographical regions. Haplotype-based analysis suggests that the Roman Catholics consist of South Asian-specific ancestry and showed high drift. Ancestry-specific historical population size estimation points to a possible bottleneck around the time of Goan inquisition (fifteenth century). Analysis of the Roman Catholics data along with ancient DNA data of Neolithic and bronze age revealed that the Roman Catholics fits well in a basic model of ancient ancestral composition, typical of most of the Indo-European caste groups of India. Mitochondrial DNA (mtDNA) analysis suggests that most of the Roman Catholics have aboriginal Indian maternal genetic ancestry; while the Y chromosomal DNA analysis indicates high frequency of R1a lineage, which is predominant in groups with higher ancestral North Indian (ANI) component. Therefore, we conclude that the Roman Catholics of Goa, Kumta and Mangalore regions are the remnants of very early lineages of Brahmin community of India, having Indo-Europeans genetic affinity along with cryptic Jewish admixture, which needs to be explored further.

Background Genetic diathesis of suicide is supported by family and twin studies. Few candidate gene pathways are known, but does not explain fully the complexity of suicide genetic risk. Recent investigations opting for Genome-Wide Association Studies (GWAS) resulted in finding additional targets, but replication remained a challenge. In this respect small isolated population approach in several complex disease phenotypes is found encouraging. The present study is an attempt to re-test some of the reported significant SNPs for suicide among a small historical high- risk isolated population from Northeast India. Methods Two hundred ten cases (inclusive of depressed, suicide attempter and depressed + suicide attempter) and 249 controls were considered in the present study which were evaluated for the psychiatric parameters. Sixteen reported significant SNPs for suicide behaviour were re-tested using association approach under various genetic models. Networking by GeneMANIA tool was used for function prediction of the associated genes. Results Seven SNPs (of 6 genes) remained significant in different genetic models. On networking genes with significant SNPs IL7, RHEB, CTNN3, KCNIP4, ARFGEF3 are found in interaction with already known candidate gene pathways while SNP rs1109089 (RHEB) gained further support from earlier expression studies. NUGGC gene is in complete isolation. Conclusions Small population approach in replicating significant SNPs is useful in complex phenotypes like suicide. This study explored the region-specific demographics of India by identifying vulnerable population for suicide via genetic association analysis in bringing into academic and administrative forum, the importance of suicide as a disease and its biological basis.

Transposable elements (TEs) are mobile genetic sequences that comprise a large portion of vertebrate genomes. The olive flounder (Paralichthys olivaceus) is a valuable marine resource in East Asia. The scope of most genomic studies on the olive flounder is limited to its immunology as their focus is the prevention of mass mortality of this species. Thus, for a broader understanding of the species, its genomic information is consistently in demand. Transcripts sequences were acquired from transcriptome analysis using gill tissues of 12 olive flounders. Distribution of TEs inserted in exonic region of the olive flounder genome was analyzed using RepeatMasker ( http://www.repeatmasker.org/ ). We found 1140 TEs in the exonic region of the genome and long interspersed nuclear elements (LINEs) and long terminal repeats (LTRs) insertions occurred with forward orientation preferences. Transposons belonging to the hAt, Gypsy, and LINE 1 (L1) subfamilies were the most abundant DNA transposons, LTRs, and long interspersed elements (LINEs), respectively. Finally, we carried out a gene ontology analysis to determine the function of TE-fused genes. These results provide some genomic information about TEs that is useful for future research on changes in properties and functions of genes by TEs in the olive flounder genome.

Members of the Iridoviridae family have been considered as aetiological agents of iridovirus diseases, causing fish mortalities and economic losses all over the world. Virus identification based on candidate gene sequencing is faster, more accurate and more reliable than other traditional phenotype methodologies. Iridoviridae viruses are covered by a protein shell (capsid) encoded by the important candidate gene, major capsid protein (MCP). In this study, we investigated the potential of the MCP gene for use in the diagnosis and identification of infections caused Megalocytivirus of the Iridoviridae family. We selected data of 66 Iridoviridae family isolates (53 strains of Megalocytivirus, eight strains of iridoviruses and five strains of Ranavirus) infecting various species of fish distributed all over the world. A total of 53 strains of Megalocytivirus were used for designing the complete primer sets for identifying the most hypervariable region of the MCP gene. Further, our in silico analysis of 102 sequences of related and unrelated viruses reconfirms that primer sets could identify strains more specifically and offers a useful and fast alternative for routine clinical laboratory testing. Our findings suggest that phenotype observation along with diagnosis using universal primer sets can help detect infection or carriers at an early stage.

Two bacterial etiological agents of the disease, Streptococcus iniae and Streptococcus parauberis has been associated with fish mortalities and heavy economic loss in all over the world. Bacterial identification based on 16S rRNA sequencing is very fast, accurate and reliable in comparison to other traditional phenotype methodologies. In this study, we investigate the usefulness of this method for diagnosis and identification of Streptococcus species. We have selected 61 phylogeographic strains of Streptococcus (34 strains of S. iniae and 27 strains of S. parauberis) and designed the universal primer against the identified most hypervariable region of the 16S rRNA gene. Our universal primer able to identify any geographical strains and offers a useful and fast alternative in a clinical laboratory under routine conditions. Based on our studies, we have developed an algorithm for appropriate control of S. iniae and S. parauberis disease. We suggested the phenotype observation along with universal primer combination to detect any kind of infection or carriers at early stages.

Late onset Alzheimer’s disease (LOAD) is the most common type of dementia and is characterized by impaired cholesterol homeostasis. Genome-wide association studies (GWAS) have shown that APOE, TOMM40, CLU, SORL1, PICALM, and BIN1 are related to cholesterol metabolism. To characterize the association between single-nucleotide polymorphisms (SNPs) and LOAD, we sequenced the SNP regions of the identified genes in a total of 11 LOAD cases and 12 healthy case controls in the Korean population. The SNP data showed a relatively high frequency in LOAD samples compared to the control samples. LOAD samples showed an average of 2.9 SNPs, whereas normal controls showed an average of 1.5 SNPs in the genes. Taken together, six genes associated with cholesterol metabolism using SNP analysis have shown frequent genetic variations in LOAD.

Long interspersed nuclear elements (LINEs) are widely distributed in the vertebrate genome, and can be either beneficial or detrimental to the host genome. Here we identified three members of LINE RT elements in the olive flounder genome. They showed high amino acid sequence identity (89–99 %), and the sequences of LINE reverse transcriptase (RT) in olive flounder are closely related to those of coral grouper, European seabass, and three-spined stickleback. Real-time reverse transcription-polymerase chain reaction analysis indicated that expression of the OF (Olive flounder)-LINE Chr3-1 RT increased more in spleen than in other tissues after treatment with the pathogen Streptococcus parauberis. These data may form the basis for further studies on the function of retroelements in infected olive flounder.

Skin color is a highly visible and variable trait across human populations. It is not yet clear how evolutionary forces interact to generate phenotypic diversity. Here we sought to unravel through an integrative framework the role played by three factors – demography and migration, sexual selection, and natural selection – in driving skin color diversity in India. Methods: Skin reflectance data were collected from 10 diverse socio-cultural populations along the latitudinal expanse of India, including both sexes. We first looked at how skin color varies within and between these populations. Secondly, we compared patterns of sexual dimorphism in skin color. Thirdly, we studied the influence of ultraviolet radiation on skin color throughout India. Finally, we attempted to disentangle the interactions between these factors in the context of available genetic data. Results: We found that the relative importance of these forces varied between populations. Social factors and population structure have played a stronger role than natural selection in shaping skin color diversity across India. Phenotypic overprinting resulted from additional genetic mutations overriding the skin lightening effect of variants such as the SLC24A5 rs1426654-A allele in some populations, in the context of the variable influence of sexual selection. Furthermore, specific genotypes are not associated reliably with specific skin color phenotypes. This result has relevance for DNA forensics and ancient DNA research. Conclusion: India is a crucible of macro- and micro-evolutionary forces, and the complex interactions of physical and social forces are visible in the patterns of skin color seen today in the country.

Body mass index (BMI) is a non-invasive measurement of obesity. It is commonly used for assessing adiposity and obesity-related risk prediction. Genetic differences between ethnic groups are important factors, which contribute to the variation in phenotypic effects. India inhabited by the first out-of-Africa human population and the contemporary Indian populations are admixture of two ancestral populations; ancestral north Indians (ANI) and ancestral south Indians (ASI). Although ANI are related to Europeans, ASI are not related to any group outside Indian-subcontinent. Hence, we expect novel genetic loci associated with BMI. In association analysis, we found eight genic SNPs in extreme of distribution (P⩽3.75 × 10(-5)), of which WWOX has already been reported to be associated with obesity-related traits hence excluded from further study. Interestingly, we observed rs1526538, an intronic SNP of THSD7A; a novel gene significantly associated with obesity (P=2.88 × 10(-5), 8.922 × 10(-6) and 2.504 × 10(-9) in discovery, replication and combined stages, respectively). THSD7A is neural N-glycoprotein, which promotes angiogenesis and it is well known that angiogenesis modulates obesity, adipose metabolism and insulin sensitivity, hence our result find a correlation. This information can be used for drug target, early diagnosis of obesity and treatment.

MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that mainly bind to the seed sequences located within the 3′ untranslated region (3′ UTR) of target genes. They perform an important biological function as regulators of gene expression. Different genes can be regulated by the same miRNA, whilst different miRNAs can be regulated by the same genes. Here, the evolutionary conservation and expression pattern of miR-10a-3p in olive flounder and rock bream was examined. Binding sites (AAAUUC) to seed region of the 3′ UTR of target genes were highly conserved in various species. The expression pattern of miR-10a-3p was ubiquitous in the examined tissues, whilst its expression level was decreased in gill tissues infected by viral hemorrhagic septicemia virus (VHSV) compared to the normal control. In the case of rock bream, the spleen, kidney, and liver tissues showed dominant expression levels of miR-10a-3p. Only the liver tissues in the rock bream samples infected by the iridovirus indicated a dominant miR-10a-3p expression. The gene ontology (GO) analysis of predicted target genes for miR-10a-3p revealed that multiple genes are related to binding activity, catalytic activity, cell components as well as cellular and metabolic process. Overall the results imply that the miR-10a-3p could be used as a biomarker to detect VHSV infection in olive flounder and iridovirus infection in rock bream. In addition, the data provides fundamental information for further study of the complex interaction between miR-10a-3p and gene expression.

Cytochrome-P450-2C9 (CYP2C9) metabolizes wide range of drugs and highly express in human liver. Various mutations of CYP2C9 (R144C, I359L etc.), associated with drug-response, are highly diverse. We aimed to investigate the genetic diversity of CYP2C9 in Indian-subcontinent, using 1278 subjects from 36 populations. High frequency of CYP2C9*3 (0-0.179) was observed, comparative to other populations, including Europeans. Subjects having CYP2C9*3/*3 requires lower dose of warfarin, comparative to CYP2C9*1/*3 or CYP2C9*1/*1. Since, Indians are practicing marriage among their caste system, we predicted and observed high frequency (0-0.05) of CYP2C9*3/*3. Out of 21 populations, living outside of Indian subcontinent, only Toscani and Southern Han-Chinese have 0.009 and 0.01 CYP2C9*3/*3, respectively, lower than Indians,. We found a non-synonymous mutation (L362V), observed only in Indian-subcontinent, and have 0-0.056 allelic, 0-0.037 L/V and 00.037 V/V genotype frequency. We observed unfavorable interatomic interactions between hydroxylation sites of warfarin and reactive oxyferryl heme in mutant, comparative to wild-type CYP2C9, in molecular dynamic simulations; and predict lower kinetic activity.

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P(combined) = 2.76 × 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.

Ninety percent of the 500,000 annual new cases of visceral leishmaniasis occur in India/Bangladesh/Nepal, Sudan and Brazil. Importantly, 80-90% of human infections are sub-clinical or asymptomatic, usually associated with strong cell-mediated immunity. Understanding the environmental and genetic risk factors that determine why two people with the same exposure to infection differ in susceptibility could provide important leads for improved therapies. Recent research using candidate gene association analysis and genome-wide linkage studies (GWLS) in collections of families from Sudan, Brazil and India have identified a number of genes/regions related both to environmental risk factors (e.g. iron), as well as genes that determine type 1 versus type 2 cellular immune responses. However, until now all of the allelic association studies carried out have been underpowered to find genes of small effect sizes (odds ratios or OR

Visceral Leishmaniasis (VL) is the most severest form of Leishmaniasis and resistance to infection is mediated by cellular immune responses. Interleukin 4 (IL-4) orchestrates of Th2 and Th1 immune responses during infections. In this study, we aimed to investigate possible association between three functional IL-4 polymorphisms -590C/T (rs2243250), -34C/T (rs2070874) and 70bp VNTR (rs79071878 in intron3) with VL in an Indian cohort comprising of 197 VL patients and 193 healthy controls. The three investigated IL-4 polymorphisms were in strong linkage disequilibrium. The investigated IL-4 alleles, genotypes and the reconstructed haplotypes were not significantly distributed between the VL patients and healthy controls. Our study signifies no possible association of functional IL-4 polymorphisms with Indian VL and postulate other vital genes involved in the IL-4 pathway may provide genetic clues to elucidate of IL-4 regulation and immune-pathogenesis during VL.

Chromosome 6q26–27 is linked to susceptibility to visceral leishmaniasis (VL) in Brazil and Sudan. DLL1 encoding the Delta-like 1 ligand for Notch 3 was implicated as the etiological gene. DLL1 belongs to the family of Notch ligands known to selectively drive antigen-specific CD4 T helper 1 cell responses, which are important in protective immune response in leishmaniasis. Here we provide further genetic and functional evidence that supports a role for DLL1 in a well-powered population-based study centred in the largest global focus of VL in India. Twenty-one single nucleotide polymorphisms (SNPs) at PHF10/C6orf70/DLL1/FAM120B/PSMB1/TBP were genotyped in 941 cases and 992 controls. Logistic regression analysis under an additive model showed association between VL and variants at DLL1 and FAM120B, with top associations (rs9460106, OR=1.17, 95%CI 1.01–1.35, P=0.033; rs2103816, OR=1.16, 95%CI 1.01–1.34, P=0.039) robust to analysis using caste as a covariate to take account of population substructure. Haplotype analysis taking population substructure into account identified a common 2-SNP risk haplotype (frequency 0.43; P=0.028) at FAM120B, while the most significant protective haplotype (frequency 0.18; P=0.007) was a 5-SNP haplotype across the interval 5’ of both DLL1 (negative strand) and FAM120B (positive strand) and extending to intron 4 of DLL1. Quantitative RT/PCR was used to compare expression of 6q27 genes in paired pre- and post-treatment splenic aspirates from VL patients (N=19). DLL1 was the only gene to show differential expression that was higher (P

Background IL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN). Variants at CXCR1 and CXCR2 have been associated with susceptibility to cutaneous and mucocutaneous leishmaniasis in Brazil. Here we investigate the role of CXCR1/CXCR2 in visceral leishmaniasis (VL) in India. Methods Three single nucleotide polymorphisms (SNPs) (rs4674259, rs2234671, rs3138060) that tag linkage disequilibrium blocks across CXCR1/CXCR2 were genotyped in primary family-based (313 cases; 176 nuclear families; 836 individuals) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between CXCR1/CXCR2 variants and VL. Quantitative RT/PCR was used to compare CXCR1/CXCR2 expression in mRNA from paired splenic aspirates taken before and after treatment from 19 VL patients. Results Family-based analysis using FBAT showed association between VL and SNPs CXCR1_rs2234671 (Z-score = 2.935, P = 0.003) and CXCR1_rs3138060 (Z-score = 2.22, P = 0.026), but not with CXCR2_rs4674259. Logistic regression analysis of the case-control data under an additive model of inheritance showed association between VL and SNPs CXCR2_rs4674259 (OR = 1.15, 95%CI = 1.01-1.31, P = 0.027) and CXCR1_rs3138060 (OR = 1.25, 95%CI = 1.02-1.53, P = 0.028), but not with CXCR1_rs2234671. The 3-locus haplotype T_G_C across these SNPs was shown to be the risk haplotype in both family- (TRANSMIT; P = 0.014) and population- (OR = 1.16, P = 0.028) samples (combined P = 0.002). CXCR2, but not CXCR1, expression was down regulated in pre-treatment compared to post-treatment splenic aspirates (P = 0.021). Conclusions This well-powered primary and replication genetic study, together with functional analysis of gene expression, implicate CXCR2 in determining outcome of VL in India.

Background SLC11A1 has pleiotropic effects on macrophage function and remains a strong candidate for infectious disease susceptibility. 5' and/or 3' polymorphisms have been associated with tuberculosis, leprosy, and visceral leishmaniasis (VL). Most studies undertaken to date were under-powered, and none has been replicated within a population. Association with tuberculosis has replicated variably across populations. Here we investigate SLC11A1 and VL in India. Methods Nine polymorphisms (rs34448891, rs7573065, rs2276631, rs3731865, rs17221959, rs2279015, rs17235409, rs17235416, rs17229009) that tag linkage disequilibrium blocks across SLC11A1 were genotyped in primary family-based (313 cases; 176 families) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between SLC11A1 variants and VL. Quantitative RT/PCR was used to compare SLC11A1 expression in mRNA from paired splenic aspirates taken before and after treatment from 24 VL patients carrying different genotypes at the functional promoter GTn polymorphism (rs34448891). Results No associations were observed between VL and polymorphisms at SLC11A1 that were either robust to correction for multiple testing or replicated across primary and replication samples. No differences in expression of SLC11A1 were observed when comparing pre- and post-treatment samples, or between individuals carrying different genotypes at the GTn repeat. Conclusions This is the first well-powered study of SLC11A1 as a candidate for VL, which we conclude does not have a major role in regulating VL susceptibility in India.

Background Genome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported. Methods and Findings We undertook a GWLS in India in which a primary ∼10 cM (515 microsatellites) scan was carried out in 58 multicase pedigrees (74 nuclear families; 176 affected, 353 total individuals) and replication sought in 79 pedigrees (102 nuclear families; 218 affected, 473 total individuals). The primary scan provided evidence (≥2 adjacent markers allele-sharing LOD≥0.59; nominal P≤0.05) for linkage on Chromosomes 2, 5, 6, 7, 8, 10, 11, 20 and X, with peaks at 6p25.3-p24.3 and 8p23.1-p21.3 contributed to largely by 31 Hindu families and at Xq21.1-q26.1 by 27 Muslim families. Refined mapping confirmed linkage across all primary scan families at 2q12.2-q14.1 and 11q13.2-q23.3, but only 11q13.2-q23.3 replicated (combined LOD = 1.59; P = 0.0034). Linkage at 6p25.3-p24.3 and 8p23.1-p21.3, and at Xq21.1-q26.1, was confirmed by refined mapping for primary Hindu and Muslim families, respectively, but only Xq21.1-q26.1 replicated across all Muslim families (combined LOD 1.49; P = 0.0045). STRUCTURE and SMARTPCA did not identify population genetic substructure related to religious group. Classification and regression tree, and spatial interpolation, analyses confirm geographical heterogeneity for linkages at 6p25.3-p24.3, 8p23.1-p21.3 and Xq21.1-q26.1, with specific clusters of families contributing LOD scores of 2.13 (P = 0.0009), 1.75 (P = 0.002) and 1.84 (P = 0.001), respectively. Conclusions GWLS has identified novel loci that show geographical heterogeneity in their influence on susceptibility to VL in India.

Our understanding of the genetics of skin pigmentation has been largely skewed towards populations of European ancestry, imparting less attention to South Asian populations, who behold huge pigmentation diversity. Here, we investigate skin pigmentation variation in a cohort of 1,167 individuals in the Middle Gangetic Plain of the Indian subcontinent. Our data confirm the association of rs1426654 with skin pigmentation among South Asians, consistent with previous studies, and also show association for rs2470102 single nucleotide polymorphism. Our haplotype analyses further help us delineate the haplotype distribution across social categories and skin color. Taken together, our findings suggest that the social structure defined by the caste system in India has a profound influence on the skin pigmentation patterns of the subcontinent. In particular, social category and associated single nucleotide polymorphisms explain about 32% and 6.4%, respectively, of the total phenotypic variance. Phylogeography of the associated single nucleotide polymorphisms studied across 52 diverse populations of the Indian subcontinent shows wide presence of the derived alleles, although their frequencies vary across populations. Our results show that both polymorphisms (rs1426654 and rs2470102) play an important role in the skin pigmentation diversity of South Asians.