PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (50)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
1.  Association of progesterone receptor gene polymorphism with male infertility and clinical outcome of ICSI 
Purpose
To investigate the association of Progesterone Receptor (PR) gene variations and male infertility
Methods
DNA extraction, PCR and sequencing of PR gene, PROGINS insertion by PCR. Association of the variations with seminal parameters and outcomes of ICSI.
Results
Four known SNPs in the PR gene were identified in the study of which three (rs3740753, rs1042838, rs104283) were co-inherited and in complete linkage disequilibrium with the PROGINS Alu insertion. There were no differences in their frequencies between fertile and infertile males. The rs2020880 was found at a very low frequency only in the controls but not in the infertile subjects. The sperm counts, fertilization rate, embryo quality or pregnancy rates were not different in individuals with or without PROGINS allele.
Conclusion
PR gene alterations are not associated with male infertility or ICSI outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s10815-013-0074-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s10815-013-0074-2
PMCID: PMC3800537  PMID: 23934021
Progesterone receptor; Polymorphism; PROGINS; Male infertility; ICSI; Azoospermia; Sperm counts
2.  Reduced prevalence of placental malaria in primiparae with blood group O 
Malaria Journal  2014;13:289.
Background
Blood group O protects African children against severe malaria and has reached high prevalence in malarious regions. However, its role in malaria in pregnancy is ambiguous. In 839 delivering Ghanaian women, associations of ABO blood groups with Plasmodium falciparum infection were examined.
Methods
Plasmodium falciparum infection was diagnosed in placental blood samples by microscopy and PCR assays. Present or past infection was defined as the detection of parasitaemia or haemozoin by microscopy, or a positive PCR result. Blood groups were inferred from genotyping rs8176719 (indicating the O allele) and rs8176746/rs8176747 (distinguishing the B allele from the A allele).
Results
The majority of women had blood group O (55.4%); present or past P. falciparum infection was seen in 62.3% of all women. Among multiparae, the blood groups had no influence on P. falciparum infection. In contrast, primiparae with blood group O had significantly less present or past infection than women with non-O blood groups (61.5 vs 76.2%, P = 0.007). In multivariate analysis, the odds of present or past placental P. falciparum infection were reduced by 45% in blood group O primiparae (aOR, 0.55 [95% CI, 0.33–0.94]).
Conclusions
The present study shows a clear protective effect of blood group O against malaria in primiparae. This accords with findings in severe malaria and in vitro results. The data underline the relevance of host genetic protection among primiparae, i.e. the high-risk group for malaria in pregnancy, and contribute to the understanding of high O allele frequencies in Africa.
doi:10.1186/1475-2875-13-289
PMCID: PMC4119177  PMID: 25066505
3.  Novel TCAP Mutation c.32C>A Causing Limb Girdle Muscular Dystrophy 2G 
PLoS ONE  2014;9(7):e102763.
TCAP encoded telethonin is a 19 kDa protein, which plays an important role in anchoring titin in Z disc of the sarcomere, and is known to cause LGMD2G, a rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. A total of 300 individuals with ARLGMD were recruited for this study. Among these we identified 8 clinically well characterised LGMD2G cases from 7 unrelated Dravidian families. Clinical examination revealed predominantly proximo - distal form of weakness, scapular winging, muscle atrophy, calf hypertrophy and foot drop, immunoblot showed either complete absence or severe reduction of telethonin. Genetic analysis revealed a novel nonsense homozygous mutation c.32C>A, p.(Ser11*) in three patients of a consanguineous family and an 8 bp homozygous duplication c.26_33dupAGGTGTCG, p.(Arg12fs31*) in another patient. Both mutations possibly lead to truncated protein or nonsense mediated decay. We could not find any functionally significant TCAP mutation in the remaining 6 samples, except for two other polymorphisms, c.453A>C, p.( = ) and c.-178G>T, which were found in cases and controls. This is the first report from India to demonstrate TCAP association with LGMD2G.
doi:10.1371/journal.pone.0102763
PMCID: PMC4108395  PMID: 25055047
4.  A Novel Arginine to Tryptophan (R144W) Mutation in Troponin T (cTnT) Gene in an Indian Multigenerational Family with Dilated Cardiomyopathy (FDCM) 
PLoS ONE  2014;9(7):e101451.
Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.
doi:10.1371/journal.pone.0101451
PMCID: PMC4081629  PMID: 24992688
5.  MBL2 Variations and Malaria Susceptibility in Indian Populations 
Infection and Immunity  2014;82(1):52-61.
Human mannose-binding lectin (MBL) encoded by the MBL2 gene is a pattern recognition protein and has been associated with many infectious diseases, including malaria. We sought to investigate the contribution of functional MBL2 gene variations to Plasmodium falciparum malaria in well-defined cases and in matched controls. We resequenced the 8.7 kb of the entire MBL2 gene in 434 individuals clinically classified with malaria from regions of India where malaria is endemic. The study cohort included 176 patients with severe malaria, 101 patients with mild malaria, and 157 ethnically matched asymptomatic individuals. In addition, 830 individuals from 32 socially, linguistically, and geographically diverse endogamous populations of India were investigated for the distribution of functional MBL2 variants. The MBL2 −221C (X) allelic variant is associated with increased risk of malaria (mild malaria odds ratio [OR] = 1.9, corrected P value [PCorr] = 0.0036; severe malaria OR = 1.6, PCorr = 0.02). The exon1 variants MBL2*B (severe malaria OR = 2.1, PCorr = 0.036; mild versus severe malaria OR = 2.5, PCorr = 0.039) and MBL2*C (mild versus severe malaria OR = 5.4, PCorr = 0.045) increased the odds of having malaria. The exon1 MBL2*D/*B/*C variant increased the risk for severe malaria (OR = 3.4, PCorr = 0.000045). The frequencies of low MBL haplotypes were significantly higher in severe malaria (14.2%) compared to mild malaria (7.9%) and asymptomatic (3.8%). The MBL2*LYPA haplotypes confer protection, whereas MBL2*LXPA increases the malaria risk. Our findings in Indian populations demonstrate that MBL2 functional variants are strongly associated with malaria and infection severity.
doi:10.1128/IAI.01041-13
PMCID: PMC3911836  PMID: 24126531
6.  Determinants of Prakriti, the Human Constitution Types of Indian Traditional Medicine and its Correlation with Contemporary Science 
Background:
Constitutional type of an individual or prakriti is the basic clinical denominator in Ayurveda, which defines physical, physiological, and psychological traits of an individual and is the template for individualized diet, lifestyle counseling, and treatment. The large number of phenotype description by prakriti determination is based on the knowledge and experience of the assessor, and hence subject to inherent variations and interpretations.
Objective:
In this study we have attempted to relate dominant prakriti attribute to body mass index (BMI) of individuals by assessing an acceptable tool to provide the quantitative measure to the currently qualitative ayurvedic prakriti determination.
Materials and Methods:
The study is cross sectional, multicentered, and prakriti assessment of a total of 3416 subjects was undertaken. Healthy male, nonsmoking, nonalcoholic volunteers between the age group of 20-30 were screened for their prakriti after obtaining written consent to participate in the study. The prakriti was determined on the phenotype description of ayurvedic texts and simultaneously by the use of a computer-aided prakriti assessment tool. Kappa statistical analysis was employed to validate the prakriti assessment and Chi-square, Cramer's V test to determine the relatedness in the dominant prakriti to various attributes.
Results:
We found 80% concordance between ayurvedic physician and software in predicting the prakriti of an individual. The kappa value of 0.77 showed moderate agreement in prakriti assessment. We observed a significant correlations of dominant prakriti to place of birth and BMI with Chi-square, P < 0.01 (Cramer's V-value of 0.156 and 0.368, respectively).
Conclusion:
The present study attempts to integrate knowledge of traditional ayurvedic concepts with the contemporary science. We have demonstrated analysis of prakriti classification and its association with BMI and place of birth with the implications to one of the ways for human classification.
doi:10.4103/0975-9476.140478
PMCID: PMC4204287  PMID: 25336848
Ayusoft; body mass index; place of birth; Prakriti
8.  A novel insertion-induced frameshift mutation of the androgen receptor gene in a patient with primary amenorrhea☆ 
Meta Gene  2013;2:11-15.
Objective
To report a novel single nucleotide insertion mutation, and present the clinical, genetic, biochemical findings in a patient with primary amenorrhea.
Methods
Chromosomal analysis was performed by harvesting lymphocytes from peripheral blood sample. Hormonal analysis was performed from the serum. After genomic DNA extraction from peripheral blood leukocytes the coding regions and corresponding exon–intron boundaries of sex-determining region Y (SRY) gene and androgen receptor (AR) gene were amplified by PCR and subjected to direct sequencing.
Results
In the patient with a karyotype 46,XX, we identified a novel single nucleotide insertion mutation of the nucleotide G at position 2369 (GenBank accession number HM010955), resulting in amino acid interchange cysteine to tryptophan at codon 669 in exon 4 [Cys669Trp] (GenBank Protein_id ADF47187).
Conclusions
We report a novel single nucleotide insertion mutation in exon 4 region of the AR gene. The nature of the mutation presented in the patient is in the ligand-binding domain (LBD) of the AR gene. This insertion mutation was predicted to produce frame shift mutation and resulted in truncated form of the AR protein, implicating it in the phenotype observed with primary amenorrhea.
Highlights
•AR is a member of the steroid receptor superfamily.•AR gene was screened in a patient with primary amenorrhea by direct PCR sequencing.•A novel insertion mutation (c.2369_2370insG, p.Cys669TrpfsX12) was identified.•This causes frame shift mutation resulting in truncated form of the AR protein.•The finding further enriched the AR mutation spectrum.
doi:10.1016/j.mgene.2013.10.011
PMCID: PMC4287795  PMID: 25606384
AR, androgen receptor; SRY, sex-determining region Y; PCR, polymerase chain reaction; LBD, ligand-binding domain.; AR gene; Primary amenorrhea; Novel mutation
10.  The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent 
PLoS Genetics  2013;9(11):e1003912.
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.
doi:10.1371/journal.pgen.1003912
PMCID: PMC3820762  PMID: 24244186
11.  Strong Impact of TGF-β1 Gene Polymorphisms on Breast Cancer Risk in Indian Women: A Case-Control and Population-Based Study 
PLoS ONE  2013;8(10):e75979.
Introduction
TGF-β1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-β1 signaling in breast cancer progression is well documented. Some TGF-β1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear.
Methods
We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-β1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-β1 were measured by ELISA.
Results
c.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (p = 0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo-Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto-Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-β1 was significantly elevated in patients in comparison to controls (p<0.001).
Conclusion
c.29C>T and c.74G>C polymorphisms in the TGF-β1 gene significantly affect breast cancer risk, which correlates with elevated TGF-β1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto-Burmans and polymorphic in other Indian populations.
doi:10.1371/journal.pone.0075979
PMCID: PMC3798290  PMID: 24146803
12.  Genetic Structure of Tibeto-Burman Populations of Bangladesh: Evaluating the Gene Flow along the Sides of Bay-of-Bengal 
PLoS ONE  2013;8(10):e75064.
Human settlement and migrations along sides of Bay-of-Bengal have played a vital role in shaping the genetic landscape of Bangladesh, Eastern India and Southeast Asia. Bangladesh and Northeast India form the vital land bridge between the South and Southeast Asia. To reconstruct the population history of this region and to see whether this diverse region geographically acted as a corridor or barrier for human interaction between South Asia and Southeast Asia, we, for the first time analyzed high resolution uniparental (mtDNA and Y chromosome) and biparental autosomal genetic markers among aboriginal Bangladesh tribes currently speaking Tibeto-Burman language. All the three studied populations; Chakma, Marma and Tripura from Bangladesh showed strikingly high homogeneity among themselves and strong affinities to Northeast Indian Tibeto-Burman groups. However, they show substantially higher molecular diversity than Northeast Indian populations. Unlike Austroasiatic (Munda) speakers of India, we observed equal role of both males and females in shaping the Tibeto-Burman expansion in Southern Asia. Moreover, it is noteworthy that in admixture proportion, TB populations of Bangladesh carry substantially higher mainland Indian ancestry component than Northeast Indian Tibeto-Burmans. Largely similar expansion ages of two major paternal haplogroups (O2a and O3a3c), suggested that they arose before the differentiation of any language group and approximately at the same time. Contrary to the scenario proposed for colonization of Northeast India as male founder effect that occurred within the past 4,000 years, we suggest a significantly deep colonization of this region. Overall, our extensive analysis revealed that the population history of South Asian Tibeto-Burman speakers is more complex than it was suggested before.
doi:10.1371/journal.pone.0075064
PMCID: PMC3794028  PMID: 24130682
13.  Androgen Receptor CAG Repeats Length Polymorphism and the Risk of Polycystic Ovarian Syndrome (PCOS) 
PLoS ONE  2013;8(10):e75709.
Objective
Polycystic ovarian syndrome (PCOS) refers to an inheritable androgen excess disorder characterized by multiple small follicles located at the ovarian periphery. Hyperandrogenism in PCOS, and inverse correlation between androgen receptor (AR) CAG numbers and AR function, led us to hypothesize that CAG length variations may affect PCOS risk.
Methods
CAG repeat region of 169 patients recruited following strictly defined Rotterdam (2003) inclusion criteria and that of 175 ethnically similar control samples, were analyzed. We also conducted a meta-analysis on the data taken from published studies, to generate a pooled estimate on 2194 cases and 2242 controls.
Results
CAG bi-allelic mean length was between 8.5 and 24.5 (mean = 17.43, SD = 2.43) repeats in the controls and between 11 and 24 (mean = 17.39, SD = 2.29) repeats in the cases, without any significant difference between the two groups. Further, comparison of bi-allelic mean and its frequency distribution in three categories (short, moderate and long alleles) did not show any significant difference between controls and various case subgroups. Frequency distribution of bi-allelic mean in two categories (extreme and moderate alleles) showed over-representation of extreme sized alleles in the cases with marginally significant value (50.3% vs. 61.5%, χ2 = 4.41; P = 0.036), which turned insignificant upon applying Bonferroni correction for multiple comparisons. X-chromosome inactivation analysis showed no significant difference in the inactivation pattern of CAG alleles or in the comparison of weighed bi-allelic mean between cases and controls. Meta-analysis also showed no significant correlation between CAG length and PCOS risk, except a minor over-representation of short CAG alleles in the cases.
Conclusion
CAG bi-allelic mean length did not differ between controls and cases/case sub-groups nor did the allele distribution. Over-representation of short/extreme-sized alleles in the cases may be a chance finding without any true association with PCOS risk.
doi:10.1371/journal.pone.0075709
PMCID: PMC3792992  PMID: 24116069
14.  Variations in ncRNA gene LOC284889 and MIF-794CATT repeats are associated with malaria susceptibility in Indian populations 
Malaria Journal  2013;12:345.
Background
There are increasing evidences on the role of non-coding RNA (ncRNA) as key regulator of cellular homeostasis. LOC284889 is an uncharacterized ncRNA gene on reverse strand to MIF mapped to 22q11.23. MIF, a lymphokine, regulates innate immune response by up-regulating the expression of TLR4, suppressing the p53 activity and has been shown to be involved in malaria pathogenesis.
Methods
In this study, the possible effect of MIF variations on malaria susceptibility was investigated by re-sequencing the complete MIF gene along with 1 kb each of 5′ and 3′ region in 425 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 160 cases of severe malaria, 101 of mild malaria and 164 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with Plasmodium falciparum malarial outcome.
Results
It is the first study, which shows that the allele A (rs34383331T > A) in ncRNA is significantly associated with increased risk to P. falciparum malaria [severe: OR = 2.08, p = 0.002 and mild: OR = 2.09, P = 0.005]. In addition, it has been observed that the higher MIF-794CATT repeats (>5) increases malaria risk (OR = 1.61, p = 0.01). Further, diplotype (MIF-794CATT and rs34383331T > A) 5 T confers protection to severe malaria (OR = 0.55, p = 0.002) while 6A (OR = 3.07, p = 0.001) increases malaria risk.
Conclusions
These findings support the involvement of ncRNA in malarial pathogenesis and further emphasize the complex genetic regulation of malaria outcome. In addition, the study shows that the higher MIF-794CATT repeats (>5) is a risk factor for severe malaria. The study would help in identifying people who are at higher risk to malaria and adapt strategies for prevention and treatment.
doi:10.1186/1475-2875-12-345
PMCID: PMC3849407  PMID: 24066864
Malaria; MIF; Non-coding RNA; Polymorphism; Indian populations; Diplotype
15.  Novel mutations of KCNQ1 in Long QT syndrome 
Indian Heart Journal  2013;65(5):552-560.
Background
Autosomal recessive Long QT syndrome is characterized by prolonged QTc along with congenital bilateral deafness depends on mutations in K+ channel genes. A family of a Long QT syndrome proband from India has been identified with novel indel variations.
Methods
The molecular study of the proband revealed 4 novel indel variations in KCNQ1. In-silico analysis revealed the intronic variations has led to a change in the secondary structure of mRNA and splice site variations. The exonic variations leads to frameshift mutations. DNA analysis of the available family members revealed a carrier status.
Results and Conclusion
It is thus predicted that the variations may lead to a change in the position of the splicing enhancer/inhibitor in KCNQ1 leading to the formation of a truncated S2–S3 fragment of KCNQ1 transmembrane protein in cardiac cells as well as epithelial cells of inner ear leading to deafness and aberrant repolarization causing prolonged QTc.
doi:10.1016/j.ihj.2013.08.025
PMCID: PMC3861163  PMID: 24206879
Long QT syndrome; JLN syndrome; 3D KCNQ1 structure; Novel mutations; Family study
16.  LRRK2 and RIPK2 Variants in the NOD 2-Mediated Signaling Pathway Are Associated with Susceptibility to Mycobacterium leprae in Indian Populations 
PLoS ONE  2013;8(8):e73103.
In recent years, genome wide association studies have discovered a large number of gene loci that play a functional role in innate and adaptive immune pathways associated with leprosy susceptibility. The immunological control of intracellular bacteria M. leprae is modulated by NOD2-mediated signaling of Th1 responses. In this study, we investigated 211 clinically classified leprosy patients and 230 ethnically matched controls in Indian population by genotyping four variants in NOD2 (rs9302752A/G), LRRK2 (rs1873613A/G), RIPK2 (rs40457A/G and rs42490G/A). The LRRK2 locus is associated with leprosy outcome. The LRRK2 rs1873613A minor allele and respective rs1873613AA genotypes were significantly associated with an increased risk whereas the LRRK2 rs1873613G major allele and rs1873613GG genotypes confer protection in paucibacillary and leprosy patients. The reconstructed GA haplotypes from RIPK2 rs40457A/G and rs42490G/A variants was observed to contribute towards increased risk whereas haplotypes AA was observed to confer protective role. Our results indicate that a possible shared mechanisms underlying the development of these two clinical forms of the disease as hypothesized. Our findings confirm and validates the role of gene variants involved in NOD2-mediated signalling pathways that play a role in immunological control of intracellular bacteria M. leprae.
doi:10.1371/journal.pone.0073103
PMCID: PMC3756038  PMID: 24015287
17.  Genetic and functional evaluation of the role of DLL1 in susceptibility to visceral leishmaniasis in India 
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<0.0001) in pre- compared to post-treatment samples, suggesting that regulation of gene expression was important in disease pathogenesis. This well-powered genetic and functional study in an Indian population provides evidence supporting DLL1 as the etiological gene contributing to susceptibility to VL at Chromosome 6q27, confirming the potential for polymorphism at DLL1 to act as a genetic risk factor across the epidemiological divides of geography and parasite species.
doi:10.1016/j.meegid.2012.04.017
PMCID: PMC3651914  PMID: 22561395
visceral leishmaniasis; DLL1; genetic association; Notch signalling
18.  Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities 
Cell reports  2012;2(6):1554-1562.
SUMMARY
The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly.
doi:10.1016/j.celrep.2012.11.017
PMCID: PMC3595605  PMID: 23246003
19.  Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities 
Cell Reports  2012;2(6):1554-1562.
Summary
The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly.
Graphical Abstract
Highlights
► The β-tubulin Tubb5 is highly expressed in the developing mouse and human cortex ► In vivo knockdown of Tubb5 perturbs the cell cycle and alters neuronal positioning ► Mutations in TUBB5 cause microcephaly with dysmorphic basal ganglia in humans ► TUBB5 mutations affect chaperone-mediated tubulin folding in different ways
The formation of the cortex requires the generation, migration, and differentiation of neurons. While specific tubulin isotypes have been implicated in postmitotic events, those that mediate neurogenesis remain unknown. Here, Keays and colleagues report that mutations in the β-tubulin gene, TUBB5, cause microcephaly. They show that this gene is highly expressed in neuronal progenitors, and its depletion in vivo perturbs the cell cycle and alters neuronal migration. This work provides insight into the functional repertoire of the tubulin gene family.
doi:10.1016/j.celrep.2012.11.017
PMCID: PMC3595605  PMID: 23246003
20.  The Phylogeography of Y-Chromosome Haplogroup H1a1a-M82 Reveals the Likely Indian Origin of the European Romani Populations 
PLoS ONE  2012;7(11):e48477.
Linguistic and genetic studies on Roma populations inhabited in Europe have unequivocally traced these populations to the Indian subcontinent. However, the exact parental population group and time of the out-of-India dispersal have remained disputed. In the absence of archaeological records and with only scanty historical documentation of the Roma, comparative linguistic studies were the first to identify their Indian origin. Recently, molecular studies on the basis of disease-causing mutations and haploid DNA markers (i.e. mtDNA and Y-chromosome) supported the linguistic view. The presence of Indian-specific Y-chromosome haplogroup H1a1a-M82 and mtDNA haplogroups M5a1, M18 and M35b among Roma has corroborated that their South Asian origins and later admixture with Near Eastern and European populations. However, previous studies have left unanswered questions about the exact parental population groups in South Asia. Here we present a detailed phylogeographical study of Y-chromosomal haplogroup H1a1a-M82 in a data set of more than 10,000 global samples to discern a more precise ancestral source of European Romani populations. The phylogeographical patterns and diversity estimates indicate an early origin of this haplogroup in the Indian subcontinent and its further expansion to other regions. Tellingly, the short tandem repeat (STR) based network of H1a1a-M82 lineages displayed the closest connection of Romani haplotypes with the traditional scheduled caste and scheduled tribe population groups of northwestern India.
doi:10.1371/journal.pone.0048477
PMCID: PMC3509117  PMID: 23209554
21.  IL-4 Haplotype -590T, -34T and Intron-3 VNTR R2 Is Associated with Reduced Malaria Risk among Ancestral Indian Tribal Populations 
PLoS ONE  2012;7(10):e48136.
Background
Interleukin 4 (IL-4) is an anti-inflammatory cytokine, which regulates balance between TH1 and TH2 immune response, immunoglobulin class switching and humoral immunity. Polymorphisms in this gene have been reported to affect the risk of infectious and autoimmune diseases.
Methods
We have analyzed three regulatory IL-4 polymorphisms; -590C>T, -34C>T and 70 bp intron-3 VNTR, in 4216 individuals; including: (1) 430 ethnically matched case-control groups (173 severe malaria, 101 mild malaria and 156 asymptomatic); (2) 3452 individuals from 76 linguistically and geographically distinct endogamous populations of India, and (3) 334 individuals with different ancestry from outside India (84 Brazilian, 104 Syrian, and 146 Vietnamese).
Results
The -590T, -34T and intron-3 VNTR R2 alleles were found to be associated with reduced malaria risk (P<0.001 for -590C>T and -34C>T, and P = 0.003 for VNTR). These three alleles were in strong LD (r2>0.75) and the TTR2 (-590T, -34T and intron-3 VNTR R2) haplotype appeared to be a susceptibility factor for malaria (P = 0.009, OR = 0.552, 95% CI = 0.356 –0.854). Allele and genotype frequencies differ significantly between caste, nomadic, tribe and ancestral tribal populations (ATP). The distribution of protective haplotype TTR2 was found to be significant (χ23 = 182.95, p-value <0.001), which is highest in ATP (40.5%); intermediate in tribes (33%); and lowest in caste (17.8%) and nomadic (21.6%).
Conclusions
Our study suggests that the IL-4 polymorphisms regulate host susceptibility to malaria and disease progression. TTR2 haplotype, which gives protection against malaria, is high among ATPs. Since they inhabited in isolation and mainly practice hunter-gatherer lifestyles and exposed to various parasites, IL-4 TTR2 haplotype might be under positive selection.
doi:10.1371/journal.pone.0048136
PMCID: PMC3480467  PMID: 23110190
22.  Genomic view on the peopling of India 
India is known for its vast human diversity, consisting of more than four and a half thousand anthropologically well-defined populations. Each population differs in terms of language, culture, physical features and, most importantly, genetic architecture. The size of populations varies from a few hundred to millions. Based on the social structure, Indians are classified into various caste, tribe and religious groups. These social classifications are very rigid and have remained undisturbed by emerging urbanisation and cultural changes. The variable social customs, strict endogamy marriage practices, long-term isolation and evolutionary forces have added immensely to the diversification of the Indian populations. These factors have also led to these populations acquiring a set of Indian-specific genetic variations responsible for various diseases in India. Interestingly, most of these variations are absent outside the Indian subcontinent. Thus, this review is focused on the peopling of India, the caste system, marriage practice and the resulting health and forensic implications.
doi:10.1186/2041-2223-3-20
PMCID: PMC3514343  PMID: 23020857
Admixture; caste; Indians; mtDNA; tribe; Y-chromosome
23.  High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians 
BMC Medical Genetics  2012;13:69.
Background
Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study.
Methods
We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India.
Results
Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing.
Conclusion
Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.
doi:10.1186/1471-2350-13-69
PMCID: PMC3495047  PMID: 22876777
TNNI3-Troponin I; Cardiomyopathy; SNPs; HCM; Indians; Mutations
24.  Population Genetic Structure in Indian Austroasiatic Speakers: The Role of Landscape Barriers and Sex-Specific Admixture 
Molecular biology and evolution  2010;28(2):1013-1024.
The geographic origin and time of dispersal of Austroasiatic (AA) speakers, presently settled in south and southeast Asia, remains disputed. Two rival hypotheses, both assuming a demic component to the language dispersal, have been proposed. The first of these places the origin of Austroasiatic speakers in southeast Asia with a later dispersal to south Asia during the Neolithic, whereas the second hypothesis advocates pre-Neolithic origins and dispersal of this language family from south Asia. To test the two alternative models, this study combines the analysis of uniparentally inherited markers with 610,000 common single nucleotide polymorphism loci from the nuclear genome. Indian AA speakers have high frequencies of Y chromosome haplogroup O2a; our results show that this haplogroup has significantly higher diversity and coalescent time (17–28 thousand years ago) in southeast Asia, strongly supporting the first of the two hypotheses. Nevertheless, the results of principal component and “structure-like” analyses on autosomal loci also show that the population history of AA speakers in India is more complex, being characterized by two ancestral components—one represented in the pattern of Y chromosomal and EDAR results and the other by mitochondrial DNA diversity and genomic structure. We propose that AA speakers in India today are derived from dispersal from southeast Asia, followed by extensive sex-specific admixture with local Indian populations.
doi:10.1093/molbev/msq288
PMCID: PMC3355372  PMID: 20978040
Austroasiatic; mtDNA; Y chromosome; autosomes; admixture
25.  Genetic Affinities of the Central Indian Tribal Populations 
PLoS ONE  2012;7(2):e32546.
Background
The central Indian state Madhya Pradesh is often called as ‘heart of India’ and has always been an important region functioning as a trinexus belt for three major language families (Indo-European, Dravidian and Austroasiatic). There are less detailed genetic studies on the populations inhabited in this region. Therefore, this study is an attempt for extensive characterization of genetic ancestries of three tribal populations, namely; Bharia, Bhil and Sahariya, inhabiting this region using haploid and diploid DNA markers.
Methodology/Principal Findings
Mitochondrial DNA analysis showed high diversity, including some of the older sublineages of M haplogroup and prominent R lineages in all the three tribes. Y-chromosomal biallelic markers revealed high frequency of Austroasiatic-specific M95-O2a haplogroup in Bharia and Sahariya, M82-H1a in Bhil and M17-R1a in Bhil and Sahariya. The results obtained by haploid as well as diploid genetic markers revealed strong genetic affinity of Bharia (a Dravidian speaking tribe) with the Austroasiatic (Munda) group. The gene flow from Austroasiatic group is further confirmed by their Y-STRs haplotype sharing analysis, where we determined their founder haplotype from the North Munda speaking tribe, while, autosomal analysis was largely in concordant with the haploid DNA results.
Conclusions/Significance
Bhil exhibited largely Indo-European specific ancestry, while Sahariya and Bharia showed admixed genetic package of Indo-European and Austroasiatic populations. Hence, in a landscape like India, linguistic label doesn't unequivocally follow the genetic footprints.
doi:10.1371/journal.pone.0032546
PMCID: PMC3290590  PMID: 22393414

Results 1-25 (50)