L859F mutation in androgen receptor gene results in complete loss of androgen binding to the receptor

Androgens drive male secondary sexual differentiation and maturation. Mutations in the androgen receptor (AR) gene cause an array of abnormal sex differentiation phenotypes in humans, ranging from mild through partial to complete androgen insensitivity. Earlier, we reported a C3693T missense mutation in the AR gene in a familial case of complete androgen insensitivity syndrome (CAIS), resulting in the replacement of a highly conserved leucine residue with phenylalanine (L859F) in ligand-binding domain (LBD) of the receptor. In silico analysis and the information from the crystal structure of AR-LBD indicated that the residue L859, located in helix 10 of AR protein, plays a significant role in overall architecture of the ligand-binding pocket. From this information we anticipated that the mutation might have resulted in the loss of the ligand binding to the receptor. In the present study, we have conducted the in vitro functional assays for this mutation. The mutation resulted in highly significant loss of the ligand binding to the receptor. The loss of ligand binding and subsequent AR function was confirmed by the transactivation assay, in which we observed very little activation of the reporter gene expressed under the control of the ligand-AR complex

Reduced prevalence of placental malaria in primiparae with blood group O

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

Complex genetic origin of Indian populations and its implications

Indian populations are classified into various caste, tribe and religious groups, which altogether makes them very unique compared to rest of the world. The long-term firm socio-religious boundaries and the strict endogamy practices along with the evolutionary forces have further supplemented the existing high-level diversity. As a result, drawing definite conclusions on its overall origin, affinity, health and disease conditions become even more sophisticated than was thought earlier. In spite of these challenges, researchers have undertaken tireless and extensive investigations using various genetic markers to estimate genetic variation and its implication in health and diseases. We have demonstrated that the Indian populations are the descendents of the very first modern humans, who ventured the journey of out-of-Africa about 65,000 years ago. The recent gene flow from east and west Eurasia is also evident. Thus, this review attempts to summarize the unique genetic variation among Indian populations as evident from our extensive study among approximately 20,000 samples across India

Atrial natriuretic peptide gene - a potential biomarker for Long QT syndrome

This study highlights the possible implication of NPPA (natriuretic peptide precursor A) gene in the etiology of Long QT syndrome (LQTS) by population-based as well as familial study. Three SNPs of NPPA- C-664G, C1363A and T1766C were examined by molecular analyses in LQTS, controls and first degree relatives (FDRs). This study revealed a possible association of 1364 C>A SNP ‘C’ allele with LQTS (p = 0.0013). All three SNPs were in tight linkage disequilibrium. The familial study highlights the association of NPPA SNP with cLQTS and implicating it as a potential biomarker in South Indian population

Complete mitochondrial genome sequence of Asiatic lion (Panthera leo persica)

The complete mitochondrial genome sequence 17,059 bp of Asiatic lion (Panthera leo persica) has been sequenced with the use of next generation sequencing technology using Ion TorrentPGM platform. The complete mitochondrial genome sequence of Asiatic lion consists of 13 protein-coding, 22 tRNA and two rRNA genes and 1 Control Region (CR). The mitochondrial genome is relatively similar to other felid mitochondrial genomes with respect to gene arrangement, composition, tRNA structures and skews of AT/GC bases to be typical of those reported for other mammals. The nucleotide composition of Asiatic lion mitogenome shows that there is more A-T% than G-C% on the positive strand as revealed by positive AT and CG skews. The overall base composition is 31.9% of A, 27.2% of C, 14.5% of G and 26.2% of T. Most of the genes have ATA start codons, except ND1, COX2, ATP8, ATP6, ND4 and ND5 have ATG start codons

Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India.

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.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

c.620C>T mutation in GATA4 is associated with congenital heart disease in South India

Background: Congenital Heart Diseases (CHDs) usually refer to abnormalities in the structure and/or function of the heart that arise before birth. GATA4 plays an important role in embryonic heart development, hence the aim of this study was to find the association of GATA4 mutations with CHD among the south Indian CHD patients. Method: GATA4 gene was sequenced in 100 CHD patients (ASD, VSD, TOF and SV) and 200 controls. Functional significance of the observed GATA4 mutations was analyzed using PolyPhen, SIFT, PMut, Plink, Haploview, ESE finder 3.0 and CONSITE. Results: We observed a total of 19 mutations, of which, one was in 5′ UTR, 10 in intronic regions, 3 in coding regions and 5 in 3′ UTR. Of the above mutations, one was associated with Atrial Septal Defect (ASD), two were found to be associated with Tetralogy of Fallot (TOF) and three (rs804280, rs4841587 and rs4841588) were strongly associated with Ventricular Septal Defect (VSD). Interestingly, one promoter mutation (−490 to 100 bp) i.e., 620 C>T (rs61277615, p-value = 0.008514), one splice junction mutation (G>A rs73203482; p-value = 9.6e-3, OR = 6.508) and one intronic mutation rs4841587 (p-value = 4.6e-3, OR = 4.758) were the most significant findings of this study. In silico analysis also proves that some of the mutations reported above are pathogenic. Conclusion: The present study found that GATA4 genetic variations are associated with ASD, TOF and VSD in South Indian patients. In silico analysis provides further evidence that some of the observed mutations are pathogenic

Standardization of PCR conditions for an Ancient DNA Amplification

An ancient DNA provides us a powerful tool to study the miniscule amounts of DNA present in hundreds of thousands of years old archaeological remains. Since the advent of the PCR, it became possible for the population biologists to use this scarce and rare genetic material (aDNA) to understand prehistoric population histories. Working with ancient DNA is challenging in itself as it needs a manifold attention in order to maintain the archaeological sample free from contemporary DNA contamination. Apart from that, there are several other complications associated with ancient DNA work such as the preservation of DNA itself that is in degraded state and low copy number, DNA isolation and its successful PCR amplification. Despite the critical role of PCR in this field of research, till date no study has comprehensively evaluated ancient DNA amplification.  In this paper, we have reported our results to optimize PCR component as well as PCR condition to amplify HVR1 region in 600 years old biological samples