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

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

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

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

Sperm mitochondrial mutations as a cause of low sperm motility

We report the unique case of a 28-year-old man who, in spite of having a varicocele and a sperm concentration of 5 million/mL, of which 10% were motile and 20% had normal forms (oligoasthenoteratozoospermia [OAT]), was fertile. This was confirmed by paternity testing using 16 autosomal and 6 Y-chromosomal short tandem repeat (STR) loci. An analysis of mitochondrial genes that included cytochrome oxidase I (COI), cytochrome oxidase II (COII), adenosine triphosphate synthase6 (ATPase6), ATPase8, transfer ribonucleic acid (tRNA) serine I, tRNA lysine, and NADH dehydrogenase3 (ND3) revealed, for the first time, 9 missense and 27 silent mutations in the sperm's mitochondrial DNA (mtDNA) but not in the DNA from the blood cells. There was a 2-nucleotide deletion in the mitochondrial COII genes, introducing a stop codon, which might be responsible for low sperm motility

No association of androgen receptor GGN repeat length polymorphism with infertility in Indian men

Androgens, acting through the androgen receptor (AR), play a role in secondary sexual differentiation from the prenatal stage to adulthood, including spermatogenesis. The AR gene has 2 polymorphic trinucleotide repeats (CAG and GGN) in exon 1. The CAG repeat length polymorphism has been well studied in a variety of medical conditions, including male infertility. Many of these studies have shown an association of the expanded CAG repeats with male infertility, although this is not true for all populations. The GGN repeat, in contrast, has been less thoroughly studied. Thus far, only 4 reports worldwide have analyzed the GGN repeat, alone or in combination with the CAG repeat, in male infertility cases. No such study has been undertaken on infertile Indian men. Therefore, we have analyzed AR-GGN repeats in a total of 595 Indian males, including 277 azoospemric, 97 oligozoospermic, and 21 oligoteratozoospermic cases, along with 200 normozoospermic controls. The analysis revealed no difference in the mean number or the range of the repeat between cases (mean=21.51 repeats, range 15-26 repeats) and controls (mean 21.58 repeats, range 15-26 repeats). Furthermore, no difference was observed when azoospermic (mean=21.53 repeats, range 15-26 repeats), oligozoospermic (mean=21.46 repeats, range 15-26 repeats), and oligoteratozoospermic cases (mean=21.48, range 19-26 repeats) were compared individually with the controls

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

Long QT syndrome- a genetic insight

Long QT syndrome is a rare arrhythmogenic disorder characterized by a prolongation of the QT interval on Electrocardiogram (ECG) with a propensity to ventricular tachyarrhythmia, leading to syncope, cardiac arrest or sudden death. It is regarded as the “Rosetta Stone” for studying the genetic basis of ventricular arrhythmogenesis. It is caused mainly due to mutations in sodium and potassium channel genes or in the genes involved in the signal transduction pathway. Molecular, genetic and functional studies revealed the impliction of about 13 genes in this disorder. Studies have also revealed the variation in mutations in different ethnic groups, thus necessitating a complete genetic analysis in all the known ethnic groups of the world. This would help to develop personalized medicine, molecular diagnosis, risk stratification, establish a genotype-phenotype correlation, to find the epidemiological variables responsible for the etiology of the disease and identify the possible mode of inheritance

Microsatellite-based phylogeny of Indian domestic goats

<p>Abstract</p> <p>Background</p> <p>The domestic goat is one of the important livestock species of India. In the present study we assess genetic diversity of Indian goats using 17 microsatellite markers. Breeds were sampled from their natural habitat, covering different agroclimatic zones.</p> <p>Results</p> <p>The mean number of alleles per locus (NA) ranged from 8.1 in Barbari to 9.7 in Jakhrana goats. The mean expected heterozygosity (He) ranged from 0.739 in Barbari to 0.783 in Jakhrana goats. Deviations from Hardy-Weinberg Equilibrium (HWE) were statistically significant (P < 0.05) for 5 loci breed combinations. The D_Ameasure of genetic distance between pairs of breeds indicated that the lowest distance was between Marwari and Sirohi (0.135). The highest distance was between Pashmina and Black Bengal. An analysis of molecular variance indicated that 6.59% of variance exists among the Indian goat breeds. Both a phylogenetic tree and Principal Component Analysis showed the distribution of breeds in two major clusters with respect to their geographic distribution.</p> <p>Conclusion</p> <p>Our study concludes that Indian goat populations can be classified into distinct genetic groups or breeds based on the microsatellites as well as mtDNA information.</p