Biology subjects

Padmanabhan, S.

Publications and source records attributed to Padmanabhan, S..

5 recordsLinked to original sources

bioRxiv2018

Identification and in silico analysis of the origin recognition complex in the human fungal pathogen Candida albicans

DNA replication in eukaryotes is initiated by the orchestrated assembly and association of initiator proteins (heterohexameric Origin Recognition Complex, ORC) on the replication origins. These functionally conserved proteins play significant roles in diverse cellular processes besides their central role in ignition of DNA replication at origins. While Candida albicans, a major human fungal pathogen, is an ascomycetous, asexual, diploid budding yeast but it is significantly diverged from a much better studied model organism Saccharomyces cerevisiae. The components of the DNA replication machinery in C. albicans remain largely uncharacterized. Identification of factors required for DNA replication is essential for understanding the evolution of the DNA replication machinery. We identified the putative ORC homologs in C. albicans and determined their relatedness with those of other eukaryotes including several yeast species. Our extensive in silico studies demonstrate that the domain architecture of CaORC proteins share similarities with the ORC proteins of S. cerevisiae. We dissect the domain organization of ORC (trans-acting factors) proteins that seem to associate with DNA replication origins in C. albicans. We present a model of the 3D structure of CaORC4 to gain further insights of this proteins function.

bioinformatics↗

bioRxiv2018

Exploring the context of diacidic motif D-E as a signal for unconventional protein secretion in eukaryotic proteins

Unconventional protein secretion (UPS) is an important phenomenon with fundamental implications to cargo export. How eukaryotic proteins transported by UPS are recognized without a conventional signal peptide has been an open question. It was recently observed that a diacidic amino acid motif (ASP-GLU or DE) is necessary for the secretion of superoxide dismutase 1 (SOD1) from yeast under nutrient starvation. Taking cue from this discovery, we explore the hypothesis of whether the diacidic motif DE, which can occur fairly ubiquitously, along with its context, can be a generic signal for unconventional secretion of proteins. Two different definitions of context were evaluated: structural order and charge signature in the neighborhood of DE as one, and the nature of the amino acid insertion ( X) when a D-X-E motif is present, as another. We observe that among the eukaryotic proteins we studied, the odds of the protein being secreted are higher when the DE motif occurs in the disordered region of the protein, with higher hydrophobicity and lower charge or when the insertion X has a propensity for phosphorylation.

cell biology↗

bioRxiv2018

Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

genetics↗

bioRxiv2017

Genetic and environmental determinants of stressful life events and their overlap with depression and neuroticism

BackgroundStressful life events (SLEs) and neuroticism are risk factors for major depressive disorder (MDD). However, SLEs and neuroticism are heritable traits that are correlated with genetic risk for MDD. In the current study, we sought to investigate the genetic and environmental contributions to SLEs in a large family-based sample, and quantify any genetic overlap with MDD and neuroticism.\n\nMethodsA subset of Generation Scotland: the Scottish Family Health Study, consisting of 9618 individuals comprise the present study. We estimated the heritability of SLEs using pedigree-based and molecular genetic data. The environment was assessed by modelling familial, couple and sibling components. Using polygenic risk scores (PRS) and LD score regression we analysed the genetic overlap between MDD, neuroticism and SLEs.\n\nResultsPast 6-month life events were positively correlated with lifetime MDD status ({beta}=0.21, r2=1.1%, p=2.5 x 10-25) and neuroticism ({beta} =0.13, r2=1.9%, p=1.04 x 10-37). Common SNPs explained 8% of the variance in personal life events (those directly affecting the individual) (S.E.=0.03, p=9 x 10-4). A significant effect of couple environment accounted for 13% (S.E.=0.03, p=0.016) of variation in SLEs. PRS analyses found that individuals with higher PRS for MDD reported more SLEs ({beta} =0.05, r2=0.3%, p=3 x 10-5). LD score regression demonstrated genetic correlations between MDD and both SLEs (rG=0.33, S.E.=0.08) and neuroticism (rG=0.15, S.E.=0.07).\n\nConclusionsThese findings suggest that SLEs are partially heritable and this heritability is shared with risk for MDD and neuroticism. Further work should determine the causal direction and source of these associations.

genetics↗

bioRxiv2017

Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112,117).

Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well known genetic variants in alcohol metabolizing genes, e.g. ALDH2, ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112,117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 8 independent loci. These include SNPs in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and 2 loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, PXDN, CADM2 and TNFRSF11A. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (CRHR1, DRD2), and genes previously associated with alcohol consumption (AUTS2). GCTA-GREML analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (S.E.=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation between male and female alcohol consumption was 0.73 (S.E.=0.09, p-value = 1.37 x 10-16). Using LD score regression, genetic overlap was found between alcohol consumption and schizophrenia (rG=0.13, S.E=0.04), HDL cholesterol (rG=0.21, S.E=0.05), smoking (rG=0.49, S.E=0.06) and various anthropometric traits (e.g. Overweight, rG=-0.19, S.E.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies 4 novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

genetics↗