Biology subjects

Ramachandran, V.

Publications and source records attributed to Ramachandran, V..

22 records · Page 2Linked to original sources

bioRxiv2020

Population sequencing data reveal a compendium of mutational processes in human germline

Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.

genetics↗

bioRxiv2019

Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown.1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence2-4 and coronary heart disease prevalence.5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed Clonal Hematopoiesis of Indeterminate Potential (CHIP).6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

genomics↗

bioRxiv2019

Prevalence, awareness and control of hypertension in Malaysia 1980 - 2017: A Systematic Review and Meta-Analysis

BackgroundHypertension is a common public health problem worldwide and is a well-known risk factor for increased risk of cardiovascular diseases, contributing to high morbidity and mortality. However, there is no systematic review and meta-analysis that has been done in a multi-ethnic population like Malaysia. This systematic review aims to determine the trend in prevalence, awareness and control of hypertension in Malaysia.\n\nMethodsSystematic searches were conducted in PubMed, Scopus, Ovid, Cumulative Index to Nursing and Allied Health Literature, Malaysian Medical Repository and Malaysia Citation Index published between 1980 and 2017. All original articles in English were included. Studies included were those on adults aged 18 years and above. Studies of prevalence in children and adolescents and pregnancy related hypertension were excluded. Two authors independently reviewed the studies, carried out data extraction and performed quality assessment. Heterogeneity between studies and publication bias was assessed and effect size was pooled by the random effect model.\n\nResultsFifty-six studies with a total of 241,796 subjects were included. The prevalence of hypertension throughout Malaysia varied (I2 = 99.3%). The overall pooled prevalence of hypertension over the past 4 decades was 28.2% in adults aged 18 years and older (95% CI: 26.1 - 33.3) and the prevalence in those 30 years and older was 40.0% (95% CI: 35.3-44.8).\n\nFor subgroup analysis, the prevalence of hypertension in male aged 18 and above was 31.4% (95% CI: 26.5 - 36.2) and 27.8% in female (95% CI: 20.7 - 34.9). The prevalence of hypertension among the ethnic groups aged 18 years and above were 37.3% in Malays (95% CI: 32.9 - 41.7); 36.4% in Chinese (95% CI 31.6 - 41.2) and 34.8% in Indians (95% CI: 31.2-38.4). The prevalence of hypertension was the lowest in the 1980s (16.2%, 95% CI: 13.4-19.0%), increases up to 36.8% in the 1990s (95% CI: 6.1-67.5), then came down to 28.7% (95% CI: 21.7-35.8) in the 2000s and 29.2% (95% CI: 24.0-34.4) in the 2010s. The prevalence of awareness was 38.7% (95% CI: 31.7 - 45.8) whereas the control of hypertension of those on treatment was 33.3% (95% CI: 28.4 - 38.2).\n\nConclusionThree in 10 adults aged 18 years old and above have hypertension, whereas four in 10 adults aged 30 years old and above have hypertension. Four out of 10 are aware of their hypertension status and only one-third of them who were under treatment achieved control of their hypertension. Concerted efforts by policymakers and healthcare professionals to improve the awareness and control of hypertension should be of high priority.

epidemiology↗

bioRxiv2018

A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy.

Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms implicated in regulating lifespan extension is the ability to induce protein chaperones to promote protein homeostasis. However, it is unclear whether protein chaperones exclusively regulate longevity. Previous work has shown that activating the unfolded protein response of the endoplasmic reticulum (UPRER) in neurons can signal peripheral tissues to promote chaperone expression, thus enhancing organismal stress resistance and extending lifespan. Here, we find that this activation not only promotes chaperones, but facilitates a dramatic restructuring of ER morphology in intestinal cells. This restructuring, which includes depletion of lipid droplets, ER expansion, and ER tubulation, depends of lipophagy. Surprisingly, we find that lipophagy is required for lifespan extension and is completely independent of chaperone function. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the canonical arm through protein chaperones, and a non-canonical mechanism through lipid depletion. In summary, our study identifies lipophagy as an integral component of UPRER-induced longevity.

cell biology↗