Dynamic Methylome Modification associated with mutational signatures in ageing and etiology of disease
Epigenetic markers and reversible change in the loci of genes regulating critical cell processes, have recently emerged as important biomarkers in the study of disease pathology. The epigenetic changes that accompany ageing in the context of population health risk needs to be explored. Additionally, the interplay between dynamic methylation changes that accompany ageing in relation to mutations that accrue in an individual genome over time needs further investigation.
Our current study captures the role for variants acting in concurrence with dynamic methylation in an individual analyzed over time, in essence reflecting the genome-epigenome interplay, affecting biochemical pathways controlling physiological processes. In our current study, we completed the whole genome methylation and variant analysis in one Zoroastrian-Parsi non-smoking individual, collected at an interval of 12 years apart (at 53 and 65 years respectively) (ZPMetG-Hv2a-1A (old, t0), ZPMetG-Hv2a-1B (recent, t0+12)) using Grid-ion Nanopore sequencer at 13X genome coverage overall.
We further identified the Single Nucleotide Variants (SNVs) and indels in known CpG islands by employing GATK and MuTect2 variant caller pipeline with GRCh37 (patch 13) human genome as the reference. We found 5258 disease relevant genes differentially methylated across this individual over 12 years. Employing the GATK pipeline, we found 24,948 genes corresponding to 4,58,148 variants specific to ZPMetG-Hv2a-1B, indicative of variants that accrued over time. 242/24948 gene variants occurred within the CpG regions that were differentially methylated with 67/247 exactly occurring on the CpG site.
Our analysis yielded a critical cluster of 10 genes which are significantly methylated and have variants at the CpG site or around 4bp CpG region window. KEGG enrichment network analysis, Reactome and STRING analysis of mutational signatures of gene specific variants indicated an impact in biological process regulating immune system, disease networks implicated in cancer and neurodegenerative diseases and transcriptional control of processes regulating cellular senescence and longevity.
Our current study provides an understanding of the ageing methylome over time through the interplay between differentially methylated genes and variants in the etiology of disease.