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A total of 14,612 regions were hypermethylated and 3838 regions were hypomethylated due to
B12 deficiency in the kidney of pups born to mothers with vitamin B12 deficiency. It was found
that out of 14,612 hypermethylated regions, 13,106 regions were reverted and of the 3838
hypomethylated sites, 3212 sites were reverted, after rehabilitation of vitamin B12 at conception
that established the causality of the effect. These reverted regions were enriched in important
biological pathways like PPAR signaling, calcium signaling, fatty acid metabolism and PI3K
signaling. In addition, genes belonging to sterol metabolism (CYP27B1, SOAT2, TM7SF2) were
hypermethylated in the female kidney. Other genes of metabolic pathway GPAM, PCYT2, DGKG
showed a gender specific difference of DNA methylation pattern. In the skeletal muscle, 3358
regions were hypermethylated and 8607 regions were hypomethylated in the male skeletal
muscle. More than 80% regions were reverted upon rehabilitation. Interestingly, it could be
observed that maternal B12 deficiency led to hypermethylation of certain regions in liver and
kidney but hypomethylation in the skeletal muscle of the 3-month-old offspring.

GERMLINE INHERITANCE OF ACQUIRED TRAITS- A CONCEPTUAL FRAMEWORK

Evidence supporting germline inheritance of environmentally acquired traits, often referred to
as transgenerational epigenetic inheritance, is a surprising new development in biology and a
subject of immense current interest and controversy. The first evidence of transgenerational
inheritance in males was reported by our group almost a decade ago, with the demonstration
that drug induced CNS gene expression changes are spermatogenically propagated to future
generations in the fruit fly, Drosophila melanogaster. A conceptual framework of epigenetic
inheritance was later on advanced by the laboratory in the ensuing years. The group led by Abhay
Sharma at IGIB, reported experimental evidence for transgenerational inheritance of acquired
metabolic traits in D. melanogaster, and analyzed multi-omics data to implicate epigenetic
inheritance in evolution and disease. The experimental work showed that high sugar diet induces
altered triglyceride levels not only in the exposed parents but also in the subsequent patrilineal
generations. The inheritance was correlated with germline regulation of diet induced coding
gene expression. This supported the hypothesis that sperm borne mRNAs may act as inherited
factors by influencing embryonic development. Available mouse data related to
intergenerational inheritance of diet induced metabolic traits was found to be consistent with
the hypothesis. His group also reported that, besides high sugar diet, cold temperature also
induces transgenerational inheritance of altered triglyceride levels and gene expression.
Previous studies in mammals on intergenerational inheritance of diet and temperature induced
metabolic traits have not been able to provide evidence for germline inheritance due to
insufficient generations analyzed. This study at IGIB , carried out in D. melanogaster, provided
the necessary evidence to establish a role of the germline because it involved male exposure and
male line derived future generations, and analyzed multi-omics data to implicate epigenetic
inheritance in evolution and disease. Cumulatively, this study provided experimental evidence
consistent with a potential role of epigenetic inheritance in metabolic diseases.

In multi-omics data analysis work, the laboratory focused on the mechanistic plausibility, and
the evolutionary and biomedical significance of epigenetic inheritance in general. By integrating
diverse human data related to disease genomics, epigenome-wide association studies, gene
mutability, evolutionary adaptation, and embryonic development, one-stop evidence has been
provided to suggest that sperm DNA methylome acts as a melting pot of gene-environment

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