Human frontal cortex is enriched for somatic variations under physiological oxidative stress compared to the corpus callosum from same individuals. A. Mukhopadhyay1,2, A. Sharma1,2, R. Kumari3,2, B. Mehani1, A. H. Ansari1, B. Varma3, R. Rehman4, B. K. Desiraju4, U. Mabalirajan4, A. Agrawal4 1) Genomics & Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Delhi, India; 2) Academy of Scientific and Innovative Research, New Delhi, India; 3) TRISUTRA Unit, CSIR-Institute of Genomics & Integrative Biology, Delhi, India; 4) Molecular Immunogenetics unit, CSIR-Institute of Genomics & Integrative Biology, Delhi, India.

   Somatic variation is important in local genomic composition and outcome unexplained by Mendelian genetics. Using deep sequencing data for whole exomes we show that human brain harbors upto three folds higher proportion of somatic single base substitutions compared to other peripheral/circulatory tissue types. More than 70% of these somatic events were contributed by G:C>T:A transversion events and 48% of them were responsible for non-synonymous changes, which was twice the proportion of synonymous changes. Up to 98% of these transversions occurred in the frontal cortex (rich in neuronal cell bodies) of the brain when compared with the corpus callosum (lack of neuronal cell bodies) of the same individuals. We further show molecular evidence that these transversion events take place due to oxidative stress mediated modification of guanosine to 8-OH-dG primarily in the neuronal cells. We demonstrate significant higher amount of 8-OH-dG in the frontal cortex compared to the corpus callosum of the same individuals, which correlated with abundance of neurons in the frontal cortex. Interestingly, majority (upto 22%) of the G:C>T:A transversion events would result in Asp>Tyr or Glu>Stop changes in the frontal cortex samples (in heterozygous condition) which might provide functional advantage to the frontal cortex. A pathway based analysis of the genes where the G:C>T:A have taken place in each individual, revealed axon guidance pathway as significantly enriched implicating a favorable selection of such somatic variations. Our results provide first genetic evidence of contribution of somatic variation in normal human cortex with biological consequences.

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