Abstract
Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain.
Highlights
Somatic variations are an inevitable consequence of continuous cell divisions in multicellular complex organisms and can lead to genomic heterogeneity
Raw data for ‘Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress’
We analyzed about 1.5 billion reads from whole exome sequencing of 18 samples each having ~60 Mb coverage and identified 2,49,607 single nucleotide variations (SNVs), with an average of ~27,700 sites per sample (Supplementary figure S3)
Summary
Somatic variations are an inevitable consequence of continuous cell divisions in multicellular complex organisms and can lead to genomic heterogeneity. The contribution of somatic variations is widely reported in cases where the DNA from affected tissue was found to harbor causal mutations whereas they were absent in the DNA from peripheral blood[2,3,4]. The rates of somatic variations have been a matter of debate, ranging between 10-4 to 10-8 per base-pair, per generation, depending on whether these estimates were genomewide (lower estimates) or locus-specific (higher estimates)[6,7]. It has been speculated that rates of somatic variations might differ for different tissue-types and different developmental times but this remains to be clarified[1]
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