It is widely accepted that within genomes, protein-coding exons are naturally more conserved over introns due to natural selection. Evolutionary biology principles dictate that nucleotide mutations that change protein function should affect the genetic fitness of subsequent generations. Recent studies, however, have shown that the rate of mutations can vary significantly among different regions in the genome, due to processes such as replication timing, level of gene expression, and chromatin structure. These notions have led genomic scientists from The Institute for Research in Biomedicine in Barcelona to question if exons and introns have different rates of mutation independent from genetic selection.
The team approaches this question through a cellular system in which the rate of genomic mutation is much higher than normal—cancer. Looking at whole genome data of multiple cancer types with a mutant, error-prone DNA polymerase, the team finds that there are proportionally less DNA mismatch mutations in exons than in introns. Based on sequence content, the team also determines that this decrease is not due to genetic selection.
“Negative selection is a key factor responsible for conserving exons between species, but we now know it is not the only factor,” says senior investigator Núria López-Bigas. “We demonstrate for the first time that exons hold fewer mutations than other regions because these regions are repaired more effectively.”
The team further determines that the mechanism behind this conservation is driven by a mismatch repair system that prefers exons. Exons appear to be enriched around specific methylated histones, H3K36me3. These areas allow for greater recruitment of repair proteins to exons for more efficient editing.
“Our repair machinery ‘knows’ that it must focus on the most important regions of the genome. This point should be taken into consideration when studying DNA mutation and repair processes and in studies on evolution, whether in tumours or species,” says López-Bigas.
In their paper, published yesterday in Nature, the team concludes that these findings in understanding DNA mutations and repair processes can have practical ramifications in the study of not just the evolution of species, but also the evolution of cancers.