Ruslan A. Soldatov | Search bioRxiv

bioRxiv2016

Evolution of local mutation rate and its determinants

Mutation rate varies along the human genome, and part of this variation is explainable by measurable local properties of the DNA molecule. Moreover, mutation rates differ between orthologous genomic regions of different species, but the drivers of this change are unclear. Here, we compare the local mutation rates of several species. We show that these rates are very similar between human and apes, implying that their variation has a strong underlying cryptic component not explainable by the known genomic features. Mutation rates become progressively less similar in more distant species, and these changes are partially explainable by changes in the local genomic features of orthologous regions, most importantly, in the recombination rate. However, they are much more rapid, implying that the cryptic component underlying the mutation rate is more ephemeral than the known genomic features. These findings shed light on the determinants of mutation rate evolution.

Molecular Biology↗

bioRxiv2014

Polymerase ζ activity is linked to replication timing in humans: evidence from mutational signatures

Replication timing is an important determinant of germline mutation patterns, with a higher rate of point mutations in late replicating regions. Mechanisms underlying this association remain elusive. One of the suggested explanations is the activity of error-prone DNA polymerases in late-replicating regions. Polymerase {zeta} (pol {zeta}), an essential error-prone polymerase biased towards transversions, also has a tendency to produce dinucleotide mutations (DNMs), complex mutational events that simultaneously affect two adjacent nucleotides. Experimental studies have shown that pol {zeta} is strongly biased towards GC->AA/TT DNMs. Using primate divergence data, we show that the GC->AA/TT pol {zeta} mutational signature is the most frequent among DNMs, and its rate exceeds the mean rate of other DNM types by a factor of ~10. Unlike the overall rate of DNMs, the pol {zeta} signature drastically increases with the replication time in the human genome. Finally, the pol {zeta} signature is enriched in transcribed regions, and there is a strong prevalence of GC->TT over GC->AA DNMs on the non-template strand, indicating association with transcription. A recurrently occurring GC->TT DNM in HRAS gene causes the Costello syndrome; we find a 2-fold increase in the mutation rate, and a 2-fold decrease in the transition/transversion ratio, at distances of up to 1 kb from the DNM, suggesting a link between the Costello syndrome and pol {zeta} activity. This study uncovers the genomic preferences of pol {zeta}, shedding light on a novel cause of mutational heterogeneity along the genome.

Molecular Biology↗