Biology subjects

Georgii A. Bazykin

Publications and source records attributed to Georgii A. Bazykin.

4 recordsLinked to original sources

bioRxiv2016

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

APOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most of APOBEC3A/B-induced mutations occur on the lagging strand during replication. Here, we use data on rare human polymorphisms, interspecies divergence, and de novo mutations to study germline mutagenesis, and analyze mutations at nucleotide contexts prone to attack by APOBEC3A/B. We show that such mutations occur preferentially on the lagging strand. Moreover, we demonstrate that APOBEC3A/B-like mutations tend to produce strand-coordinated clusters, which are also biased towards the lagging strand. Finally, we show that the mutation rate is increased 3 of C[->]G mutations to a greater extent than 3 of C[->]T mutations, suggesting pervasive translesion bypass of the APOBEC3A/B-induced damage. Our study demonstrates that 20% of C[->]T and C[->]G mutations segregating as polymorphisms in human population are attributable to APOBEC3A/B activity.

Molecular Biology↗

bioRxiv2016

Parallel evolution of metazoan mitochondrial proteins

Amino acid propensities at amino acid sites change with time due to epistatic interactions or changing environment, affecting the probabilities of fixation of different amino acids. Such changes should lead to an increased rate of homoplasies (reversals, parallelisms, and convergences) at closely related species. Here, we reconstruct the phylogeny of twelve mitochondrial proteins from several thousand metazoan species, and measure the phylogenetic distances between branches at which either the same allele originated repeatedly due to homoplasies, or different alleles originated due to divergent substitutions. The mean phylogenetic distance between parallel substitutions is [~]20% lower than the mean phylogenetic distance between divergent substitutions, indicating that a variant fixed in a species is more likely to be deleterious in a more phylogenetically remote species, compared to a more closely related species. These findings are robust to artefacts of phylogenetic reconstruction or of pooling of sites from different conservation classes or functional groups, and imply that single-position fitness landscapes change at rates similar to rates of amino acid changes.

Genomics↗

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↗

bioRxiv2014

Coordinated Evolution of Influenza A Surface Proteins

Surface proteins hemagglutinin (HA) and neuraminidase (NA) of the human influenza A virus evolve under selection pressure to escape the human adaptive immune response and antiviral drug treatments. In addition to these external selection pressures, some mutations in HA are known to affect the adaptive landscape of NA, and vice versa, because these two proteins are physiologically interlinked. However, the extent to which evolution of one protein affects the evolution of the other is unknown. Here we develop a novel phylogenetic method for detecting the signatures of such genetic interactions between mutations in different genes, that is, inter-gene epistasis. Using this method, we show that influenza surface proteins evolve in a coordinated way, with substitutions in HA affecting substitutions in NA and vice versa, at many sites. Of particular interest is our finding that the oseltamivir-resistance mutations in NA in subtype H1N1 were likely facilitated by prior mutations in HA. Our results illustrate that the adaptive landscape of a viral protein is remarkably sensitive to its genomic context and, more generally, imply that the evolution of any single protein must be understood within the context of the entire evolving genome.

Evolutionary Biology↗