Biology subjects

Bazykin, G.

Publications and source records attributed to Bazykin, G..

5 recordsLinked to original sources

bioRxiv2025

Mutation bias in driver genes reveals the distribution of effects of oncogenic mutations

Although many cancer driver genes have been identified, the full set of mutations within these genes that can promote tumorigenesis remains unknown. The contribution of a mutation depends on both its probability of occurrence and the selective advantage it confers. Here, we introduce a metric that quantifies how selection biases the spectrum of observed mutations in driver genes, and use it to develop a method estimating the number of driver mutations and their effect distribution at individual genes. Applying this framework to large cancer cohorts, we find that in most oncogenes, nearly all driver mutations have already been observed, whereas in most tumor-suppressor genes, the majority remain undiscovered. These results reveal fundamental differences in how mutation and selection shape mutational patterns across gene classes and provide a framework for interpreting newly detected variants.

genetics↗

bioRxiv2022

Evidence for coordinated evolution at amino acid sites of SARS-CoV-2 spike

It is currently unclear why SARS-Cov-2 has adapted in a stepwise manner, with multiple beneficial mutations accumulating in a rapid succession at the origins of VOCs. Here, we searched for coordinated evolution of amino acid sites in the spike protein of SARS-Cov-2. We searched for concordantly evolving site pairs (CSP) for which changes at one site were rapidly followed by changes at the other site in the same lineage. We detected 46 sites which formed 45 CSP. Sites in CSP were closer to each other in the protein structure than random pairs, indicating that concordant evolution has a functional basis. Notably, site pairs carrying lineage defining mutations of the four VOCs that circulated before May 2021 are enriched in CSP, indicating that the origin of these VOCs could have been facilitated by positive epistasis. Additionally, we detected four discordantly evolving pairs of sites where mutations at one site unexpectedly rarely occurred on the background of a specific allele at another site, namely on the wild-type D at site 614 (for two pairs) or at derived Y in the site 501 (for two other pairs). Our findings hint that positive epistasis between accumulating mutations could have delayed the assembly of advantageous combinations of mutations comprising at least some of the VOCs.

evolutionary biology↗

bioRxiv2022

Genomic perspectives on the emerging SARS-CoV-2 Omicron variant

A new variant of concern for SARS-CoV-2, Omicron (B.1.1.529), was designated by the World Health Organization on November 26, 2021. This study analyzed the viral genome sequencing data of 108 samples collected from patients infected with Omicron. First, we found that the enrichment efficiency of viral nucleic acids was reduced due to mutations in the region where the primers anneal to. Second, the Omicron variant possesses an excessive number of mutations compared to other variants circulating at the same time (62 vs. 45), especially in the Spike gene. Mutations in the Spike gene confer alterations in 32 amino acid residues, which was more than those observed in other SARS-CoV-2 variants. Moreover, a large number of nonsynonymous mutations occur in the codons for the amino acid residues located on the surface of the Spike protein, which could potentially affect the replication, infectivity, and antigenicity of SARS-CoV-2. Third, there are 53 mutations between the Omicron variant and its closest sequences available in public databases. Many of those mutations were rarely observed in the public database and had a low mutation rate. In addition, the linkage disequilibrium between these mutations were low, with a limited number of mutations (6) concurrently observed in the same genome, suggesting that the Omicron variant would be in a different evolutionary branch from the currently prevalent variants. To improve our ability to detect and track the source of new variants rapidly, it is imperative to further strengthen genomic surveillance and data sharing globally in a timely manner.

genomics↗

bioRxiv2020

Episodic evolution of coadapted sets of amino acid sites in mitochondrial proteins

The rate of evolution differs between protein sites and changes with time. However, the link between these two phenomena remains poorly understood. Here, we design a phylogenetic approach for distinguishing pairs of amino acid sites that undergo coordinated evolution, i.e., such that substitutions at one site trigger subsequent substitutions at the other; and also pairs of sites that undergo discordant evolution, so that substitutions at one site impede subsequent substitutions at the other. We distinguish groups of amino acid sites that undergo coordinated evolution and evolve discordantly from other such groups. In mitochondrially encoded proteins of metazoans and fungi, we show that concordantly evolving sites are clustered in protein structures. Moreover, the substitution rates within individual concordant groups themselves change in the course of evolution, and phylogenetic positions of these changes are consistent between proteins, suggesting common selective forces underlying them. Author summaryEvolution in most protein sites is constrained by alleles in other sites, this phenomena is called epistasis. Generally, newly arisen allele, if it would not be lost, increases its fitness with time due to adaptive mutations occurred in other sites in the process called the entrenchment. Thus, we expect that the evolution of sites would be coordinated, such that mutations in sites rapidly follow each other on phylogenetic lineages. Indeed, we have observed such coordinated evolution of sites in five proteins encoded in the mitochondria genomes of metazoan and fungi. Unexpectedly, coordinated evolution is observed only for nearby sites on protein structures, such that each protein could be partitioned into several groups of concordantly evolving sites. Evolution of sites from different groups is discordant, i.e. their mutations repel each other into different phylogenetic lineages or clades. Thus, the proteins encoded in mitochondrial genome consist of the sort of structural blocks like elements of the LEGO kit. Some of them have functional specialization, e.g. some blocks are associated with interfaces between proteins composing respiratory complexes.

evolutionary biology↗

bioRxiv2017

Are Nonsense Alleles of Drosophila melanogaster Genes under Any Selection?

A gene which carries a bona fide loss-of-function mutation effectively becomes a functionless pseudogene, free from selective constraint. However, there is a number of molecular mechanisms that may lead to at least a partial preservation of the function of genes carrying even drastic alleles. We performed a direct measurement of the strength of negative selection acting on nonsense alleles of protein-coding genes in the Zambian population of Drosophila melanogaster. Within those exons that carry nonsense mutations, negative selection, assayed by the ratio of missense over synonymous nucleotide diversity levels, appears to be absent, consistent with total loss of function. In other exons of nonsense alleles, negative selection was deeply relaxed but likely not completely absent, and the per site number of missense alleles declined significantly with the distance from the premature stop codon. This pattern may be due to alternative splicing which preserves function of some isoforms of nonsense alleles of genes.

evolutionary biology↗