Biology subjects

Bazykin, G. A.

Publications and source records attributed to Bazykin, G. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Within-host antigenic selection of influenza A virus dominates over stochasticity but is limited by fitness tradeoffs and timing of the immune response

Despite antigenic evolution at the global scale, positive selection of influenza virus antigenic variants is not readily observed within hosts. Here, we tested the extent to which fitness tradeoffs, the timing of immune pressure, and stochastic effects impede antigenic selection within pre-immune hosts. We used genetically barcoded influenza A/Texas/50/2012 (H3N2) viruses (Tx/12) in a guinea pig model to probe these dynamics. Positive selection of an antigenic variant was reliant on a high strength of immune pressure acting early in infection. However, when fitness tradeoffs of the antigenic change were lessened, a lower strength and later introduction of immune pressure favored the antigenic variant. In all conditions, barcode dynamics revealed moderate stochastic effects. Our results suggest that stochastic evolution does not impede selection during acute influenza virus infection. The rarity of antigenic escape may instead stem from low mutational supply, fitness tradeoffs, and the intrinsic delay between infection and antibody recall.

microbiology↗

bioRxiv2024

EpiPAMPAS: Rapid detection of intra-protein epistasis via parsimonious ancestral state reconstruction and counting mutations

MotivationAn epistatic interaction is a non-linear combination of effects of individual mutations on fitness. This type of interaction is a known driver for evolution, as they alter the organisms fitness and adaptability. In this work we introduce EpiPAMPAS, a statistical method that is based on multiple sequence alignments (MSA) and detecting mutations in the same direction on a dendrogram instead of a phylogenetic tree using the Sankoff algorithm. ResultsWe tested EpiPAMPAS on both simulated and real sequencing data. On the simulated data, our method was able to detect the simulated epistatic pairs with very low p-value. In a real-world application, we tested the influenza proteins N1, N2, H1, H3 and HIV-1 envelope protein subtypes A, B and C. We observe that EpiPAMPAS detects fewer interacting pairs than comparable statistical approaches, although the overlap between detected positions is good. Moreover, some of the amino acids from the detected pairs are known to be deleterious for viral fitness. AvailabilityEpiPAMPAS is available under MIT license at https://github.com/kalininalab/EpiPAMPAS

bioinformatics↗

bioRxiv2024

Mitochondrial direct repeat reduction as a strategy for enhancing human longevity: the case of the common repeat

Aging, characterized by a series of functional declines correlated with advancing chronological age, has a significant mitochondrial DNA (mtDNA) component, with somatic mtDNA deletions playing a central role. In post-mitotic or slow-dividing cells like neurons and skeletal muscles, selfish mtDNA deletions clonally expand within a cell, ultimately leading to the deterioration and death of host cells and appearence of age-related phenotypes. Thus reducing the burden of somatic deletions could have far- reaching systemic benefits for the entire human body. Given the crucial role of direct nucleotide repeats in the formation of mitochondrial deletions, we hypothesize that minimizing these repeats in the human mitochondrial genome could enhance healthspan by decreasing somatic deletions. To investigate this hypothesis, we focus on the "common repeat", a 13-base pair perfect direct repeat sequence (ACCTCCCTCACCA) located at positions 8470-8482 and 13447-13459, respectively. This perfect repeat: (i) is highly prevalent, with its potential deleterious consequences affecting the majority of humans; (ii) represents one of the most fragile sites, highly prone to forming deletions; (iii) when disrupted, is associated with a decreased somatic deletion load and enhanced human healthspan; (iv) is likely to experience positive selection in the present or near future due to indirect fitness effects, such as the "grandmother effect", and direct fitness effects, such as (v) a decreased mutation rate. These observations support the argument that reducing the mtDNA somatic deletion load through targeted disruption of these repeats, or by using naturally occurring polymorphisms with disrupted repeats in mitochondrial medicine, could be an effective approach to increasing human longevity.

genetics↗

bioRxiv2023

Mutational signatures in wild type Escherichia coli strains reveal dominance of DNA polymerase errors

While mutational processes operating in the Escherichia coli genome have been revealed by multiple laboratory experiments, the contribution of these processes to accumulation of bacterial polymorphism and evolution in natural environments is unknown. To address this question, we reconstruct signatures of distinct mutational processes from experimental data on E. coli hypermutators, and ask how these processes contribute to differences between naturally occurring E. coli strains. We show that both mutations accumulated in the course of evolution of wild type strains in nature and in the lab-grown non-mutator laboratory strains are explained predominantly by the low fidelity of DNA polymerases II and III. By contrast, contributions specific to disruption of DNA repair systems cannot be detected, suggesting that temporary accelerations of mutagenesis associated with such disruptions are unimportant for within-species evolution. These observations demonstrate that accumulation of diversity in bacterial strains in nature is predominantly associated with errors of DNA polymerases.

evolutionary biology↗

bioRxiv2022

Extended family with germline pathogenic variant in polymerase delta provides strong evidence for recessive effect of proofreading inactivation

Mutational processes in germline and in somatic cells are vastly different, and it remains unclear how the same genetic background affects somatic and transmissible mutations. Here, we estimate the impact of an inherited pathogenic variant in the exonuclease domain of polymerase delta (Pol{delta}) on somatic and germline mutational processes and cancer development. In germline cells and in non-cancer somatic cells, the POLD1 L474P variant increases the mutation burden only slightly, contributing [~]11.8% and [~]14.7% of mutations respectively, although it strongly distorts the mutational spectra. By contrast, tumors developed by carriers of inherited pathogenic variants in POLD1 harbor a DNA rearrangement that results in a homozygous state of the pathogenic variant, leading to an extremely high mutation rate. Thus, mutations in both alleles of POLD1 gene are required for strong increase in mutation rate suggesting recessiveness of Pold{delta} proofreading. These results show a similar role of Pol{delta} in germline and somatic replication, and, together with previous findings, illustrate the important differences between Pol{delta} and Pol{varepsilon} in the disruption of their replication fidelity.

genetics↗

bioRxiv2022

Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires

The stability and plasticity of B cell-mediated immune memory ensures the ability to respond to the repeated challenges. We have analyzed the longitudinal dynamics of immunoglobulin heavy chain repertoires from memory B cells, plasmablasts, and plasma cells from the peripheral blood of generally healthy volunteers. We reveal a high degree of clonal persistence in individual memory B cell subsets, with inter-individual convergence in memory and antibody-secreting cells (ASCs). ASC clonotypes demonstrate clonal relatedness to memory B cells, and are transient in peripheral blood. We identify two clusters of expanded clonal lineages with differing prevalence of memory B cells, isotypes, and persistence. Phylogenetic analysis revealed signs of reactivation of persisting memory B cell-enriched clonal lineages, accompanied by new rounds of affinity maturation during proliferation and differentiation into ASCs. Negative selection contributes to both persisting and reactivated lineages, preserving the functionality and specificity of BCRs to protect against current and future pathogens.

immunology↗

bioRxiv2021

Complex fitness landscape shapes variation in a hyperpolymorphic species

It is natural to assume that patterns of genetic variation in hyperpolymorphic species can reveal large-scale properties of the fitness landscape that are hard to detect by studying species with ordinary levels of genetic variation1,2. Here, we study such patterns in a fungus Schizophyllum commune, the most polymorphic species known3. Throughout the genome, short-range linkage disequilibrium caused by attraction of rare alleles is higher between pairs of nonsynonymous than of synonymous sites. This effect is especially pronounced for pairs of sites that are located within the same gene, especially if a large fraction of the gene is covered by haploblocks, genome segments where the gene pool consists of two highly divergent haplotypes, which is a signature of balancing selection. Haploblocks are usually shorter than 1000 nucleotides, and collectively cover about 10% of the S. commune genome. LD tends to be substantially higher for pairs of nonsynonymous sites encoding amino acids that interact within the protein. There is a substantial correlation between LDs at the same pairs of nonsynonymous sites in the USA and the Russian populations. These patterns indicate that selection in S. commune involves positive epistasis due to compensatory interactions between nonsynonymous alleles. When less polymorphic species are studied, analogous patterns can be detected only through interspecific comparisons.

evolutionary biology↗

bioRxiv2020

Pairs of compensatory frameshifting mutations contribute to evolution of protein-coding sequences in vertebrates and insects

Insertions and deletions of lengths not divisible by 3 in protein-coding sequences cause frameshifts that usually induce premature stop codons and may carry a high fitness cost. However, this cost can be partially offset by a second compensatory indel restoring the reading frame. The role of such pairs of compensatory frameshifting mutations (pCFMs) in evolution has not been studied systematically. Here, we use whole-genome alignments of protein coding genes of 100 vertebrate species, and of 122 insect species, studying the prevalence of pCFMs in their divergence. We detect a total of 619 candidate pCFM-genes; 11 of them pass stringent quality filtering, including three human genes: RAB36, ARHGAP6 and NCR3LG1. In some instances, amino acid substitutions closely predating or following pCFMs restored the biochemical similarity of the frameshifted segment to the ancestral amino acid sequence, possibly reducing or negating the fitness cost of the pCFM. Typically, however, the resulting sequence bore no biochemical similarity to the ancestral one, indicating that pCFMs can uncover radically novel regions of protein space. In total, pCFMs represent an appreciable and previously overlooked source of novel variation in amino acid sequences.

evolutionary biology↗

bioRxiv2020

Convergent adaptation in mitochondria of phylogenetically distant birds: does it exist?

In a wide range of taxa, proteins encoded by mitochondrial genomes are involved in adaptation to lifestyle that requires oxygen starvation or elevation of metabolism rate. It remains poorly understood to what extent adaptation to similar conditions is associated with parallel changes in these proteins. We search for genetic signal of parallel or convergent evolution in recurrent molecular adaptation to high altitude, migration, diving, wintering, unusual flight abilities, or loss of flight in mitochondrial genomes of birds. Developing on previous work, we design an approach for detection of recurrent coincident changes in genotype and phenotype, indicative of an association between the two. We describe a number of candidate sites involved in recurrent adaptation in ND genes. However, we find that the majority of convergence events can be explained by random coincidences without invoking adaptation.

bioinformatics↗

bioRxiv2020

Population genomics of two closely related anhydrobiotic midges reveals differences in adaptation to extreme desiccation

The sleeping chironomid Polypedilum vanderplanki is capable of anhydrobiosis, a striking example of adaptation to extreme desiccation. Tolerance to complete desiccation in this species is associated with the emergence of multiple paralogs of protective genes. One of the gene families highly expressed under anhydrobiosis and involved in this process are protein-L-isoaspartate (D-aspartate) O-methyltransferases (PIMTs). Recently, a closely related anhydrobiotic midge from Malawi, P. pembai, showing the ability to tolerate complete desiccation similar to that of P. vanderplanki, but experiences more frequent desiccation-rehydration cycles due to differences in ecology, was discovered. Here, we sequenced and assembled the genome of P. pembai and performed a population genomics analysis of several populations of P. vanderplanki and a population of P. pembai. We observe positive selection and radical changes in the genetic architecture of the PIMT locus between the two species, including multiple duplication events in the P. pembai lineage. In particular, PIMT-4, the most highly expressed of these PIMTs, is present in six copies in the P. pembai; these copies differ in expression profiles, suggesting possible sub- or neofunctionalization. The nucleotide diversity ({pi}) of the genomic region carrying these new genes is decreased in P. pembai, but not in the orthologous region carrying the ancestral gene in P. vanderplanki, providing evidence for a selective sweep associated with post-duplication adaptation in the former. Overall, our results suggest an extensive recent and likely ongoing, adaptation of the mechanisms of anhydrobiosis.

evolutionary biology↗

bioRxiv2020

Adaptive evolution at mRNA editing sites in soft-bodied cephalopods

The bulk of variability in mRNA sequence arises due to mutation - change in DNA sequence which is heritable if it occurs in the germline. However, variation in mRNA can also be achieved by post-translational modification including mRNA editing, changes in mRNA nucleotide sequence that mimic the effect of mutations. Such modifications are not inherited directly; however, as the processes affecting them are encoded in the genome, they have a heritable component, and therefore can be shaped by selection. In soft-bodied cephalopods, adenine-to-inosine RNA editing is very frequent, and much of it occurs at nonsynonymous sites, affecting the sequence of the encoded protein. Here, we show that mRNA editing of individual nonsynonymous sites in cephalopods originates in evolution through substitutions at regions adjacent to these sites. As such substitutions mimic the effect of the substitution at the edited site itself, we hypothesize that they are favored by selection if the inosine is selectively advantageous to adenine at the edited position. Consistent with this hypothesis and with observations on Drosophila and human editing sites, we show that edited adenines are more frequently substituted with guanine, an informational analogue of inosine, in the course of evolution than their unedited counterparts, and for heavily edited adenines, these transitions are favored by positive selection. Thus, our study shows that coleoid editing sites may enhance adaptation, which, together with distinct evolutionary features of Drosophila and human editing sites, points at a general role of RNA editing in the molecular evolution of metazoans.

evolutionary biology↗

bioRxiv2019

Senescence and entrenchment in evolution of amino acid sites

Amino acid propensities at a site change in the course of protein evolution. This may happen for two reasons. Changes may be triggered by substitutions at epistatically interacting sites elsewhere in the genome; alternatively, they may arise due to environmental changes that are external to the genome. Here, we design a framework for distinguishing between these alternatives. Using analytical modelling and simulations, we show that they cause opposite dynamics of the fitness of the allele currently occupying the site: its fitness tends to increase with the time since its origin due to epistasis (\"entrenchment\"), but to decrease due to random environmental fluctuations (\"senescence\"). We analyse the phylogenetic distribution of substitutions in nuclear genomes, and show that among the amino acids originating at negatively selected sites of vertebrates, nearly all experience strong entrenchment. By contrast, among the amino acids originating at positively selected sites, 18% experience senescence. A similar pattern is observed in phylogenies of insects. We propose that senescence of the current allele is a cause of adaptive evolution.

evolutionary biology↗

bioRxiv2019

Rapid accumulation of mutations in growing mycelia of a hypervariable fungus Schizophyllum commune

The number of mutations that occur per nucleotide per generation varies between species by several orders of magnitude. In multicellular eukaryotes, the per generation mutation rate depends both on the per cell division mutation rate and on the number of germline cell divisions per generation. In a range of species, from fungi to humans, the number of germline cell divisions is lower than that of somatic cells, reducing the mutation burden on the offspring. The basidiomycete Schizophyllum commune has the highest level of genetic polymorphism known among eukaryotes. In a previous study, it was also found to have a high per generation mutation rate, probably contributing to its high polymorphism. However, this rate has been measured only in a breeding experiment on Petri dishes, and it is unclear how this result translates to natural populations. Here, we used an experimental design that measures the rate of accumulation of de novo mutations in a linearly growing mycelium. We show that S. commune accumulates mutations at a uniform rate of 1.4{middle dot}10-7 substitutions per nucleotide per meter of growth, which is 3 orders of magnitude higher than the corresponding rates in the oak Quercus robur and the fungus Armillaria gallica. This figure is consistent with the estimate obtained before, and suggests the lack of a dedicated germline in this system. If so, even a low per cell division mutation rate can translate into a very high per generation mutation rate when the number of cell divisions between consecutive meioses is large.

evolutionary biology↗

bioRxiv2019

SELVa: Simulator of Evolution with Landscape Variation

Organisms evolve to increase their fitness, a process that may be described as climbing the fitness landscape. However, the fitness landscape of an individual site, i.e., the vector of fitness values corresponding to different variants at this site, can change with time due to changes in the environment or substitutions at other epistatically interacting sites. We present SELVa, the Simulator of Evolution with Landscape Variation, aimed at modeling the substitution process under a changing single position fitness landscape in a set of evolving lineages forming a phylogeny of arbitrary shape. Written in Java and distributed as an executable jar file, SELVa provides a flexible framework that allows the user to choose from a number of implemented rules governing landscape change.\n\nAvailabilityhttps://github.com/bazykinlab/SELVa

evolutionary biology↗

bioRxiv2019

Deleterious in late life mitochondrial alleles and aging: secrets of Japanese centenarians

Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Deletions in mitochondrial DNA (mtDNA) are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded DNA might play a role in the formation of deletions. By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a "hot spot" where one deletion breakpoint occurred within the region of 6-9kb and another within 13-16kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11kb and contacting regions between 6-9 kb and 13-16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470-8482 bp and a second arm at 13447-13459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. An analysis of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.

genetics↗

bioRxiv2019

Phylogenetic inference of changes in amino acid propensities with single-position resolution

Fitness conferred by the same allele may differ between genotypes, and these differences shape variation and evolution. Changes in amino acid propensities at protein sites over the course of evolution have been inferred from sequence alignments statistically, but the existing methods are data-intensive and aggregate multiple sites. Here, we develop an approach to detect individual amino acids that confer different fitness in different groups of species from combined sequence and phylogenetic data. Using the fact that the probability of a substitution to an amino acid depends on its fitness, our method looks for amino acids such that substitutions to them occur more frequently in one group of lineages than in another. We validate our method using simulated evolution of a protein site under different scenarios and show that it has high specificity for a wide range of assumptions regarding the underlying changes in selection, while its sensitivity differs between scenarios. We apply our method to the env gene of two HIV-1 subtypes, A and B, and to the HA gene of two influenza A subtypes, H1 and H3, and show that the inferred fitness changes are consistent with the fitness differences observed in deep mutational scanning experiments. We find that changes in relative fitness of different amino acid variants within a site do not always trigger episodes of positive selection and therefore may not result in an overall increase in the frequency of substitutions, but can still be detected from changes in relative frequencies of different substitutions. Author summaryWhich amino acids are acceptable at a certain protein site can change with time. In viruses, for example, this can be due to changes in mechanisms of drug resistance and immune escape in the course of evolution. Here, we develop a method for detecting such changes from how evolutionary events are distributed over an evolutionary tree. Informally, we infer that a certain amino acid is favored in a certain group of lineages if substitutions giving rise to it repeatedly occur in the evolution of this group, and disfavored if such substitutions are rare. In surface proteins of HIV-1 and influenza A, we find that changes in preferences detected with d-test match those observed in deep mutational scanning experiments. Our purely bioinformatic approach allows inference of changes in selection between lineages from sequences alone, shedding light on the functional differences between strains or species even in the absence of any structural or functional data.

evolutionary biology↗

bioRxiv2019

Accurate Fetal Variant Calling in the Presence of Maternal Cell Contamination

High-throughput sequencing of fetal DNA is a promising and increasingly common method for the discovery of all (or all coding) genetic variants in the fetus, either as part of prenatal screening or diagnosis, or for genetic diagnosis of spontaneous abortions. In many cases, the fetal DNA (from chorionic villi, amniotic fluid, or abortive tissue) can be contaminated with maternal cells, resulting in the mixture of fetal and maternal DNA. This maternal cell contamination (MCC) undermines the assumption, made by traditional variant callers, that each allele in a heterozygous site is covered, on average, by 50% of the reads, and therefore can lead to erroneous genotype calls. We present a panel of methods for reducing the genotyping error in the presence of MCC. All methods start with the output of GATK HaplotypeCaller on the sequencing data for the (contaminated) fetal sample and both of its parents, and additionally rely on information about the MCC fraction (which itself is readily estimated from the high-throughput sequencing data). The first of these methods uses a Bayesian probabilistic model to correct the fetal genotype calls produced by MCC-unaware HaplotypeCaller. The other two methods “learn” the genotype-correction model from examples. We use simulated contaminated fetal data to train and test the models. Using the test sets, we show that all three methods lead to substantially improved accuracy when compared with the original MCC-unaware HaplotypeCaller calls. We then apply the best-performing method to three chorionic villus samples from spontaneously terminated pregnancies.Code and training data availability https://github.com/bazykinlab/ML-maternal-cell-contaminationCompeting Interest StatementThe authors have declared no competing interest.View Full Text

bioinformatics↗

bioRxiv2018

Recombination in a natural population of the bdelloid rotifer Adineta vaga

Sexual reproduction which involves alternation of meiosis and syngamy is the ancestral condition of extant eukaryotes. Transitions to asexual reproduction were numerous, but most of the resulting eukaryotic lineages are rather short-lived. Still, there are several exceptions to this rule including darwinulid ostracods1,2 and timema stick insects3. The most striking of them is bdelloid rotifers4-6, microscopic freshwater invertebrates which underwent an extensive adaptive radiation after apparently losing meiosis over 10 Mya. Indeed, both the lack of males in numerous bdelloid species and the lack of proper homology between chromosomes6 rule out ordinary sex. However, this does not exclude the possibility of some other mode of interindividual genetic exchange and recombination in their populations7. Recent analyses based on a few loci suggested genetic exchanges in this group8,9, although this has been controversial10. Here, we compare complete genomes of 11 individuals from the wild population of the bdelloid rotifer Adineta vaga, and show that its genetic structure, which involves Hardy-Weinberg proportions of genotypes within loci and lack of linkage disequilibrium between distant loci, is incompatible with strictly clonal reproduction. Instead, it can emerge only under ongoing recombination between different individuals within this species, possibly through transformation. Such a genetic structure makes the population immune to negative long-term consequences of the loss of conventional meiosis11, although this does not necessarily imply that interindividual genetic exchanges in A. vaga are directly maintained by natural selection.

evolutionary biology↗