Biology subjects

Grishin, N. V.

Publications and source records attributed to Grishin, N. V..

26 records · Page 2Linked to original sources

bioRxiv2020

Manipulation of IRE1-dependent MAPK signaling by a Vibrio agonist-antagonist effector pair

Diverse bacterial pathogens employ effector delivery systems to disrupt vital cellular processes in the host (1). The type III secretion system 1 of the marine pathogen, Vibrio parahaemolyticus, utilizes the sequential action of four effectors to induce a rapid, pro-inflammatory cell death uniquely characterized by a pro-survival host transcriptional response (2, 3). Herein, we show that this pro-survival response is caused by the action of the channel-forming effector VopQ that targets the host V-ATPase resulting in lysosomal deacidification and inhibition of lysosome-autophagosome fusion. Recent structural studies have shown how VopQ interacts with the V-ATPase and, while in the ER, a V-ATPase assembly intermediate can interact with VopQ causing a disruption in membrane integrity. Additionally, we observe that VopQ-mediated disruption of the V-ATPase activates the IRE1 branch of the unfolded protein response (UPR) resulting in an IRE1-dependent activation of ERK1/2 MAPK signaling. We also find that this early VopQ-dependent induction of ERK1/2 phosphorylation is terminated by the VopS-mediated inhibitory AMPylation of Rho GTPase signaling. Since VopS dampens VopQ-induced IRE1-dependent ERK1/2 activation, we propose that IRE1 activates ERK1/2 phosphorylation at or above the level of Rho GTPases. This study illustrates how temporally induced effectors can work as in tandem as agonist/antagonist to manipulate host signaling and reveal new connections between V-ATPase function, UPR and MAPK signaling. ImportanceVibrio parahaemolyticus (V. para) is a seafood-borne pathogen that encodes two Type 3 Secretion Systems (T3SS). The first system T3SS1 is thought to be maintained in all strains of V. para to to maintain survival in the environment, whereas the second sytem T3SS2 is linked to clinical isolates and disease in humans. Herein, we find that first system targets evolutionarily conserved signaling systems to manipulate host cells, eventually causing a rapid, orchestrated cells death within three hours. We have found that the T3SS1 injects virulence factors that temporally manipulate host signaling. Within the first hour of infection, the effector VopQ acts first by activating host surval signals while diminishing the host cell apoptotic machinery. Less than an hour later, another effector VopS reverses activation and inhibition of these signaling systems ultimately leading to death of the host cell. This work provides example of how pathogens have evolved to manipulate the interplay between T3SS effectors to regulate host signaling pathways.

microbiology↗

bioRxiv2020

A combined RAD-Seq and WGS approach reveals the genomic basis of yellow colour variation in bumble bee Bombus terrestris

BackgroundIn the model bumble bee species B. terrestris, both males and females exhibit black coloration on the third thoracic and first metasomal segments. We discovered a fortuitous lab-generated mutant in which this typical black coloration is replaced by yellow. As this same color variant is found in several sister lineages to B. terrestris within the Bombus s.s. subgenus, this could be a result of ancestral allele sorting. ResultsUtilizing a combination of RAD-Seq and whole-genome re-sequencing approaches, we localized the color-generating variant to a single SNP in the protein-coding sequence of a homeobox transcription factor, cut. Sanger sequencing confirmed fixation of this SNP between wildtype and yellow mutants. Protein domain analysis revealed this SNP to generate an amino acid change (Ala38Pro) that modifies the conformation of coiled-coil structural elements which lie outside the characteristic DNA binding domains. We found all Hymenopterans including B. terrestris sister lineages possess the non-mutant allele, indicating different mechanism(s) are involved in the same black to yellow transition in nature. ConclusionsCut is a highly pleiotropic gene important for multiple facets of development, yet this mutation generated no noticeable external phenotypic effects outside of setal characteristics. Reproductive capacity was observed to be reduced, however, with queens being less likely to mate and produce female offspring, in a manner similar to workers. Our research implicates a novel developmental player in pigmentation, and potentially caste as well, thus contributing to a better understanding of the evolution of diversity in both of these processes.

genomics↗

bioRxiv2020

The relationship between gene flow and population difference during secondary contact between butterfly sister species

Comparisons of genomes from recently diverged butterfly populations along a suture zone in central Texas have revealed high levels of divergence on the Z chromosome relative to autosomes, as measured by fixation index, Fst. The pattern of divergence appears to result from accumulation of incompatible alleles, obstructing introgression on the Z chromosome in hybrids. However, it is unknown whether this mechanism is sufficient to explain the data. Here, we simulate the effects of hybrid incompatibility on interbreeding butterfly populations using a model in which populations accumulate cross-incompatible alleles in allopatry prior to contact. We compute statistics for introgression and population divergence during contact between model butterfly populations and compare them to statistics obtained for 15 pairs of butterfly species interbreeding along the Texas suture zone. For populations that have evolved sufficiently in allopatry, the model exhibits high levels of divergence on the Z chromosome relative to autosomes in populations inter-breeding on time scales comparable to periods of interglacial contact between butterfly populations in central Texas. Levels of divergence on the Z chromosome increase when interacting groups of genes are closely linked, consistent with interacting clusters of functionally related genes in butterfly genomes. Results for various periods in allopatry are in qualitative agreement with the pattern of data for butterflies, supporting a picture of speciation in which populations are subjected to cycles of divergence in glacial isolation, and partial fusion during interglacial contact.

biophysics↗

bioRxiv2019

Mutation severity spectrum of rare alleles in the human genome is predictive of disease type

The human genome harbors a variety of genetic variations. Single-nucleotide changes that alter amino acids in protein-coding regions are one of the major causes of human phenotypic variation and diseases. These single-amino acid variations (SAVs) are routinely found in whole genome and exome sequencing. Evaluating the functional impact of such genomic alterations is crucial for diagnosis of genetic disorders. We developed DeepSAV, a deep-learning convolutional neural network to differentiate disease-causing and benign SAVs based on a variety of protein sequence, structural and functional properties. Our method outperforms most stand-alone programs and has similar predictive power as some of the best available. We transformed DeepSAV scores of rare SAVs observed in the general population into a mutation severity measure of protein-coding genes. This measure reflects a genes tolerance to deleterious missense mutations and serves as a useful tool to study gene-disease associations. Genes implicated in cancer, autism, and viral interaction are found by this measure as intolerant to mutations, while genes associated with a number of other diseases are scored as tolerant. Among known disease-associated genes, those that are mutation-intolerant are likely to function in development and signal transduction pathways, while those that are mutation-tolerant tend to encode metabolic and mitochondrial proteins.

bioinformatics↗

bioRxiv2019

Genomics of a complete butterfly continent

Never before have we had the luxury of choosing a continent, picking a large phylogenetic group of animals, and obtaining genomic data for its every species. Here, we sequence all 845 species of butterflies recorded from North America north of Mexico. Our comprehensive approach reveals the pattern of diversification and adaptation occurring in this phylogenetic lineage as it has spread over the continent, which cannot be seen on a sample of selected species. We observe bursts of diversification that generated taxonomic ranks: subfamily, tribe, subtribe, genus, and species. The older burst around 70 Mya resulted in the butterfly subfamilies, with the major evolutionary inventions being unique phenotypic traits shaped by high positive selection and gene duplications. The recent burst around 5 Mya is caused by explosive radiation in diverse butterfly groups associated with diversification in transcription and mRNA regulation, morphogenesis, and mate selection. Rapid radiation correlates with more frequent introgression of speciation-promoting and beneficial genes among radiating species. Radiation and extinction patterns over the last 100 million years suggest the following general model of animal evolution. A population spreads over the land, adapts to various conditions through mutations, and diversifies into several species. Occasional hybridization between these species results in accumulation of beneficial alleles in one, which eventually survives, while others become extinct. Not only butterflies, but also the hominids may have followed this path.

genomics↗

bioRxiv2019

Genomics reveals the origins of ancient specimens

Centuries of zoological studies amassed billions of specimens in collections worldwide. Genomics of these specimens promises to rejuvenate biodiversity research. The obstacles stem from DNA degradation with specimen age. Overcoming this challenge, we set out to resolve a series of long-standing controversies involving a group of butterflies. We deduced geographical origins of several ancient specimens of uncertain provenance that are at the heart of these debates. Here, genomics tackles one of the greatest problems in zoology: countless old, poorly documented specimens that serve as irreplaceable embodiments of species concepts. The ability to figure out where they were collected will resolve many on-going disputes. More broadly, we show the utility of genomics applied to ancient museum specimens to delineate the boundaries of species and populations, and to hypothesize about genotypic determinants of phenotypic traits.

zoology↗

bioRxiv2019

How often do Protein Genes Navigate Valleys of Low Fitness?

In order escape from local fitness peaks, a population must navigate across valleys of low fitness. How these transitions occur, and what role they play in adaptation, have been subjects of active interest in evolutionary genetics for almost a century. However, to our knowledge, this problem has never been addressed directly, by considering the evolution of a gene, or group of genes, as a whole, including the complex effects of fitness interactions among multiple loci. Here, we use a precise model of protein fitness to compute the probability P(s, {Delta}t) that an allele, randomly sampled from a population at time t, has crossed a fitness valley of depth s during an interval [t - {Delta}t, t] in the immediate past. We study populations of model genes evolving under equilibrium conditions consistent with those in mammalian mitochondria. From this data, we estimate that genes encoding small protein motifs navigate fitness valleys of depth 2Ns {gtrsim} 30 with probability P {gtrsim} 0.1 on a time scale of human evolution, where N is the (mitochondrial) effective population size. The results are consistent with recent findings for Watson-Crick switching in mammalian mitochondrial tRNA molecules.

genetics↗

bioRxiv2018

Inference of epistatic effects in a key mitochondrial protein

We use Potts model inference to predict pair epistatic effects in a key mitochondrial protein - cytochrome c oxidase subunit 2 - for ray-finned fishes. We examine the effect of phylogenetic correlations on our predictions using a simple exact fitness model, and we find that, although epistatic effects are under-predicted, they maintain a roughly linear relationship to their true (model) values. After accounting for these corrections, epistatic effects in the protein are still relatively weak, leading to fitness valleys of depth 2Ns ~ -5 in compensatory double mutants. Positive epistasis is more pronounced than negative epistasis, and the strongest positive effects capture nearly all sites subject to positive selection in fishes, similar to virus proteins evolving under selection pressure in the context of drug therapy.

evolutionary biology↗