Biology subjects

Ryabov, F.

Publications and source records attributed to Ryabov, F..

3 recordsLinked to original sources

bioRxiv2024

Comparative genomics of macaques and integrated insights into genetic variation and population history

The crab-eating macaques (Macaca fascicularis) and rhesus macaques (M. mulatta) are widely studied nonhuman primates in biomedical and evolutionary research. Despite their significance, the current understanding of the complex genomic structure in macaques and the differences between species requires substantial improvement. Here, we present a complete genome assembly of a crab-eating macaque and 20 haplotype-resolved macaque assemblies to investigate the complex regions and major genomic differences between species. Segmental duplication in macaques is [~]42% lower, while centromeres are [~]3.7 times longer than those in humans. The characterization of [~]2 Mbp fixed genetic variants and [~]240 Mbp complex loci highlights potential associations with metabolic differences between the two macaque species (e.g., CYP2C76 and EHBP1L1). Additionally, hundreds of alternative splicing differences show post-transcriptional regulation divergence between these two species (e.g., PNPO). We also characterize 91 large-scale genomic differences between macaques and humans at a single-base-pair resolution and highlight their impact on gene regulation in primate evolution (e.g., FOLH1 and PIEZO2). Finally, population genetics recapitulates macaque speciation and selective sweeps, highlighting potential genetic basis of reproduction and tail phenotype differences (e.g., STAB1, SEMA3F, and HOXD13). In summary, the integrated analysis of genetic variation and population genetics in macaques greatly enhances our comprehension of lineage-specific phenotypes, adaptation, and primate evolution, thereby improving their biomedical applications in human diseases.

genomics↗

bioRxiv2024

SCRAPPY - a single cell rapid assay of proteome perturbation in yeast uncovers a joint role of aromatic amino acids and oxidative stress in the toxicity of lipophilic nucleoside analogs

Assaying cellular responses to antimicrobial molecules is a path to understanding modes of action of potential drugs. This is often achieved via transcriptomics and proteomics, but simple and inexpensive methods for rapid characterization are lacking. To bridge this gap, we assayed changes in the abundance of a panel of 64 "sentinel" proteins fused to GFP in the yeast Saccharomyces cerevisiae using flow cytometry. This method produced expected patterns for classical antifungals and allowed inference of common mechanisms between known and novel compounds. Single-cell data also revealed diverging responses in mitochondrial protein abundance in response to thiazolidine antifungals, and perturbations of the cell cycle caused by various compounds. Finally, the method provided insight into the unknown mode of action of alkylated nucleosides, which can be used against fungi residing on works of art. These substances elevate levels of proteins involved in the biosynthesis of aromatic amino acids (AAA), as well as in oxidative stress. Furthermore, deficiencies of Trp and Tyr biosynthesis increased the efficacy of these compounds, while antioxidants reduced it. Most surprisingly, antioxidant effectiveness relied on AAA biosynthesis. Thus, our approach and its possible modifications for other microbes provides an easy and reliable platform for revealing modes of action of novel compounds.

microbiology↗

bioRxiv2023

The variation and evolution of complete human centromeres

We completely sequenced and assembled all centromeres from a second human genome and used two reference sets to benchmark genetic, epigenetic, and evolutionary variation within centromeres from a diversity panel of humans and apes. We find that centromere single-nucleotide variation can increase by up to 4.1-fold relative to other genomic regions, with the caveat that up to 45.8% of centromeric sequence, on average, cannot be reliably aligned with current methods due to the emergence of new -satellite higher-order repeat (HOR) structures and two to threefold differences in the length of the centromeres. The extent to which this occurs differs depending on the chromosome and haplotype. Comparing the two sets of complete human centromeres, we find that eight harbor distinctly different -satellite HOR array structures and four contain novel -satellite HOR variants in high abundance. DNA methylation and CENP-A chromatin immunoprecipitation experiments show that 26% of the centromeres differ in their kinetochore position by at least 500 kbp--a property not readily associated with novel -satellite HORs. To understand evolutionary change, we selected six chromosomes and sequenced and assembled 31 orthologous centromeres from the common chimpanzee, orangutan, and macaque genomes. Comparative analyses reveal nearly complete turnover of -satellite HORs, but with idiosyncratic changes in structure characteristic to each species. Phylogenetic reconstruction of human haplotypes supports limited to no recombination between the p- and q-arms of human chromosomes and reveals that novel -satellite HORs share a monophyletic origin, providing a strategy to estimate the rate of saltatory amplification and mutation of human centromeric DNA.

genomics↗