Biology subjects

Alexandrov, I.

Publications and source records attributed to Alexandrov, I..

3 recordsLinked to original sources

bioRxiv2026

A Complete Genome for the Common Marmoset

The common marmoset is a New World monkey (NWM) commonly used as a model organism to investigate questions in primate evolution and human disease, including Alzheimers and other neurodegenerative diseases, as well as neuropsychiatric disorders. Here we present the first telomere-to-telomere (T2T) reference genome for the common marmoset, adding over 88 Mb of sequence and resolving challenging genomic regions. An additional near-T2T assembly from a second unrelated individual yields a total of four high-quality haplotypes for analysis. The improved contiguity and accuracy of these assemblies enable unprecedented insights into complex and rapidly evolving genomic regions such as centromeres, sex chromosomes, ribosomal DNA (rDNA) structure, and the major histocompatibility complex (MHC). We fully resolved all marmoset centromeres, uncovering dimeric alpha satellites with chromosomal specificity and stratified inactive layers documenting ancestral centromere turnover. We assembled six acrocentric autosomes with gene-poor, satellite-rich short arms and provide evidence that most of them can harbor rDNA and all of them share large pseudo-homologous regions (PHRs). The Y chromosome, but not the X chromosome, carries active rDNA and PHRs, and the rDNA copy number is sexually dimorphic. Chromosomes that share PHRs also share closely related centromeric satellite DNA, supporting a model of ongoing recombinational exchange between heterologous chromosomes facilitated by rDNA. We discovered multiple novel, marmoset-specific MHC genes that are predicted to protect against pathogens encountered in its environment. Leveraging this complete reference, we further identified over 500 transcribed genes with transcript models or expansions specific to the marmoset lineage. Together with additional long-read marmoset assemblies, these genomes were used to construct a marmoset pangenome, providing a robust reference framework for short-read mapping across diverse individuals. This resource will improve the utility of the common marmoset as a biomedical model organism and fill key gaps in our understanding of primate evolution.

genomics↗

bioRxiv2021

Homologous recombination repair creates mutations in the non-coding genome that alter Topoisomerase-1 cleavage sites & orchestrates irinotecan resistance

Resistance to chemotherapy is a leading cause of treatment failure. Drug-resistance mechanisms involve mutations in specific proteins or changes in their expression levels. It is commonly understood that resistance mutations happen randomly prior to treatment and are selected during the treatment. However, selection of drug-resistant mutants in culture could be achieved by multiple drug exposures of cloned genetically identical cells, and thus cannot result from selection of pre-existent mutations. Accordingly, adaptation must involve generation of mutations de-novo upon drug treatment. Here we explored the origin of resistance mutations to a widely used Top1 inhibitor irinotecan, which triggers DNA breaks, causing cytotoxicity. Resistance mechanism involved gradual accumulation of recurrent mutations in non-coding regions of DNA at Top1-cleavage sites. Surprisingly, cancer cells had higher number of such sites than reference genome, which may define their increased sensitivity to irinotecan. Homologous recombination repair of DNA double strand breaks at these sites following initial drug exposures gradually reverted cleavage-sensitive "cancer" sequences back to cleavage-resistant "normal" sequences. These mutations reduced generation of DNA breaks upon subsequent exposures, thus gradually increasing the drug resistance. Together, large target size for mutations and their Top1-guided generation lead to their gradual and rapid accumulation, synergistically accelerating development of resistance. Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/470089v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@d9d93forg.highwire.dtl.DTLVardef@45b88forg.highwire.dtl.DTLVardef@157cafeorg.highwire.dtl.DTLVardef@cff4a4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

HORmon: automated annotation of human centromeres

Recent advances in long-read sequencing opened a possibility to address the long-standing questions about the architecture and evolution of human centromeres. They also emphasized the need for centromere annotation (partitioning human centromeres into monomers and higher-order repeats (HORs)). Even though there was a half-century-long series of semi-manual studies of centromere architecture, a rigorous centromere annotation algorithm is still lacking. Moreover, an automated centromere annotation is a prerequisite for studies of genetic diseases associated with centromeres, and evolutionary studies of centromeres across multiple species. Although the monomer decomposition (transforming a centromere into a monocentromere written in the monomer alphabet) and the HOR decomposition (representing a monocentromere in the alphabet of HORs) are currently viewed as two separate problems, we demonstrate that they should be integrated into a single framework in such a way that HOR (monomer) inference affects monomer (HOR) inference. We thus developed the HORmon algorithm that integrates the monomer/HOR inference and automatically generates the human monomers/HORs that are largely consistent with the previous semi-manual inference.

bioinformatics↗