Biology subjects

Maksimov, M.

Publications and source records attributed to Maksimov, M..

4 recordsLinked to original sources

bioRxiv2023

A deep population reference panel of tandem repeat variation

Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3,550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.

genomics↗

bioRxiv2022

Genome-wide selection inference at short tandem repeats

Short tandem repeats (STRs) comprising repeated sequences of 1-6 bp are one of the largest sources of genetic variation in humans. STRs are known to contribute to a variety of disorders, including Mendelian diseases, complex traits, and cancer. Based on their functional importance, mutations at some STRs are likely to introduce negative effects on reproductive fitness over evolutionary time. We previously developed SISTR (Selection Inference at STRs), a population genetics framework to measure negative selection against individual STR alleles. Here, we extend SISTR to enable joint estimation of the distribution of selection coefficients across a set of STRs. This method (SISTR2) allows for more accurate analysis of a broader range of STRs, including loci with low mutation rates. We apply SISTR2 to explore the range of feasible mutation parameters and demonstrate substantial variation in mutation and selection parameters across different classes of STRs. Finally, we show that de novo STR mutations tend to confer a greater selective burden compared to standing STR variation in the population and measure the relative burden of STRs vs. single nucleotide variants in a typical genome. Overall, we anticipate that the evolutionary insights gained from this study will be important for future studies of variation at STRs and their role in evolution and disease.

genomics↗

bioRxiv2022

Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

The BXD family of recombinant inbred mice were developed by crossing and inbreeding progeny of C57BL/6J and DBA/2J strains. This family is the largest and most extensively phenotyped mammalian experimental genetic resource. Although used in genetics for 52 years, we do not yet have comprehensive data on DNA variants segregating in the BXDs. Using linked-read whole-genome sequencing, we sequenced 152 members of the family at about 40X coverage and quantified most variants. We identified 6.25 million polymorphism segregating at a near-optimal minor allele frequency of 0.42. We also defined two other major variants: strain-specific de novo singleton mutations and epoch-specific de novo polymorphism shared among subfamilies of BXDs. We quantified per-generation mutation rates of de novo variants and demonstrate how founder-derived, strain-specific, and epoch-specific variants can be analyzed jointly to model genome-phenome causality. This integration enables forward and reverse genetics at scale, rapid production of any of more than 10,000 diallel F1 hybrid progeny to test predictions across diverse environments or treatments. Combined with five decades of phenome data, the BXD family and F1 hybrids are a major resource for systems genetics and experimental precision medicine.

genomics↗

bioRxiv2022

A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements characterized by repeated units of 1 or more nucleotides. We leveraged whole genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family derived from C57BL/6J and DBA/2J mice to study the effects of genetic background on genome-wide patterns of new mutations at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and identified a locus on chromosome 13 associated with the propensity of STRs to expand. Several dozen genes lie in the QTL region, including Msh3, a known modifier of STR stability at pathogenic repeat expansions in mice and humans. Detailed analysis of the locus revealed a cluster of variants near the 5 end of Msh3, including multiple protein-coding variants within the DNA mismatch recognition domain of MSH3, and a retrotransposon insertion overlapping an annotated exon. Additionally, gene expression analysis demonstrates co-localization of this QTL with expression QTLs for multiple nearby genes, including Msh3. Our results suggest a novel role for Msh3 in regulating genome-wide patterns of germline STR mutations and demonstrate that inherited genetic variation can contribute to variability in accumulation of new mutations across individuals.

genomics↗