Biology subjects

Gordon, D. S.

Publications and source records attributed to Gordon, D. S..

3 recordsLinked to original sources

bioRxiv2023

Structurally divergent and recurrently mutated regions of primate genomes

To better understand the pattern of primate genome structural variation, we sequenced and assembled using multiple long-read sequencing technologies the genomes of eight nonhuman primate species, including New World monkeys (owl monkey and marmoset), Old World monkey (macaque), Asian apes (orangutan and gibbon), and African ape lineages (gorilla, bonobo, and chimpanzee). Compared to the human genome, we identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. Across 50 million years of primate evolution, we estimate that 819.47 Mbp or ~27% of the genome has been affected by SVs based on analysis of these primate lineages. We identify 1,607 structurally divergent regions (SDRs) wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (CARDs, ABCD7, OLAH) and new lineage-specific genes are generated (e.g., CKAP2, NEK5) and have become targets of rapid chromosomal diversification and positive selection (e.g., RGPDs). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species for the first time.

genomics↗

bioRxiv2022

Resolution of structural variation in diverse mouse genomes reveals chromatin remodeling due to transposable elements

Diverse inbred mouse strains are among the foremost models for biomedical research, yet genome characterization of many strains has been fundamentally lacking in comparison to human genomics research. In particular, the discovery and cataloging of structural variants is incomplete, limiting the discovery of potentially causative alleles for phenotypic variation across individuals. Here, we utilized long-read sequencing to resolve genome-wide structural variants (SVs, variants [≥] 50 bp) in 20 genetically distinct inbred mice. We report 413,758 site-specific SVs that affect 13% (356 Mbp) of the current mouse reference assembly, including 510 previously unannotated variants which alter coding sequences. We find that 39% of SVs are attributed to transposable element (TE) variation accounting for 75% of bases altered by SV. We then utilized this callset to investigate the impact of TE heterogeneity on mouse embryonic stem cells (mESCs), and find multiple TE classes that influence chromatin accessibility across loci. We also identify strain-specific transcription start sites originating in polymorphic TEs that modify gene expression. Our work provides the first long-read based analysis of mouse SVs and illustrates that previously unresolved TEs underlie epigenetic and transcriptome differences in mESCs.

genomics↗

bioRxiv2021

Haplotype-resolved inversion landscape reveals hotspots of mutational recurrence associated with genomic disorders

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1-retrotransposition; 80% of the larger inversions are balanced and affect twice as many base pairs as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or mobile elements. Since this suggests recurrence due to non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7x10-4 per locus and generation. Recurrent inversions exhibit a sex- chromosomal bias, and significantly co-localize to the critical regions of genomic disorders. We propose that inversion recurrence results in an elevated number of heterozygous carriers and structural SD diversity, which increases mutability in the population and predisposes to disease- causing CNVs.

genomics↗