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

Ardian Ferraj; Peter A Audano; Parithi Balachandran; Anne Czechanski; Jacob I Flores; Alexander A Radecki; Varun Mosur; David S Gordon; Isha A Walawalkar; Evan E Eichler; Laura G Reinholdt; Christine R Beck

doi:10.1016/j.xgen.2023.100291

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

Cell Genom. 2023 Apr 5;3(5):100291. doi: 10.1016/j.xgen.2023.100291. eCollection 2023 May 10.

Authors

Ardian Ferraj^{1

2}, Peter A Audano², Parithi Balachandran², Anne Czechanski³, Jacob I Flores², Alexander A Radecki^{1

2}, Varun Mosur², David S Gordon⁴, Isha A Walawalkar^{1

2}, Evan E Eichler⁴, Laura G Reinholdt³, Christine R Beck^{1

2

5}

Affiliations

¹ Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06032, USA.
² The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
³ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
⁴ Howard Hughes Medical Institute and Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
⁵ Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA.

Abstract

Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many strains is fundamentally lacking in comparison with humans. In particular, catalogs of structural variants (SVs) (variants ≥ 50 bp) are incomplete, limiting the discovery of causative alleles for phenotypic variation. Here, we resolve genome-wide SVs in 20 genetically distinct inbred mice with long-read sequencing. We report 413,758 site-specific SVs affecting 13% (356 Mbp) of the mouse reference assembly, including 510 previously unannotated coding variants. We substantially improve the Mus musculus transposable element (TE) callset, and we find that TEs comprise 39% of SVs and account for 75% of altered bases. We further utilize this callset to investigate how TE heterogeneity affects mouse embryonic stem cells and find multiple TE classes that influence chromatin accessibility. Our work provides a comprehensive analysis of SVs found in diverse mouse genomes and illustrates the role of TEs in epigenetic differences.

Keywords: chromatin accessibility; collaborative cross; effects of structural variation; embryonic stem cells; inbred micetransposable elements; long read sequencing; mouse genomics; structural variation; whole genome assembly.

Abstract

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