Impact and characterization of serial structural variations across humans and great apes

Modern sequencing technology enables the systematic detection of complex structural variation (SV) across genomes. However, extensive DNA rearrangements arising through a series of mutations, a phenomenon we refer to as serial SV (sSV), remain underexplored, posing a challenge for SV discovery. Here...

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Bibliographic Details
Published in:Nature communications 2024-09, Vol.15 (1), p.8007-15, Article 8007
Main Authors: Höps, Wolfram, Rausch, Tobias, Jendrusch, Michael, Korbel, Jan O., Sedlazeck, Fritz J.
Format: Article
Language:English
Subjects:
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45/23
631/208/211
631/208/737/211
Animals
Apes
Assemblies
Chromosome 22
Chromosome 8
Complexity
Gene sequencing
Genome, Human - genetics
Genomes
Genomic Structural Variation
Genomics
Genomics - methods
Haplotypes
Hominidae - genetics
Homologous recombination
Humanities and Social Sciences
Humans
multidisciplinary
Science
Science (multidisciplinary)
Structural analysis
Variation
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Summary:Modern sequencing technology enables the systematic detection of complex structural variation (SV) across genomes. However, extensive DNA rearrangements arising through a series of mutations, a phenomenon we refer to as serial SV (sSV), remain underexplored, posing a challenge for SV discovery. Here, we present NAHRwhals ( https://github.com/WHops/NAHRwhals ), a method to infer repeat-mediated series of SVs in long-read genomic assemblies. Applying NAHRwhals to haplotype-resolved human genomes from 28 individuals reveals 37 sSV loci of various length and complexity. These sSVs explain otherwise cryptic variation in medically relevant regions such as the TPSAB1 gene, 8p23.1, 22q11 and Sotos syndrome regions. Comparisons with great ape assemblies indicate that most human sSVs formed recently, after the human-ape split, and involved non-repeat-mediated processes in addition to non-allelic homologous recombination. NAHRwhals reliably discovers and characterizes sSVs at scale and independent of species, uncovering their genomic abundance and suggesting broader implications for disease. Structural variants (SV) can accumulate in repeat-rich parts of the genome and transform them in unexpected ways. Here, with their new assembly-based genotyper (NAHRwhals), the authors verify multi-step SVs in 37 human loci and identify alleles at risk for copy-number variation.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-52027-9