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Increased mutation and gene conversion within human segmental duplications.

Publication ,  Journal Article
Vollger, MR; Dishuck, PC; Harvey, WT; DeWitt, WS; Guitart, X; Goldberg, ME; Rozanski, AN; Lucas, J; Asri, M; Munson, KM; Lewis, AP; Paten, B ...
Published in: Nature
May 2023

Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data1,2. Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions3,4. We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have 'relocated' on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences5,6.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

May 2023

Volume

617

Issue

7960

Start / End Page

325 / 334

Location

England

Related Subject Headings

  • Segmental Duplications, Genomic
  • Polymorphism, Single Nucleotide
  • Mutation
  • Humans
  • Haplotypes
  • Guanine
  • Genome, Human
  • General Science & Technology
  • Gene Conversion
  • Exons
 

Citation

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Vollger, M. R., Dishuck, P. C., Harvey, W. T., DeWitt, W. S., Guitart, X., Goldberg, M. E., … Eichler, E. E. (2023). Increased mutation and gene conversion within human segmental duplications. Nature, 617(7960), 325–334. https://doi.org/10.1038/s41586-023-05895-y
Vollger, Mitchell R., Philip C. Dishuck, William T. Harvey, William S. DeWitt, Xavi Guitart, Michael E. Goldberg, Allison N. Rozanski, et al. “Increased mutation and gene conversion within human segmental duplications.Nature 617, no. 7960 (May 2023): 325–34. https://doi.org/10.1038/s41586-023-05895-y.
Vollger MR, Dishuck PC, Harvey WT, DeWitt WS, Guitart X, Goldberg ME, et al. Increased mutation and gene conversion within human segmental duplications. Nature. 2023 May;617(7960):325–34.
Vollger, Mitchell R., et al. “Increased mutation and gene conversion within human segmental duplications.Nature, vol. 617, no. 7960, May 2023, pp. 325–34. Pubmed, doi:10.1038/s41586-023-05895-y.
Vollger MR, Dishuck PC, Harvey WT, DeWitt WS, Guitart X, Goldberg ME, Rozanski AN, Lucas J, Asri M, Human Pangenome Reference Consortium, Munson KM, Lewis AP, Hoekzema K, Logsdon GA, Porubsky D, Paten B, Harris K, Hsieh P, Eichler EE. Increased mutation and gene conversion within human segmental duplications. Nature. 2023 May;617(7960):325–334.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

May 2023

Volume

617

Issue

7960

Start / End Page

325 / 334

Location

England

Related Subject Headings

  • Segmental Duplications, Genomic
  • Polymorphism, Single Nucleotide
  • Mutation
  • Humans
  • Haplotypes
  • Guanine
  • Genome, Human
  • General Science & Technology
  • Gene Conversion
  • Exons