Increased mutation and gene conversion within human segmental duplications

被引：0

作者：

Mitchell R. Vollger

Philip C. Dishuck

William T. Harvey

William S. DeWitt

Xavi Guitart

Michael E. Goldberg

Allison N. Rozanski

Julian Lucas

Mobin Asri

Katherine M. Munson

Alexandra P. Lewis

Kendra Hoekzema

Glennis A. Logsdon

David Porubsky

Benedict Paten

Kelley Harris

PingHsun Hsieh

Evan E. Eichler

机构：

[1] University of Washington School of Medicine,Department of Genome Sciences

[2] University of Washington School of Medicine,Division of Medical Genetics

[3] Computational Biology Program,Department of Electrical Engineering and Computer Sciences

[4] Fred Hutchinson Cancer Research Center,UC Santa Cruz Genomics Institute

[5] University of California,Division of Oncology, Department of Internal Medicine

[6] Berkeley,Department of Human Genetics

[7] University of California,Canadian Center for Computational Genomics

[8] Santa Cruz,Institute for the Advanced Study of Human Biology (WPI

[9] Howard Hughes Medical Institute,ASHBi)

[10] Washington University School of Medicine,Department of Quantitative and Computational Biology

[11] McDonnell Genome Institute,Department of Data Sciences

[12] Washington University School of Medicine,Department of Biomedical Informatics

[13] Google LLC,Department of Genetics, Genomics and Informatics

[14] European Molecular Biology Laboratory,Department of Ecology and Evolutionary Biology

[15] European Bioinformatics Institute,Center for Digital Medicine

[16] McGill University,Core Unit Bioinformatics, Medical Faculty

[17] McGill University,Department of Genetics

[18] Kyoto University,Novo Nordisk Foundation Center for Biosustainability

[19] Institute of Genetics and Biophysics,Institute for Society and Genetics, College of Letters and Science

[20] National Research Council,Institute for Precision Health, David Geffen School of Medicine

[21] University of Southern California,Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine

[22] Dana-Farber Cancer Institute,Department of Biomolecular Engineering

[23] Harvard Medical School,Quantitative Life Sciences

[24] University of Tennessee Health Science Center,Department of Genetics

[25] Barrett and O’Connor Washington Center,Center for Genomic Health

[26] Arizona State University,Quantitative Biology Center (QBiC)

[27] University of California,Biomedical Data Science, Department of Computer Science

[28] Santa Cruz,Laboratory of Neurogenetics of Language

[29] Institute for Medical Biometry and Bioinformatics,Division of Oncology, Department of Medicine

[30] Medical Faculty,Division of Biology and Biomedical Sciences

[31] Heinrich Heine University Düsseldorf,Departament d’Arquitectura de Computadors i Sistemes Operatius

[32] Heinrich Heine University Düsseldorf,Department of Computer Science

[33] Heinrich Heine University Düsseldorf,Department of Public Health Sciences

[34] Vertebrate Genome Laboratory,Department of Biomedical Engineering

[35] The Rockefeller University,Department of Ecology and Evolutionary Biology

[36] National Institutes of Health (NIH)–National Human Genome Research Institute,Center for Health Data Science

[37] Washington University School of Medicine,Center for Genomic Discovery

[38] Center for Computational and Genomic Medicine,Center for Computational Biology

[39] The Children’s Hospital of Philadelphia,undefined

[40] Technical University of Denmark,undefined

[41] University of California,undefined

[42] Los Angeles,undefined

[43] University of California,undefined

[44] Los Angeles,undefined

[45] University of California,undefined

[46] Los Angeles,undefined

[47] University of California,undefined

[48] Santa Cruz,undefined

[49] Dovetail Genomics,undefined

[50] McGill University,undefined

来源：

Nature | 2023年 / 617卷

关键词：

D O I：

暂无

中图分类号：

学科分类号：

摘要：

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.

引用

页码：325 / 334

页数：9