GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data

Mehrtash Babadi; Jack M Fu; Samuel K Lee; Andrey N Smirnov; Laura D Gauthier; Mark Walker; David I Benjamin; Xuefang Zhao; Konrad J Karczewski; Isaac Wong; Ryan L Collins; Alba Sanchis-Juan; Harrison Brand; Eric Banks; Michael E Talkowski

doi:10.1038/s41588-023-01449-0

GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data

Nat Genet. 2023 Sep;55(9):1589-1597. doi: 10.1038/s41588-023-01449-0. Epub 2023 Aug 21.

Authors

Mehrtash Babadi^#¹, Jack M Fu^#^{2

3

4}, Samuel K Lee^#⁵, Andrey N Smirnov^#⁵, Laura D Gauthier⁵, Mark Walker^{5

3}, David I Benjamin⁵, Xuefang Zhao^{2

3

4}, Konrad J Karczewski^{2

6

7}, Isaac Wong^{2

3}, Ryan L Collins^{2

3}, Alba Sanchis-Juan^{2

3

4}, Harrison Brand^{2

3

4}, Eric Banks⁵, Michael E Talkowski^{8

9

10

11

12}

Affiliations

¹ Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
² Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
¹⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
¹¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. [email protected].
¹² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].

^# Contributed equally.

Abstract

Copy number variants (CNVs) are major contributors to genetic diversity and disease. While standardized methods, such as the genome analysis toolkit (GATK), exist for detecting short variants, technical challenges have confounded uniform large-scale CNV analyses from whole-exome sequencing (WES) data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, we developed GATK-gCNV, a flexible algorithm to discover rare CNVs from sequencing read-depth information, complete with open-source distribution via GATK. We benchmarked GATK-gCNV in 7,962 exomes from individuals in quartet families with matched genome sequencing and microarray data, finding up to 95% recall of rare coding CNVs at a resolution of more than two exons. We used GATK-gCNV to generate a reference catalog of rare coding CNVs in WES data from 197,306 individuals in the UK Biobank, and observed strong correlations between per-gene CNV rates and measures of mutational constraint, as well as rare CNV associations with multiple traits. In summary, GATK-gCNV is a tunable approach for sensitive and specific CNV discovery in WES data, with broad applications.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Chromosome Mapping
DNA Copy Number Variations* / genetics
Exome Sequencing
Exome* / genetics
Exons
Humans

Abstract

Publication types

MeSH terms

Grants and funding