ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data

Egor Dolzhenko; Mark F Bennett; Phillip A Richmond; Brett Trost; Sai Chen; Joke J F A van Vugt; Charlotte Nguyen; Giuseppe Narzisi; Vladimir G Gainullin; Andrew M Gross; Bryan R Lajoie; Ryan J Taft; Wyeth W Wasserman; Stephen W Scherer; Jan H Veldink; David R Bentley; Ryan K C Yuen; Melanie Bahlo; Michael A Eberle

doi:10.1186/s13059-020-02017-z

ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data

Genome Biol. 2020 Apr 28;21(1):102. doi: 10.1186/s13059-020-02017-z.

Authors

Egor Dolzhenko¹, Mark F Bennett^{2

3

4}, Phillip A Richmond⁵, Brett Trost^{6

7}, Sai Chen¹, Joke J F A van Vugt⁸, Charlotte Nguyen^{6

7

9}, Giuseppe Narzisi¹⁰, Vladimir G Gainullin¹, Andrew M Gross¹, Bryan R Lajoie¹, Ryan J Taft¹, Wyeth W Wasserman⁵, Stephen W Scherer^{6

7

9

11}, Jan H Veldink⁸, David R Bentley¹², Ryan K C Yuen^{6

7

9}, Melanie Bahlo^{2

3}, Michael A Eberle¹³

Affiliations

¹ Illumina Inc., 5200 Illumina Way, San Diego, CA, 92122, USA.
² Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
³ Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, 3052, Australia.
⁴ Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, 245 Burgundy Street, Heidelberg, VIC, 3084, Australia.
⁵ Centre for Molecular Medicine and Therapeutics, BC Children's Hospital, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
⁶ Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
⁷ The Centre for Applied Genomics, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
⁸ Department of Neurology, UMC Utrecht Brain Center, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
⁹ Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 2E5, Canada.
¹⁰ New York Genome Center, 101 Avenue of the Americas, New York, 10013, USA.
¹¹ The McLaughlin Centre, University of Toronto, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
¹² Illumina Cambridge Ltd, Illumina Centre, 19 Granta Park, Great Abington, Cambridge, CB21 6DF, UK.
¹³ Illumina Inc., 5200 Illumina Way, San Diego, CA, 92122, USA. meberle@illumina.com.

Abstract

Repeat expansions are responsible for over 40 monogenic disorders, and undoubtedly more pathogenic repeat expansions remain to be discovered. Existing methods for detecting repeat expansions in short-read sequencing data require predefined repeat catalogs. Recent discoveries emphasize the need for methods that do not require pre-specified candidate repeats. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide repeat expansion detection. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference repeat expansions not discoverable via existing methods.

Keywords: Fragile X syndrome; Friedreich ataxia; Genome-wide analysis; Huntington disease; Myotonic dystrophy type 1; Repeat expansions; Short tandem repeats; Whole-genome sequencing data.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
DNA Repeat Expansion*
Fragile X Syndrome / genetics
Friedreich Ataxia / genetics
High-Throughput Nucleotide Sequencing
Humans
Huntington Disease / genetics
Microsatellite Repeats
Myotonic Dystrophy / genetics
Software*
Whole Genome Sequencing

Grants and funding

CIHR/Canada