Curated variation benchmarks for challenging medically relevant autosomal genes

Justin Wagner; Nathan D. Olson; Lindsay Harris; Jennifer McDaniel; Haoyu Cheng; Arkarachai Fungtammasan; Yih Chii Hwang; Richa Gupta; Aaron M. Wenger; William J. Rowell; Ziad M. Khan; Jesse Farek; Yiming Zhu; Aishwarya Pisupati; Medhat Mahmoud; Chunlin Xiao; Byunggil Yoo; Sayed Mohammad Ebrahim Sahraeian; Danny E. Miller; David Jáspez; José M. Lorenzo-Salazar; Adrián Muñoz-Barrera; Luis A. Rubio-Rodríguez; Carlos Flores; Giuseppe Narzisi; Uday Shanker Evani; Wayne E. Clarke; Joyce Lee; Christopher E. Mason; Stephen E. Lincoln; Karen H. Miga; Mark T.W. Ebbert; Alaina Shumate; Heng Li; Chen Shan Chin; Justin M. Zook; Fritz J. Sedlazeck

doi:10.1038/s41587-021-01158-1

Curated variation benchmarks for challenging medically relevant autosomal genes

Justin Wagner, Nathan D. Olson, Lindsay Harris, Jennifer McDaniel, Haoyu Cheng, Arkarachai Fungtammasan, Yih Chii Hwang, Richa Gupta, Aaron M. Wenger, William J. Rowell, Ziad M. Khan, Jesse Farek, Yiming Zhu, Aishwarya Pisupati, Medhat Mahmoud, Chunlin Xiao, Byunggil Yoo, Sayed Mohammad Ebrahim Sahraeian, Danny E. Miller, David JáspezJosé M. Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A. Rubio-Rodríguez, Carlos Flores, Giuseppe Narzisi, Uday Shanker Evani, Wayne E. Clarke, Joyce Lee, Christopher E. Mason, Stephen E. Lincoln, Karen H. Miga, Mark T.W. Ebbert, Alaina Shumate, Heng Li, Chen Shan Chin, Justin M. Zook, Fritz J. Sedlazeck

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93 Scopus citations

Abstract

The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.

Original language	English
Pages (from-to)	672-680
Number of pages	9
Journal	Nature Biotechnology
Volume	40
Issue number	5
DOIs	https://doi.org/10.1038/s41587-021-01158-1
State	Published - May 2022

Bibliographical note

Publisher Copyright:
© 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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10.1038/s41587-021-01158-1

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Wagner, J., Olson, N. D., Harris, L., McDaniel, J., Cheng, H., Fungtammasan, A., Hwang, Y. C., Gupta, R., Wenger, A. M., Rowell, W. J., Khan, Z. M., Farek, J., Zhu, Y., Pisupati, A., Mahmoud, M., Xiao, C., Yoo, B., Sahraeian, S. M. E., Miller, D. E., ... Sedlazeck, F. J. (2022). Curated variation benchmarks for challenging medically relevant autosomal genes. Nature Biotechnology, 40(5), 672-680. https://doi.org/10.1038/s41587-021-01158-1

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title = "Curated variation benchmarks for challenging medically relevant autosomal genes",

abstract = "The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.",

author = "Justin Wagner and Olson, {Nathan D.} and Lindsay Harris and Jennifer McDaniel and Haoyu Cheng and Arkarachai Fungtammasan and Hwang, {Yih Chii} and Richa Gupta and Wenger, {Aaron M.} and Rowell, {William J.} and Khan, {Ziad M.} and Jesse Farek and Yiming Zhu and Aishwarya Pisupati and Medhat Mahmoud and Chunlin Xiao and Byunggil Yoo and Sahraeian, {Sayed Mohammad Ebrahim} and Miller, {Danny E.} and David J{\'a}spez and Lorenzo-Salazar, {Jos{\'e} M.} and Adri{\'a}n Mu{\~n}oz-Barrera and Rubio-Rodr{\'i}guez, {Luis A.} and Carlos Flores and Giuseppe Narzisi and Evani, {Uday Shanker} and Clarke, {Wayne E.} and Joyce Lee and Mason, {Christopher E.} and Lincoln, {Stephen E.} and Miga, {Karen H.} and Ebbert, {Mark T.W.} and Alaina Shumate and Heng Li and Chin, {Chen Shan} and Zook, {Justin M.} and Sedlazeck, {Fritz J.}",

note = "Publisher Copyright: {\textcopyright} 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2022",

month = may,

doi = "10.1038/s41587-021-01158-1",

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Wagner, J, Olson, ND, Harris, L, McDaniel, J, Cheng, H, Fungtammasan, A, Hwang, YC, Gupta, R, Wenger, AM, Rowell, WJ, Khan, ZM, Farek, J, Zhu, Y, Pisupati, A, Mahmoud, M, Xiao, C, Yoo, B, Sahraeian, SME, Miller, DE, Jáspez, D, Lorenzo-Salazar, JM, Muñoz-Barrera, A, Rubio-Rodríguez, LA, Flores, C, Narzisi, G, Evani, US, Clarke, WE, Lee, J, Mason, CE, Lincoln, SE, Miga, KH, Ebbert, MTW, Shumate, A, Li, H, Chin, CS, Zook, JM & Sedlazeck, FJ 2022, 'Curated variation benchmarks for challenging medically relevant autosomal genes', Nature Biotechnology, vol. 40, no. 5, pp. 672-680. https://doi.org/10.1038/s41587-021-01158-1

TY - JOUR

T1 - Curated variation benchmarks for challenging medically relevant autosomal genes

AU - Wagner, Justin

AU - Olson, Nathan D.

AU - Harris, Lindsay

AU - McDaniel, Jennifer

AU - Cheng, Haoyu

AU - Fungtammasan, Arkarachai

AU - Hwang, Yih Chii

AU - Gupta, Richa

AU - Wenger, Aaron M.

AU - Rowell, William J.

AU - Khan, Ziad M.

AU - Farek, Jesse

AU - Zhu, Yiming

AU - Pisupati, Aishwarya

AU - Mahmoud, Medhat

AU - Xiao, Chunlin

AU - Yoo, Byunggil

AU - Sahraeian, Sayed Mohammad Ebrahim

AU - Miller, Danny E.

AU - Jáspez, David

AU - Lorenzo-Salazar, José M.

AU - Muñoz-Barrera, Adrián

AU - Rubio-Rodríguez, Luis A.

AU - Flores, Carlos

AU - Narzisi, Giuseppe

AU - Evani, Uday Shanker

AU - Clarke, Wayne E.

AU - Lee, Joyce

AU - Mason, Christopher E.

AU - Lincoln, Stephen E.

AU - Miga, Karen H.

AU - Ebbert, Mark T.W.

AU - Shumate, Alaina

AU - Li, Heng

AU - Chin, Chen Shan

AU - Zook, Justin M.

AU - Sedlazeck, Fritz J.

PY - 2022/5

Y1 - 2022/5

N2 - The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.

AB - The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.

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EP - 680

JO - Nature Biotechnology

JF - Nature Biotechnology

IS - 5

ER -

Curated variation benchmarks for challenging medically relevant autosomal genes

Abstract

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ASJC Scopus subject areas

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