Health and population effects of rare gene knockouts in adult humans with related parents

Vagheesh M. Narasimhan; Karen A. Hunt; Dan Mason; Christopher L. Baker; Konrad J. Karczewski; Michael R. Barnes; Anthony H. Barnett; Chris Bates; Srikanth Bellary; Nicholas A. Bockett; Kristina Giorda; Christopher J. Griffiths; Harry Hemingway; Zhilong Jia; M. Ann Kelly; Hajrah A. Khawaja; Monkol Lek; Shane McCarthy; Rosie McEachan; Anne O’Donnell-Luria; Kenneth Paigen; Constantinos A. Parisinos; Eamonn Sheridan; Laura Southgate; Louise Tee; Mark Thomas; Yali Xue; Michael Schnall-Levin; Petko M. Petkov; Chris Tyler-Smith; Eamonn R. Maher; Richard C. Trembath; Daniel G. MacArthur; John Wright; Richard Durbin; David A. van Heel

doi:10.1126/science.aac8624

Health and population effects of rare gene knockouts in adult humans with related parents

Vagheesh M. Narasimhan, Karen A. Hunt, Dan Mason, Christopher L. Baker, Konrad J. Karczewski, Michael R. Barnes, Anthony H. Barnett, Chris Bates, Srikanth Bellary, Nicholas A. Bockett, Kristina Giorda, Christopher J. Griffiths, Harry Hemingway, Zhilong Jia, M. Ann Kelly, Hajrah A. Khawaja, Monkol Lek, Shane McCarthy, Rosie McEachan, Anne O’Donnell-LuriaKenneth Paigen, Constantinos A. Parisinos, Eamonn Sheridan, Laura Southgate, Louise Tee, Mark Thomas, Yali Xue, Michael Schnall-Levin, Petko M. Petkov, Chris Tyler-Smith, Eamonn R. Maher, Richard C. Trembath, Daniel G. MacArthur, John Wright, Richard Durbin^*, David A. van Heel

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British Pakistani-heritage adults with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of gene function (knockouts) in 781 genes. We observed 13.7% fewer than expected homozygous knockout genotypes, implying an average load of 1.6 recessive-lethal-equivalent LOF variants per adult. Linking genetic data to lifelong health records, knockouts were not associated with clinical consultation or prescription rate. In this dataset we identified a healthy PRDM9 knockout mother, and performed phased genome sequencing on her, her child and controls, which showed meiotic recombination sites localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform upon essential genetic loci, and demonstrate PRDM9 redundancy in humans.

Original language	English
Pages (from-to)	474-477
Number of pages	8
Journal	Science
Volume	352
Issue number	6284
Early online date	3 Mar 2016
DOIs	https://doi.org/10.1126/science.aac8624
Publication status	Published - 1 Apr 2016

Bibliographical note

-Funding: Wellcome Trust (WT102627, WT098051,WT099769 and WT101597); Barts Charity (845/1796); Medical Research Council (MR/M009017/1); NIHR under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber and NIHR Cambridge Biomedical Research Centre; National Institute of General Medical Sciences of the National Institutes of Health (R01GM104371); MRC; Arthritis Research UK; British Heart Foundation, Cancer Research UK; Chief Scientist Office; ESRC; EPSRC; National Institute for Social Care and Health Research.

Data reported in the paper are presented in the supplementary materials, and are available under a Data Access Agreement at the European Genotype-phenome Archive (www.ebi.ac.uk/ega) under accession numbers EGAS00001000462, EGAS00001000511, EGAS00001000567, EGAS00001000717 and EGAS00001001301.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/cgi/content/full/science.aac8624/DC1
Materials and Methods
Figures S1 to S8
Tables S1 to S8
References (27–60)
Data S1 to S3

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10.1126/science.aac8624

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Narasimhan, V. M., Hunt, K. A., Mason, D., Baker, C. L., Karczewski, K. J., Barnes, M. R., Barnett, A. H., Bates, C., Bellary, S., Bockett, N. A., Giorda, K., Griffiths, C. J., Hemingway, H., Jia, Z., Kelly, M. A., Khawaja, H. A., Lek, M., McCarthy, S., McEachan, R., ... van Heel, D. A. (2016). Health and population effects of rare gene knockouts in adult humans with related parents. Science, 352(6284), 474-477. https://doi.org/10.1126/science.aac8624

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title = "Health and population effects of rare gene knockouts in adult humans with related parents",

abstract = "Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British Pakistani-heritage adults with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of gene function (knockouts) in 781 genes. We observed 13.7% fewer than expected homozygous knockout genotypes, implying an average load of 1.6 recessive-lethal-equivalent LOF variants per adult. Linking genetic data to lifelong health records, knockouts were not associated with clinical consultation or prescription rate. In this dataset we identified a healthy PRDM9 knockout mother, and performed phased genome sequencing on her, her child and controls, which showed meiotic recombination sites localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform upon essential genetic loci, and demonstrate PRDM9 redundancy in humans.",

author = "Narasimhan, {Vagheesh M.} and Hunt, {Karen A.} and Dan Mason and Baker, {Christopher L.} and Karczewski, {Konrad J.} and Barnes, {Michael R.} and Barnett, {Anthony H.} and Chris Bates and Srikanth Bellary and Bockett, {Nicholas A.} and Kristina Giorda and Griffiths, {Christopher J.} and Harry Hemingway and Zhilong Jia and Kelly, {M. Ann} and Khawaja, {Hajrah A.} and Monkol Lek and Shane McCarthy and Rosie McEachan and Anne O{\textquoteright}Donnell-Luria and Kenneth Paigen and Parisinos, {Constantinos A.} and Eamonn Sheridan and Laura Southgate and Louise Tee and Mark Thomas and Yali Xue and Michael Schnall-Levin and Petkov, {Petko M.} and Chris Tyler-Smith and Maher, {Eamonn R.} and Trembath, {Richard C.} and MacArthur, {Daniel G.} and John Wright and Richard Durbin and {van Heel}, {David A.}",

note = "-Funding: Wellcome Trust (WT102627, WT098051,WT099769 and WT101597); Barts Charity (845/1796); Medical Research Council (MR/M009017/1); NIHR under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber and NIHR Cambridge Biomedical Research Centre; National Institute of General Medical Sciences of the National Institutes of Health (R01GM104371); MRC; Arthritis Research UK; British Heart Foundation, Cancer Research UK; Chief Scientist Office; ESRC; EPSRC; National Institute for Social Care and Health Research. Data reported in the paper are presented in the supplementary materials, and are available under a Data Access Agreement at the European Genotype-phenome Archive (www.ebi.ac.uk/ega) under accession numbers EGAS00001000462, EGAS00001000511, EGAS00001000567, EGAS00001000717 and EGAS00001001301. SUPPLEMENTARY MATERIALS www.sciencemag.org/cgi/content/full/science.aac8624/DC1 Materials and Methods Figures S1 to S8 Tables S1 to S8 References (27–60) Data S1 to S3",

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doi = "10.1126/science.aac8624",

language = "English",

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journal = "Science",

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Narasimhan, VM, Hunt, KA, Mason, D, Baker, CL, Karczewski, KJ, Barnes, MR, Barnett, AH, Bates, C, Bellary, S, Bockett, NA, Giorda, K, Griffiths, CJ, Hemingway, H, Jia, Z, Kelly, MA, Khawaja, HA, Lek, M, McCarthy, S, McEachan, R, O’Donnell-Luria, A, Paigen, K, Parisinos, CA, Sheridan, E, Southgate, L, Tee, L, Thomas, M, Xue, Y, Schnall-Levin, M, Petkov, PM, Tyler-Smith, C, Maher, ER, Trembath, RC, MacArthur, DG, Wright, J, Durbin, R & van Heel, DA 2016, 'Health and population effects of rare gene knockouts in adult humans with related parents', Science, vol. 352, no. 6284, pp. 474-477. https://doi.org/10.1126/science.aac8624

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AU - Narasimhan, Vagheesh M.

AU - Hunt, Karen A.

AU - Mason, Dan

AU - Baker, Christopher L.

AU - Karczewski, Konrad J.

AU - Barnes, Michael R.

AU - Barnett, Anthony H.

AU - Bates, Chris

AU - Bellary, Srikanth

AU - Bockett, Nicholas A.

AU - Giorda, Kristina

AU - Griffiths, Christopher J.

AU - Hemingway, Harry

AU - Jia, Zhilong

AU - Kelly, M. Ann

AU - Khawaja, Hajrah A.

AU - Lek, Monkol

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AU - McEachan, Rosie

AU - O’Donnell-Luria, Anne

AU - Paigen, Kenneth

AU - Parisinos, Constantinos A.

AU - Sheridan, Eamonn

AU - Southgate, Laura

AU - Tee, Louise

AU - Thomas, Mark

AU - Xue, Yali

AU - Schnall-Levin, Michael

AU - Petkov, Petko M.

AU - Tyler-Smith, Chris

AU - Maher, Eamonn R.

AU - Trembath, Richard C.

AU - MacArthur, Daniel G.

AU - Wright, John

AU - Durbin, Richard

AU - van Heel, David A.

N1 - -Funding: Wellcome Trust (WT102627, WT098051,WT099769 and WT101597); Barts Charity (845/1796); Medical Research Council (MR/M009017/1); NIHR under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber and NIHR Cambridge Biomedical Research Centre; National Institute of General Medical Sciences of the National Institutes of Health (R01GM104371); MRC; Arthritis Research UK; British Heart Foundation, Cancer Research UK; Chief Scientist Office; ESRC; EPSRC; National Institute for Social Care and Health Research. Data reported in the paper are presented in the supplementary materials, and are available under a Data Access Agreement at the European Genotype-phenome Archive (www.ebi.ac.uk/ega) under accession numbers EGAS00001000462, EGAS00001000511, EGAS00001000567, EGAS00001000717 and EGAS00001001301. SUPPLEMENTARY MATERIALS www.sciencemag.org/cgi/content/full/science.aac8624/DC1 Materials and Methods Figures S1 to S8 Tables S1 to S8 References (27–60) Data S1 to S3

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British Pakistani-heritage adults with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of gene function (knockouts) in 781 genes. We observed 13.7% fewer than expected homozygous knockout genotypes, implying an average load of 1.6 recessive-lethal-equivalent LOF variants per adult. Linking genetic data to lifelong health records, knockouts were not associated with clinical consultation or prescription rate. In this dataset we identified a healthy PRDM9 knockout mother, and performed phased genome sequencing on her, her child and controls, which showed meiotic recombination sites localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform upon essential genetic loci, and demonstrate PRDM9 redundancy in humans.

AB - Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British Pakistani-heritage adults with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of gene function (knockouts) in 781 genes. We observed 13.7% fewer than expected homozygous knockout genotypes, implying an average load of 1.6 recessive-lethal-equivalent LOF variants per adult. Linking genetic data to lifelong health records, knockouts were not associated with clinical consultation or prescription rate. In this dataset we identified a healthy PRDM9 knockout mother, and performed phased genome sequencing on her, her child and controls, which showed meiotic recombination sites localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform upon essential genetic loci, and demonstrate PRDM9 redundancy in humans.

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VL - 352

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Health and population effects of rare gene knockouts in adult humans with related parents

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Bibliographical note

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