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

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

226 Citations (Scopus)

Abstract

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.

Original language	English
Pages (from-to)	474-477
Number of pages	4
Journal	Science
Volume	352
Issue number	6284
Early online date	22 Apr 2016
DOIs	https://doi.org/10.1126/science.aac8624
Publication status	Published - 22 Apr 2016

Keywords

Adult
Consanguinity
DNA Mutational Analysis
Drug Prescriptions
Exome
Female
Fertility
Gene Knockout Techniques
Genes, Lethal
Genetic Loci
Genome, Human
Great Britain
Health
Histone-Lysine N-Methyltransferase
Homologous Recombination
Homozygote
Humans
Male
Mothers
Pakistan
Phenotype

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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 adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.",

keywords = "Adult, Consanguinity, DNA Mutational Analysis, Drug Prescriptions, Exome, Female, Fertility, Gene Knockout Techniques, Genes, Lethal, Genetic Loci, Genome, Human, Great Britain, Health, Histone-Lysine N-Methyltransferase, Homologous Recombination, Homozygote, Humans, Male, Mothers, Pakistan, Phenotype",

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'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}",

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year = "2016",

month = apr,

day = "22",

doi = "10.1126/science.aac8624",

language = "English",

volume = "352",

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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

TY - JOUR

T1 - Health and population effects of rare gene knockouts in adult humans with related parents

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

AU - McCarthy, Shane

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

PY - 2016/4/22

Y1 - 2016/4/22

N2 - Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on 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 adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.

KW - Adult

KW - Consanguinity

KW - DNA Mutational Analysis

KW - Drug Prescriptions

KW - Exome

KW - Female

KW - Fertility

KW - Gene Knockout Techniques

KW - Genes, Lethal

KW - Genetic Loci

KW - Genome, Human

KW - Great Britain

KW - Health

KW - Histone-Lysine N-Methyltransferase

KW - Homologous Recombination

KW - Homozygote

KW - Humans

KW - Male

KW - Mothers

KW - Pakistan

KW - Phenotype

U2 - 10.1126/science.aac8624

DO - 10.1126/science.aac8624

M3 - Article

C2 - 26940866

SN - 0036-8075

VL - 352

SP - 474

EP - 477

JO - Science

JF - Science

IS - 6284

ER -

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

Abstract

Keywords

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