CoChat
Sign Up
Cited by 286Genomics and Rare DiseasesGenetic Associations and EpidemiologyEvolution and Genetic Dynamics

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

Open access
Narasimhan, Vagheesh M., Hunt, Karen A., Mason, Dan, Baker, Christopher L., Karczewski, Konrad J., Barnes, Michael R., Barnett, Anthony H., Bates, Chris +28 more·2016·Science
DOI 10.1126/science.aac8624PMC PMC4985238

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Rare gene knockouts in adult humans: On average, most people's genomes contain approximately 100 completely nonfunctional genes. These loss-of-function (LOF) mutations tend to be rare and/or occur only as a single copy within individuals. Narasimhan et al. investigated LOF in a Pakistani population with high levels of consanguinity. Examining LOF alleles that were identical by descent, they found, as expected, an absence of homozygote LOF for certain protein-coding genes. However, they also identified many homozygote LOF alleles with no apparent deleterious phenotype, including some that were expected to confer genetic disease. Indeed, one family had lost the recombination-associated gene PRDM9 . Science , this issue p. 474

Integrity signals

Registry

Crossref · 10.1126/science.aac8624

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 50 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Overall, 1,111 rhLOF genotypes at 847 variants in 781 different protein-coding genes were identified in 821 individuals.

    “Overall we identified 1,111 rhLOF genotypes at 847 variants (575 annotated as LOF in all GENCODE-basic transcripts) in 781 different protein-coding genes (fig. 1C)(5) in 821 individuals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

  • Findingcitation

    107 rhLOF genes were common to all three datasets.

    “In total, 107 rhLOF genes were common to all three datasets (5)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

  • Findingcitation

    The observed deficit (13.7%) is higher than the 6.4% deficit reported in the Icelandic population.

    “This deficit is higher than in the Icelandic population (6.4%)(3)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Sulem P Identification of a large set of rare complete human knockouts Nat. Genet 2015 47 448 452 25807282 source

      Not checked in the free run.

  • Findingown data

    Matching 16,708 rare annotated loss-of-function variants to randomly selected synonymous variants of the same allele frequency, 842 rare loss-of-function variants had at least one homozygous genotype versus an average of 975.5 rare synonymous variants with at least one homozygote, indicating a deficit of 13.7% (95% CI 8-20%) of variants with rhLOF genotypes.

    “We matched each of the 16,708 rare annotated LOF (heterozygous and homozygous) variants to a randomly selected synonymous variant of the same allele frequency, and observed 842 rare LOF variants with >= 1 homozygous genotype versus an average of 975.5 rare synonymous variants with >= 1 homozygote, indicating a deficit of 13.7% (95% confidence interval 8–20%) of variants with rhLOF genotypes (fig.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

  • Findingown data

    A healthy adult mother with a predicted rare homozygous loss-of-function mutation in PRDM9 was identified and confirmed experimentally.

    “we identified a healthy PRDM9 knockout mother”
    • Also stated in: § Abstract · plain
      “One of our subjects was a healthy adult mother with a predicted rare homozygous LOF mutation in PRDM9, which we confirmed experimentally(5)(fig. S7A, S7B).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

  • May combine two claims. 23
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingown data

    Per subject, there were on average 140.3 non-reference predicted loss-of-function genotypes, comprising 16.1 rare heterozygotes, 0.34 rare homozygotes, 83.2 common heterozygotes and 40.6 common homozygotes.

    “We identified, per subject, on average 140.3 non-reference predicted LOF genotypes comprising 16.1 rare (minor allele frequency <1%) heterozygotes, 0.34 rare homozygotes, 83.2 common heterozygotes and 40.6 common homozygotes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Nearly all rhLOF genotypes were found within autozygous segments (94.9%), and the mean number of rhLOF per individual was proportional to autozygosity.

    “Nearly all rhLOF genotypes were found within autozygous segments (94.9%)(5), and the mean number of rhLOF per individual was proportional to autozygosity (fig. 1B).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The majority of identified genes with rhLOF genotypes (422) had not been previously reported, while 167 had been reported in Iceland and 299 in ExAC.

    “The majority of identified genes with rhLOF genotypes (422) had not been previously reported, although 167 had been reported as containing homozygous or compound heterozygous LOF genotypes in Iceland, and 299 in ExAC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Knockouts were not associated with clinical consultation rate or prescription rate.

    “knockouts were not associated with clinical consultation or prescription rate.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

    • Rests on an assumption: Predicted loss-of-function genotypes in this dataset generally cause complete loss of function of the corresponding gene.

  • May combine two claims.

    Findingcitation

    Autozygous segments were observed across all exomic sites with a density distribution not significantly different from random (Shapiro-Wilks P=0.112).

    “Autozygous segments were observed across all exomic sites with a density distribution not significantly different from random (5)(Shapiro-Wilks P=0.112).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    On average, 5.6% of the coding genome was autozygous in the sampled adults, much higher than in outbred European heritage populations.

    “On average, 5.6% of the coding genome was autozygous, much higher than that in outbred European heritage populations (figs. 1A, S4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    89 rhLOF genotypes were homozygotes without observed heterozygotes, and three subjects each had 5 rhLOF genotypes.

    “89 rhLOF genotypes were homozygotes without observed heterozygotes, and we observed three subjects each with 5 rhLOF genotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The estimate of 1.6 lethal equivalents is similar to previous estimates from correlating miscarriages, stillbirths and infant mortalities with autozygosity, and to measurements in other species.

    “This is similar to previous estimates of the lethal load calculated by correlating the number of miscarriages, stillbirths and infant mortalities with the level of autozygosity (fig. 2C)(7, 8), and also similar to measurements in other species(9).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Chakraborty R Chakravarti A On consanguineous marriages and the genetic load Hum. Genet 1977 36 47 54 870410 source

      Not checked in the free run.

    • cites [8] Bittles AH Neel JV The costs of human inbreeding and their implications for variations at the DNA level Nat. Genet 1994 8 117 121 7842008 source

      Not checked in the free run.

    • cites [9] McCune AR A low genomic number of recessive lethals in natural populations of bluefin killifish and zebrafish Science 2002 296 2398 2401 12089444 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Comparing individuals with one or more rhLOF (n=638) to those without rhLOF (n=1524), there was no association with prescription rate (OR 1.001, 95% CI 0.988-1.0144) or consultation rate (OR 1.017, 95% CI 0.996-1.038), nor any associations in rhLOF subgroups.

    “We compared individuals with one or more rhLOF (n=638) to individuals without rhLOF (n=1524), and found no association with prescription rate (logistic regression, OR 1.001, 95% CI 0.988 - 1.0144) or consultation rate (OR 1.017, 95% CI 0.996 - 1.038), nor any associations in rhLOF subgroups (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    rhLOF genes that are drug targets have an 11.4% phase I to approval rate versus 6.7% for all target-indication pairs, but there is no difference in the proportion of genes known or predicted to be druggable targets for rhLOF genes (15%) compared to all genes (13%).

    “Furthermore rhLOF genes that are drug targets have 11.4% phase I to approval rate versus 6.7% for all target-indication pairs (chi-squared P=0.046), although we observed no difference in the proportion of genes known or predicted to be druggable targets(11) for rhLOF genes (15%) compared to all genes (13%, P=0.098)(5).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Nelson MR The support of human genetic evidence for approved drug indications Nat. Genet 2015 47 856 860 26121088 source

      Not checked in the free run.

    • cites [5] Supplementary Materials source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Genes containing rhLOF showed 50% fewer molecular interactions compared to all genes in the STRING interactome dataset, predominantly driven by the Binding Interaction class.

    “Genes containing rhLOF showed 50% fewer molecular interactions compared to all genes in the STRING interactome dataset (Kruskal-Wallis P=3.4 × 10−9), predominantly driven by the Binding Interaction class (Kruskal-Wallis P=9.3 × 10−11).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the remaining 38 rhLOF subjects, only six had definite lifetime primary health record diagnoses consistent with the OMIM phenotype, with a further three genotypes suggestively compatible.

    “Only six of the remaining 38 rhLOF subjects had definite lifetime primary health record diagnoses recorded consistent with the OMIM phenotype, with a further three genotypes suggestively compatible (table S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The PRDM9-knockout duo did not show increased overlap of crossover intervals with promoters and their flanking regions or enrichment in GC content compared to the control duo.

    “However we did not see an increased overlap in our PRDM9-knockout duo crossover intervals with promoters and their flanking regions or enrichment in GC content, compared to the control duo(5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Supplementary Materials source

      Not checked in the free run.

    • Rests on an assumption: The control mother-child CEPH pedigree duo is comparable to the PRDM9 knockout duo for crossover hotspot analyses apart from PRDM9 genotype.

  • May combine two claims.

    Findingown data

    The PRDM9 genotype predicts protein truncation in the SET methyltransferase domain, lacking the DNA-binding zinc-finger domain, confirmed in an in vitro expression system.

    “Her genotype predicts protein truncation in the SET methyltransferase domain (thus lacking the DNA-binding zinc-finger domain) which we confirmed in an in vitro expression system (fig. S8A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    18.5% of crossovers in the PRDM9 knockout duo (CI 1%-42%) occurred in linkage disequilibrium based hotspots versus 75.7% in the control duo (CI 57%-89%).

    “Using similar methods we saw that 18.5% of crossovers observed in the PRDM9 knockout duo (confidence interval: 1% - 42%) occurred in linkage disequilibrium based hotspots versus 75.7% in the control duo (confidence interval 57%-89% consistent with a previously published estimate of an average of 60% of crossovers occurring at hotspots(18))(5).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Baudat F PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice Science 2010 327 836 840 20044539 PMC4295902 source

      Not checked in the free run.

    • cites [5] Supplementary Materials source

      Not checked in the free run.

    • Rests on an assumption: The control mother-child CEPH pedigree duo is comparable to the PRDM9 knockout duo for crossover hotspot analyses apart from PRDM9 genotype.

  • May combine two claims.

    Findingown data

    There was absence of increase in H3K4Me3 global methylation on transfection of the truncation allele, and R345Ter specifically disrupted PRDM9-dependent H3K4Me3 methylation at hotspots.

    “We observed absence of increase in H3K4Me3 global methylation on transfection (20) of the truncation allele (fig. S8A), and that R345Ter specifically disrupted PRDM9-dependent H3K4Me3 methylation at hotspots (fig. S8B).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Baker CL Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots PLoS Genet 2015 11 e1005512 26368021 PMC4569383 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The difference between the two estimates (1.6 vs 0.5) can be accounted for by the first including embryonic lethals whereas the second only involves deaths after a registered pregnancy, suggesting there are twice as many recessive mutations that are embryonically lethal as those that result in fetal or infant death.

    “The difference between our two estimates can be accounted for by the fact that the first includes embryonic lethals, whereas the second only involves deaths after a registered pregnancy, suggesting that there are twice as many recessive mutations that are embryonically lethal as those that result in fetal or infant death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A survey of loss-of-function variants in adult humans found about 100 predicted loss-of-function genotypes per individual, describing around 20 genes carrying homozygous predicted loss-of-function alleles likely completely inactivated.

    “A survey of LOF variants in adult humans demonstrated ~100 predicted LOF genotypes per individual, describing around ~20 genes carrying homozygous predicted LOF alleles and hence likely completely inactivated(1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] MacArthur DG A systematic survey of loss-of-function variants in human protein-coding genes Science 2012 335 823 828 22344438 PMC3299548 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Modest enrichment for homozygous predicted loss-of-function genotypes was shown in Finnish individuals.

    “and modest enrichment for homozygous predicted LOF genotypes shown in Finnish individuals(4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Lim ET Distribution and medical impact of loss-of-function variants in the Finnish founder population PLoS Genet 2014 10 e1004494 25078778 PMC4117444 source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Even in large samples, homozygous predicted loss-of-function genotypes tend to be for variants at moderate allele frequency around 1%, so these approaches will not readily assess knockouts in most genes lacking such variants.

    “However, even in these large samples, homozygous predicted LOF genotypes tend to be for variants at moderate (around 1%) allele frequency, and hence these approaches will not readily assess knockouts in most genes, which are lacking such variants.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ExAC identified 1,775 genes with homozygous predicted loss-of-function genotypes in 60,706 individuals.

    “A large exome sequencing aggregation study (ExAC), of predominantly outbred individuals, identified 1,775 genes with homozygous predicted LOF genotypes in 60,706 individuals(2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Exome Aggregation Consortium Analysis of protein-coding genetic variation in 60,706 humans 2015 http://biorxiv.org/content/early/2015/10/30/030338 PMC5018207 27535533

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Drug prescription rate and clinical staff consultation rate have previously been shown to correlate strongly with health status.

    “Drug prescription rate and clinical staff consultation rate have previously been shown to correlate strongly with health status(17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Brilleman SL Implications of comorbidity for primary care costs in the UK: a retrospective observational study Br. J. Gen. Pract 2013 63 e274 e282 23540484 PMC3609475 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The remaining 29 are suggested to be due to a combination of incomplete penetrance, late onset of disease, mild symptoms not seeking medical attention, unrecognised technical issues with sequencing or annotation, or dubious evidence to support the gene-phenotype assignment.

    “We suggest that the remaining 29 are due to a combination of incomplete penetrance[12–16], late onset of disease (i.e. not yet having occurred), individuals with mild symptoms not seeking medical attention, unrecognised technical issues with sequencing or annotation (e.g. tissue specific alternative splicing), or dubious evidence to support the gene-phenotype assignment”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [12] Flannick J Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes Nat. Genet 2013 45 1380 1385 24097065 PMC4051627 source

      Not checked in the free run.

    • cites [13] Rehm HL ClinGen--the Clinical Genome Resource N. Engl. J. Med 2015 372 2235 2242 26014595 PMC4474187 source

      Not checked in the free run.

    • cites [14] UK10K Consortium The UK10K project identifies rare variants in health and disease Nature 2015 526 82 90 26367797 PMC4773891 source

      Not checked in the free run.

    • cites [15] Johnston JJ Individualized iterative phenotyping for genome-wide analysis of loss-of-function mutations Am. J. Hum. Genet 2015 96 913 925 26046366 PMC4457956 source

      Not checked in the free run.

    • cites [16] Van Driest SL Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records JAMA 2016 315 47 57 26746457 PMC4758131 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Although this class of variants has the greatest predicted effect on protein function, loss of most proteins is relatively harmless to the individual, and even in previously annotated disease genes predicted rare loss-of-function homozygotes may not always be as clinically relevant as often considered.

    “Although this class of variants has the greatest predicted effect on protein function, loss of most proteins is relatively harmless to the individual, and even in previously annotated disease genes predicted rare LOF homozygotes may not always be as clinically relevant as often considered.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Predicted loss-of-function genotypes in this dataset generally cause complete loss of function of the corresponding gene.

  • Classified as probably not a substantial claim.

    Premisecitation

    PRDM9 is the major known determinant of the genomic locations of meiotic recombination events in humans and mice through its DNA binding site zinc finger domain.

    “PRDM9 is the major known determinant of the genomic locations of meiotic recombination events in humans and mice through its DNA binding site zinc finger domain (6, 18, 19).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Parvanov ED Petkov PM Paigen K Prdm9 controls activation of mammalian recombination hotspots Science 2010 327 835 20044538 PMC2821451 source

      Not checked in the free run.

    • cites [18] Baudat F PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice Science 2010 327 836 840 20044539 PMC4295902 source

      Not checked in the free run.

    • cites [19] Myers S Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination Science 2010 327 876 879 20044541 PMC3828505 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prdm9 knockout mice demonstrate abnormal location of recombination hotspots with enrichment at gene promoters and enhancers, fail to properly repair double-stranded breaks, and are infertile.

    “Prdm9 knockout mice demonstrate abnormal location of recombination hotspots with enrichment at gene promoters and enhancers, and also fail to properly repair double-stranded breaks and are infertile (both sexes sterile)(21, 22).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Hayashi K Yoshida K Matsui Y A histone H3 methyltransferase controls epigenetic events required for meiotic prophase Nature 2005 438 374 378 16292313 source

      Not checked in the free run.

    • cites [22] Brick K Smagulova F Khil P Camerini-Otero RD Petukhova GV Genetic recombination is directed away from functional genomic elements in mice Nature 2012 485 642 645 22660327 PMC3367396 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The healthy and fertile PRDM9-deficient adult human suggests differences from both mice and dogs, and supports the possibility of alternative mechanisms of localizing human meiotic crossovers.

    “Thus the healthy and fertile PRDM9-deficient adult human suggests differences from both mice and dogs, and supports the possibility of alternative mechanisms of localizing human meiotic crossovers(25, 26).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Pratto F DNA recombination. Recombination initiation maps of individual human genomes Science 2014 346 1256442 25395542 PMC5588152 source

      Not checked in the free run.

    • cites [26] Lichten M Molecular biology. Putting the breaks on meiosis Science 2015 350 913 26586748 source

      Not checked in the free run.

    • Rests on an assumption: The control mother-child CEPH pedigree duo is comparable to the PRDM9 knockout duo for crossover hotspot analyses apart from PRDM9 genotype.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    Apparent rhLOF genotypes identified by exome or genome sequencing from adult populations require cautious interpretation.

    “Together these data suggest that apparent rhLOF genotypes identified by exome or genome sequencing from adult populations require cautious interpretation.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Predicted loss-of-function genotypes in this dataset generally cause complete loss of function of the corresponding gene.
28 of 28

  • The paper relies on this without support.

    Predicted loss-of-function genotypes in this dataset generally cause complete loss of function of the corresponding gene.

    “predicted loss of gene function (knockouts)”
    “rhLOF”

  • The paper relies on this without support.

    The sampled adults are representative of the British Pakistani-heritage population with high parental relatedness for estimating knockout frequency and recessive lethal load.

    “3,222 Pakistani-heritage adults living in the UK who were ascertained as healthy, type 2 diabetic, or pregnant(5).”

  • The paper relies on this without support.

    The control mother-child CEPH pedigree duo is comparable to the PRDM9 knockout duo for crossover hotspot analyses apart from PRDM9 genotype.

    “In comparison, in a control mother-child CEPH pedigree duo homozygous for PRDM9-A we estimated that 52.1% (confidence interval: 36 - 69%) of the crossovers occurred in known DSB sites.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Studies in populations with high rates of consanguinity make it possible to identify individuals homozygous for otherwise rare loss-of-function alleles, forming the basis for a human knockout project.

    “In addition, studies in populations with high rates of consanguinity make it possible to identify individuals homozygous for otherwise rare loss-of-function alleles, the basis for a ‘human knockout’ project to systematically investigate the phenotypic consequences of gene disruption in humans53,54.”

    From A brief history of human disease genetics (2020) · cites this paper as [53]

  • Efforts to probe clinical consequences of coding alleles with large phenotypic effects, particularly null alleles, in humans and animal models represent powerful strategies for extending functional analyses to the whole-body level.

    “Efforts to probe the clinical consequences of coding alleles with large phenotypic effects (particularly null alleles) in humans53,54 and across diverse animal models116 represent powerful strategies for extending functional analyses to the whole-body level.”

    From A brief history of human disease genetics (2020) · cites this paper as [53]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
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., O’Donnell-Luria, A., Paigen, K., Parisinos, C. A., Sheridan, E., Southgate, L., Tee, L., Thomas, M., Xue, Y., Schnall-Levin, M., Petkov, P. M., Tyler-Smith, C., Maher, E. R., Trembath, R. C., MacArthur, D. G., Wright, J., Durbin, R., & van Heel, D. A.
Affiliations
  • Wellcome Sanger Institute (GB)
  • Queen Mary University of London (GB)
  • National Health Service (GB)
  • Jackson Laboratory (US)
  • Broad Institute (US)
  • Heart of England NHS Foundation Trust (GB)
  • TPP, Mill House, Troy Road, Leeds LS18 5TN, UK.
  • Aston University (GB)
  • 10X Genomics (United States) (US)
  • Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Farr Institute (GB)
  • University of Birmingham (GB)
  • Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
  • Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • University of Cambridge (GB)
Corresponding author
  • Hunt, Karen A.
  • Mason, Dan
  • Baker, Christopher L.
  • Karczewski, Konrad J.
  • Durbin, Richard
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2016-04-22
Volume
352
Issue
6284
Pages
474-477
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.aac8624
PMC
PMC4985238
OpenAlex
W2294521862
Semantic Scholar
f123dcaa6f5b9c8aaa78d60b5b423bb16e42ee30
Cited by
286
References
67
Citations by year
2026: 13 · 2025: 10 · 2024: 21 · 2023: 22 · 2022: 22 · 2021: 24 · 2020: 30 · 2019: 33 · 2018: 32 · 2017: 48 · 2016: 31
FWCI
39.00
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Funders
  • Barts Charity (845/1796)
  • Wellcome Trust Ph.D. Studentship (WT099769)
  • NIH National Institute of General Medical Sciences (R01GM104371)
  • NIHR Cambridge Biomedical Research Centre
  • Farr Institute of Health Informatics Research, London
  • UK Medical Research Council (MR/M009017/1)
  • Arthritis Research UK
  • British Heart Foundation
  • Cancer Research UK
  • Chief Scientist Office
  • Economic and Social Research Council
  • Engineering and Physical Sciences Research Council
  • NIHR
  • National Institute for Social Care and Health Research
  • Wellcome Trust (WT102627, WT098051, WT101597)
  • NIH (GM 099640)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
gene knockout, loss-of-function mutations, homozygous variant, recessive lethality, PRDM9, meiotic recombination, recombination hotspots, exome sequencing, health outcomes, population genetics
MeSH terms
Adult, Consanguinity, DNA Mutational Analysis, Female, Fertility, Genes, Lethal, United Kingdom, Health, Homozygote, Humans, Male, Mothers, Pakistan, Phenotype, Drug Prescriptions, Histone-Lysine N-Methyltransferase, Genome, Human, Gene Knockout Techniques, Genetic Loci, Exome, Homologous Recombination

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review