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 journalArticlepeer-review

207 Citations (Scopus)


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 languageEnglish
Pages (from-to)474-477
Number of pages4
Issue number6284
Early online date22 Apr 2016
Publication statusPublished - 22 Apr 2016


  • 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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