RT Journal Article
SR Electronic
T1 Human knockouts in a cohort with a high rate of consanguinity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 031518
DO 10.1101/031518
A1 Danesh Saleheen
A1 Pradeep Natarajan
A1 Wei Zhao
A1 Asif Rasheed
A1 Sumeet Khetarpal
A1 Hong-Hee Won
A1 Konrad J. Karczewski
A1 Anne H O’Donnell-Luria
A1 Kaitlin E. Samocha
A1 Namrata Gupta
A1 Mozzam Zaidi
A1 Maria Samuel
A1 Atif Imran
A1 Shahid Abbas
A1 Faisal Majeed
A1 Madiha Ishaq
A1 Saba Akhtar
A1 Kevin Trindade
A1 Megan Mucksavage
A1 Nadeem Qamar
A1 Khan Shah Zaman
A1 Zia Yaqoob
A1 Tahir Saghir
A1 Syed Nadeem Hasan Rizvi
A1 Anis Memon
A1 Nadeem Hayyat Mallick
A1 Mohammad Ishaq
A1 Syed Zahed Rasheed
A1 Fazal-ur-Rehman Memon
A1 Khalid Mahmood
A1 Naveeduddin Ahmed
A1 Ron Do
A1 Daniel G. MacArthur
A1 Stacey Gabriel
A1 Eric S. Lander
A1 Mark J. Daly
A1 Philippe Frossard
A1 John Danesh
A1 Daniel J. Rader
A1 Sekar Kathiresan
YR 2015
UL http://biorxiv.org/content/early/2015/11/12/031518.abstract
AB A major goal of biomedicine is to understand the function of every gene in the human genome.1 Null mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such ‘human knockouts’ can provide insight into gene function. To date, comprehensive analysis of genes knocked out in humans has been limited by the fact that null mutations are infrequent in the general population and so, observing an individual homozygous null for a given gene is exceedingly rare.2,3 However, consanguineous unions are more likely to result in offspring who carry homozygous null mutations. In Pakistan, consanguinity rates are notably high.4 Here, we sequenced the protein-coding regions of 7,078 adult participants living in Pakistan and performed phenotypic analysis to identify homozygous null individuals and to understand consequences of complete gene disruption in humans. We enumerated 36,850 rare (<1 % minor allele frequency) null mutations. These homozygous null mutations led to complete inactivation of 961 genes in at least one participant. Homozygosity for null mutations at APOC3 was associated with absent plasma apolipoprotein C-III levels; at PLAG27, with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; and at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations. After physiologic challenge with oral fat, APOC3 knockouts displayed marked blunting of the usual post-prandial rise in plasma triglycerides compared to wild-type family members. These observations provide a roadmap to understand the consequences of complete disruption of a large fraction of genes in the human genome.