1. Human knockouts in a cohort with a high rate of consanguinity
- Author
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Danesh Saleheen, Pradeep Natarajan, Wei Zhao, Asif Rasheed, Sumeet Khetarpal, Hong-Hee Won, Konrad J Karczewski, Anne H ODonnell-Luria, Kaitlin E Samocha, Namrata Gupta, Mozzam Zaidi, Maria Samuel, Atif Imran, Shahid Abbas, Faisal Majeed, Madiha Ishaq, Saba Akhtar, Kevin Trindade, Megan Mucksavage, Nadeem Qamar, Khan S Zaman, Zia Yaqoob, Tahir Saghir, Syed NH Rizvi, Anis Memon, Nadeem H Mallick, Mohammad Ishaq, Syed Z Rasheed, Fazal ur Rehman Memon, Khalid Mahmood, Naveeduddin Ahmed, Ron Do, Daniel G MacArthur, Stacey Gabriel, Eric S Lander, Mark J Daly, Philippe Frossard, John Danesh, Daniel J Rader, and Sekar Kathiresan
- Subjects
Genetics ,0303 health sciences ,education.field_of_study ,Null (mathematics) ,Population ,Consanguinity ,Biology ,Null allele ,Minor allele frequency ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Human genome ,education ,Gene ,Gene knockout ,030304 developmental biology - Abstract
A major goal of biomedicine is to understand the function of every gene in the human genome. 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. However, consanguineous unions are more likely to result in offspring who carry homozygous null mutations. In Pakistan, consanguinity rates are notably high. 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 (
- Published
- 2015