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

22 Apr 2016
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 and David A. van Heel,


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.