Journal
TRENDS IN GENETICS
Volume 31, Issue 2, Pages 108-115Publisher
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tig.2014.11.003
Keywords
loss of function; autozygome; evolution; druggable targets; adaptation
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Funding
- King Abdulaziz City for Science and Technology (KACST) [13-BIO1113-20, 10-BIO1357-20]
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Although numerous approaches have been pursued to understand the function of human genes, Mendelian genetics has by far provided the most compelling and medically actionable dataset. Biallelic loss-of-function (LOF) mutations are observed in the majority of autosomal recessive Mendelian disorders, representing natural human knockouts and offering a unique opportunity to study the physiological and developmental context of these genes. The restriction of such context to 'disease' states is artificial, however, and the recent ability to survey entire human genomes for biallelic LOF mutations has revealed a surprising landscape of knockout events in 'healthy' individuals, sparking interest in their role in phenotypic diversity beyond disease causation. As I discuss in this review, the potentially wide implications of human knockout research warrant increased investment and multidisciplinary collaborations to overcome existing challenges and reap its benefits.
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