Editing Human genome (section)

=== Human knockouts ===

In humans, [[gene knockouts]] naturally occur as [[heterozygous]] or [[homozygous]] [[loss-of-function]] gene knockouts. These knockouts are often difficult to distinguish, especially within [[heterogeneous]] genetic backgrounds. They are also difficult to find as they occur in low frequencies.
[[File:Gene Knockouts in Outbred vs. Parentally-related populations.jpg|thumb|Populations with a high level of parental-relatedness result in a larger number of homozygous gene knockouts as compared to outbred populations.<ref name="Narasimhan VM 2016">{{cite journal | vauthors = Narasimhan VM, Xue Y, Tyler-Smith C | title = Human Knockout Carriers: Dead, Diseased, Healthy, or Improved? | journal = Trends in Molecular Medicine | volume = 22 | issue = 4 | pages = 341–351 | date = April 2016 | pmid = 26988438 | pmc = 4826344 | doi = 10.1016/j.molmed.2016.02.006 }}</ref>]]

Populations with high rates of [[consanguinity]], such as countries with high rates of first-cousin marriages, display the highest frequencies of homozygous gene knockouts. Such populations include Pakistan, Iceland, and Amish populations. These populations with a high level of parental-relatedness have been subjects of human knock out research which has helped to determine the function of specific genes in humans. By distinguishing specific knockouts, researchers are able to use phenotypic analyses of these individuals to help characterize the gene that has been knocked out.

[[File:Consanguineous Mating resulting in Knockout.jpg|thumb|A pedigree displaying a first-cousin mating (carriers both carrying heterozygous knockouts mating as marked by double line) leading to offspring possessing a homozygous gene knockout]]

Knockouts in specific genes can cause genetic diseases, potentially have beneficial effects, or even result in no phenotypic effect at all. However, determining a knockout's phenotypic effect and in humans can be challenging. Challenges to characterizing and clinically interpreting knockouts include difficulty calling of DNA variants, determining disruption of protein function (annotation), and considering the amount of influence [[mosaicism]] has on the phenotype.<ref name="Narasimhan VM 2016"/>

One major study that investigated human knockouts is the Pakistan Risk of Myocardial Infarction study. It was found that individuals possessing a heterozygous loss-of-function gene knockout for the [[APOC3]] gene had lower triglycerides in the blood after consuming a high fat meal as compared to individuals without the mutation. However, individuals possessing homozygous loss-of-function gene knockouts of the APOC3 gene displayed the lowest level of triglycerides in the blood after the fat load test, as they produce no functional APOC3 protein.<ref>{{cite journal | vauthors = Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O'Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SN, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S  | title = Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity | journal = Nature | volume = 544 | issue = 7649 | pages = 235–239 | date = April 2017 | pmid = 28406212 | pmc = 5600291 | doi = 10.1038/nature22034 | bibcode = 2017Natur.544..235S }}</ref>