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Human Knockouts Help Clarify Gene Function

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Lisa Winter

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42 Human Knockouts Help Clarify Gene Function

The easiest way to explore a gene’s function is to turn it off and see what goes wrong. This typically involves using model organisms that have been bred to be genetically identical, to reduce the possibility of some other factor confounding the results. The gene in question is then “knocked out” and scientists observe the results. While there are many homologs between the genes found in model organisms compared to those found in humans, they do not always faithfully replicate what happens in humans.

Last week at the 2014 American Society of Human Genetics meeting in San Diego, Daniel MacArthur of Massachusetts General Hospital in Boston presented his team’s research that uses human knockouts. These people have not been genetically altered in any way, but some genetic variations can cause a loss of function in genes, creating a natural knock-out. MacArthur’s team analyzed the genomes and medical records of 90,000 patients in Finland and found 150,000 of these knock-outs, which will lead to a better understanding of a gene’s effect on human health and could lead to the development of new drugs. The results will be published in Nature.


It was discovered around a decade ago that loss of function mutations on the PCSK9 gene result in extremely low LDL cholesterol. This led to the development of drugs that block PCSK9’s expression and lower cholesterol. The drugs are expected to be available in 2015. MacArthur’s group was encouraged by this discovery and hope to find other useful knock-outs like PCSK9. 

According to the researchers, the average person will have about 200 genes with one copy experiencing a loss of function, and about 20 genes with both copies knocked out. Not all of these knocked out genes are expected to cause disease. Some are expected to be neutral or even confer some advantage.

These natural knock-outs could identify genes whose function changes over time. Some genes are very active during embryonic development, but are not expressed later in life. These loss of function variations could also identify the root cause of serious diseases, potentially creating a new form of treatment. Some genes of interest aside from PCSK9 that could be used to develop treatments include CCR5 (protection against HIV infection), ACTN3 (boosts endurance), CASP12 (resistance to septic infection), SCN9A (reduces pain sensation). 

[Hat tip: Nature]


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