Genetics
Comparative genomics finds widespread natural loss of the CETP gene across placental mammals (NAR Genom Bioinform 2019)
Original title: Losses of human disease-associated genes in placental mammals
Researchers systematically investigated whether genes associated with human disease have been naturally lost during evolution in 62 non-human mammals. While genes lost across mammals were generally depleted for essential and disease-associated genes, the study identified multiple exceptions, including widespread losses of PCSK9 and CETP, genes whose loss-of-function mutations in humans are known to protect against atherosclerosis. Other notable natural knockouts included the uric-acid-degrading enzyme UOX in elephants and manatees, which unlike its loss in hominoids does not raise uric acid levels. The findings identify numerous mammalian species as natural knockouts of human disease genes, including CETP, offering comparative models for understanding gene-loss phenotypes.
Original abstract
We systematically investigate whether losses of human disease-associated genes occurred in other mammals during evolution. We first show that genes lost in any of 62 non-human mammals generally have a lower degree of pleiotropy, and are highly depleted in essential and disease-associated genes. Despite this under-representation, we discovered multiple genes implicated in human disease that are truly lost in non-human mammals. In most cases, traits resembling human disease symptoms are present but not deleterious in gene-loss species, exemplified by losses of genes causing human eye or teeth disorders in poor-vision or enamel-less mammals. We also found widespread losses of PCSK9 and CETP genes, where loss-of-function mutations in humans protect from atherosclerosis. Unexpectedly, we discovered losses of disease genes (TYMP, TBX22, ABCG5, ABCG8, MEFV, CTSE) where deleterious phenotypes do not manifest in the respective species. A remarkable example is the uric acid-degrading enzyme UOX, which we found to be inactivated in elephants and manatees. While UOX loss in hominoids led to high serum uric acid levels and a predisposition for gout, elephants and manatees exhibit low uric acid levels, suggesting alternative ways of metabolizing uric acid. Together, our results highlight numerous mammals that are 'natural knockouts' of human disease genes.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.