Patterns and tempo of PCSK9 pseudogenizations suggest an ancient divergence in mammalian cholesterol homeostasis mechanisms

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in cholesterol homeostasis in humans as a major regulator of LDLR levels. PCSK9 is an intriguing protease in that it does not act by proteolysis but by preventing LDLR recirculation from endosomes to the plasma membrane. This, and the inexistence of any other proteolytic substrate but itself could suggest that PCSK9 is an exquisite example of evolutionary fine-tuning. However, the gene has been lost in several mammalian species, and null alleles are present (albeit at low frequencies) in some human populations without apparently deleterious health effects, raising the possibility that the PCSK9 may have become dispensable in the mammalian lineage. To address this issue, we systematically recovered, assembled, corrected, annotated and analysed publicly available PCSK9 sequences for 420 eutherian species to determine the distribution, frequencies, mechanisms and timing of PCSK9 pseudogenization events, as well as the evolutionary pressures underlying the preservation or loss of the gene. We found a dramatic difference in the patterns of PCSK9 retention and loss between Euarchontoglires—where there is strong pressure for gene preservation—and Laurasiatheria, where multiple independent events have led to PCSK9 loss in most species. These results suggest that there is a fundamental difference in the regulation of cholesterol metabolism between Euarchontoglires and Laurasiatheria, which in turn has important implications for the use of Laurasiatheria species (e.g. pigs) as animal models of human cholesterol-related diseases.

PCSK9 deficiency results in a specific shedding of excess LDLR in female mice only: Role of hepatic cholesterol

“…In this context, we previously observed that the loss of PCSK9 leads to higher surface levels of the LDLR in enterocytes and VLDLR in visceral adipose tissue of female, but not male mice [19]. Interestingly, PCSK9 pseudogenization in the large group of placental mammals Laurasiatheria occurred repeatedly, indicating that alteration in their cholesterol metabolism made them more susceptible to lose PCSK9 [54]. Therefore, in species lacking PCSK9, including pigs, bovines, camels, whales, bats, cats, dogs, bears and horses, it would be interesting to evaluate the functional relevance and metabolic consequences of E2-mediated shedding of liver surface LDLR.…”

The Multifaceted Biology of PCSK9

“…A recent study revealed a dramatic difference in the patterns of PCSK9 retention and loss between the 4 major clades of placental mammals ( 288 ). Namely, the Euarchontoglires clade that includes primates, rodents, and rabbits exhibit a strong pressure for gene preservation, whereas the Laurasiatheria clade is characterized by multiple independent events that led to the loss of PCSK9 in many species, such as pigs, bovine, camels, whales, bats, cats, dogs, bears, and horses ( 289 ). The loss of PCSK9 expression in pigs, suggests that studies of cholesterol metabolism therein would be advantageous for understanding cholesterol-related human diseases, as recently reported in D374Y-PCSK9 transgenics ( 152 ) resulting in hypercholesterolemic minipigs, a porcine model of advanced coronary atherosclerosis ( 290 ).…”

Is It Ever Wise to Edit Wild-Type Alleles? Engineered CRISPR Alleles Versus Millions of Years of Human Evolution

“…PCSK9 is present in most vertebrates including humans, primates, and rodents, yet, has been lost in pigs, cows, camels, horses, dogs, and cats. 24 It is immediately apparent that loss of PCSK9 occurred in domesticated animals where humans were likely controlling food sources and availability. Restricting food availability can remove a potentially powerful selective force that could maintain a gene in the genome.…”

“…Restricting food availability can remove a potentially powerful selective force that could maintain a gene in the genome. Gene loss during domestication, 24 and a decrease in gene expression diversity have been observed in domesticated animals. 25 Often, domesticated species are, in fact, not very good at surviving in the wild without human cultivation.…”