Gene Loss

Publication Details

Identifier: JB_QCEQJ0

Curator: Gonçalo Themudo

DOI: 10.1007/s10709-021-00113-x

PMID: 33515402

Title:

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.

Last update:

08-09-2024

Associated Glosses (165 results)

GlossID	Species	Symbol	Gene Loss Mechanism	Loss Type	Lineage Specific	Citation
GL_ZNVFGI	Canis aureus	PCSK9	Exon(s) deletion	Full	Canidae	10.1007/s10709-021-00113-x
GL_ZTL67A	Tapirus terrestris	PCSK9	Exon(s) deletion	Full	Perissodactyla	10.1007/s10709-021-00113-x
GL_ZWNW2S	Rangifer tarandus	PCSK9	Exon(s) deletion	Full		10.1007/s10709-021-00113-x
GL_ZXGTOC	Equus hemionus	PCSK9	Exon(s) deletion	Full	Perissodactyla	10.1007/s10709-021-00113-x
GL_ZY8XVU	Oryx gazella	PCSK9	Exon(s) deletion	Full	Pecora	10.1007/s10709-021-00113-x