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_BKDDY7	Saiga tatarica	PCSK9	Exon(s) deletion	Full	Pecora	10.1007/s10709-021-00113-x
GL_BNUH5V	Lynx pardinus	PCSK9	Exon(s) deletion	Full	Felidae	10.1007/s10709-021-00113-x
GL_CAGFUD	Mustela putorius furo	PCSK9	Exon(s) deletion	Full		10.1007/s10709-021-00113-x
GL_CLE0IA	Pantholops hodgsonii	PCSK9	Exon(s) deletion	Full	Pecora	10.1007/s10709-021-00113-x
GL_CRKD1V	Panthera uncia	PCSK9	Exon(s) deletion	Full	Felidae	10.1007/s10709-021-00113-x
GL_CTJOVP	Eidolon helvum	PCSK9	Exon(s) deletion	Full	Chiroptera	10.1007/s10709-021-00113-x
GL_CTMERO	Mirounga angustirostris	PCSK9	Exon(s) deletion	Full	Phocidae	10.1007/s10709-021-00113-x
GL_CUGPIR	Okapia johnstoni	PCSK9	Exon(s) deletion	Full		10.1007/s10709-021-00113-x
GL_D16MZM	Enhydra lutris	PCSK9	Exon(s) deletion	Full		10.1007/s10709-021-00113-x
GL_DAFOMF	Echinops telfairi	PCSK9	LOF (frameshift, premature stop, ss)	Full	No	10.1007/s10709-021-00113-x