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Patterns and tempo of PCSK9 pseudogenizations suggest an ancient divergence in mammalian cholesterol homeostasis mechanisms
- Source :
- Genetica
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
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.
- Subjects :
- 0106 biological sciences
0301 basic medicine
Gene loss
Swine
Lineage (evolution)
Plant Science
010603 evolutionary biology
01 natural sciences
PCSK9
Evolution, Molecular
03 medical and health sciences
Euarchontoglires
Molecular evolution
Genetics
Cholesterol homeostasis
Animals
Humans
Phylogeny
Original Paper
biology
Eutheria
Genetic Variation
Human disease
General Medicine
biology.organism_classification
Proprotein convertase
Null allele
Laurasiatheria
Animal models
Cholesterol
030104 developmental biology
Receptors, LDL
Evolutionary biology
Insect Science
Kexin
Animal Science and Zoology
Proprotein Convertase 9
Pseudogenes
Subjects
Details
- ISSN :
- 15736857 and 00166707
- Volume :
- 149
- Database :
- OpenAIRE
- Journal :
- Genetica
- Accession number :
- edsair.doi.dedup.....7f069365b0933895e83dc4da0bdd355f