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

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dc.contributor.authorVan Asch, Barbaraen_ZA
dc.contributor.authorDa Costa, Luís Filipe Teixeiraen_Za
dc.date.accessioned2023-04-18T13:22:12Z
dc.date.available2023-04-18T13:22:12Z
dc.date.issued2021-01-30
dc.descriptionCITATION: van Asch, B., Teixeira da Costa, L.F. Patterns and tempo of PCSK9 pseudogenizations suggest an ancient divergence in mammalian cholesterol homeostasis mechanisms. Genetica 149, 1–19 (2021). doi.10.1007/s10709-021-00113-xen_ZA
dc.descriptionThe original publication is available at: springer.comen_ZA
dc.description.abstractProprotein 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.en_ZA
dc.description.versionPublisher’s versionen_ZA
dc.format.extent19 pages : illustrations (some color)en_ZA
dc.identifier.citationvan Asch, B., Teixeira da Costa, L.F. Patterns and tempo of PCSK9 pseudogenizations suggest an ancient divergence in mammalian cholesterol homeostasis mechanisms. Genetica 149, 1–19 (2021). doi.10.1007/s10709-021-00113-xen_ZA
dc.identifier.issn0016-6707 (print)en_ZA
dc.identifier.issn1573-6857 (online)en_ZA
dc.identifier.otherdoi.10.1007/s10709-021-00113-xen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/126797
dc.language.isoen_ZAen_ZA
dc.publisherSpringer Natureen_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectCholesterol homeostasisen_ZA
dc.subjectMolecular evolutionen_ZA
dc.subjectGene lossen_ZA
dc.subjectProprotein convertase subtilisin/kexin type 9 (PCSK9)en_ZA
dc.subjectHuman beings -- Diseasesen_ZA
dc.subjectCholesterol -- Animal modelsen_ZA
dc.subjectCholesterol -- Genetic aspectsen_ZA
dc.titlePatterns and tempo of PCSK9 pseudogenizations suggest an ancient divergence in mammalian cholesterol homeostasis mechanismsen_ZA
dc.typeArticleen_ZA
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