Patterns and tempo of PCSK9 pseudogenizations suggest an ancient divergence in mammalian cholesterol homeostasis mechanisms
Date
2021-01-30
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Nature
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.
Description
CITATION: 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-x
The original publication is available at: springer.com
The original publication is available at: springer.com
Keywords
Cholesterol homeostasis, Molecular evolution, Gene loss, Proprotein convertase subtilisin/kexin type 9 (PCSK9), Human beings -- Diseases, Cholesterol -- Animal models, Cholesterol -- Genetic aspects
Citation
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-x