Absence of CD59 in Guinea Pigs: Analysis of the Cavia porcellus Genome Suggests the Evolution of a CD59 Pseudogene

Abstract

CD59 is a membrane-bound regulatory protein that inhibits the assembly of the terminal membrane attack complex (C5b-9) of complement. From its original discovery in humans almost 30 years ago, CD59 has been characterized in a variety of species, from primates to early vertebrates, such as teleost fish. CD59 is ubiquitous in mammals; however, we have described circumstantial evidence suggesting that guinea pigs () lack CD59, at least on erythrocytes. In this study, we have used a combination of phylogenetic analyses with syntenic alignment of mammalian genes to identify the only span of genomic DNA in that is homologous to a portion of mammalian and show that this segment of DNA is not transcribed. We describe a pseudogene sharing homology to exons 2 through 5 of human present in the genome. This pseudogene was flanked by homologs of two genes, and, a relationship and orientation that were consistent with other known mammalian genes. Analysis using RNA sequencing confirmed that this segment of chromosomal DNA was not transcribed. We conclude that guinea pigs lack an intact gene encoding CD59; to our knowledge, this is the first report of a mammalian species that does not express a functional CD59. The pseudogene we describe is likely the product of a genomic deletion event during its evolutionary divergence from other members of the rodent order.

Alternative splicing encodes functional intracellular CD59 isoforms that mediate insulin secretion and are down-regulated in diabetic islets

“…The final protein-coding exon of human CD59–IRIS-1 is found within C11orf91 , which is highly conserved and found adjacent to the CD59 gene across mammalian species, suggesting the existence of a conserved CD59–IRIS-1 homolog. It was recently described that CD59 exists only as a pseudogene in guinea pigs, due to the lack of any encoded C-terminal GPI-anchor signal peptide, no detectable cell-surface expression, and low or undetectable transcription levels in tested tissues ( 11 ); but our findings suggest that a tissue-restricted expression of the non–GPI-anchored guinea pig CD59 protein should be investigated for functions in insulin secretion. This would suggest that, in the guinea pig, only the secretory rather than complement inhibitory function of Cd59 may have been evolutionarily conserved.…”

Integration of fluorescence in situ hybridization and chromosome-length genome assemblies revealed synteny map for guinea pig, naked mole-rat, and human

“…Their number continues to grow to this day. Even these data have already made it possible to use model organisms more effectively, including the guinea pig and the naked mole-rat, for a clearer understanding of mole-rat evolutionary history and for suggesting molecular pathways that may explain the extraordinarily longevity and unique health traits of this species 41 , 45 , 85 – 87 . Later, comparison of sequence data with cytogenetic data reveals the imperfection of exclusively bioinformatic approaches in chromosome-level assembly 12 .…”

Evolution and Medical Significance of LU Domain−Containing Proteins

“…CD59 protects host cells from autologous complement damage by binding to the premature membrane attack complex C5b–8, thus preventing maturation into the terminal pore-forming cytolytic complex. Phylogenetically, CD59 exhibits a broad taxonomic distribution in vertebrates, spanning from teleost to mammals, but CD59 is lacking in Cavia porcellus (guinea pig), where the CD59 gene has been transformed into a pseudogene [53]. A few rare cases of homozygous missense mutations leading to defective CD59 have been identified in humans [54,55,56,57].…”