Gene Duplication and Positive Selection Explains Unusual Physiological Roles of the Relaxin Gene in the European Rabbit

Abstract

The relaxin gene family is a group of genes involved in different physiological roles, most of them related to reproduction. In vertebrates the genes in this family are located in three separate chromosomal locations, and have been called relaxin family locus (RFL) A, B, and C. Among mammals the RFLA and RFLC are the most conserved as no gene copy-number variation has been observed thus far. The RFLB locus is also conserved on most mammals other than primates, where there are several gene gains and losses. Interestingly, the relaxin gene found on the RFLB locus in the European rabbit has acquired a novel role. In addition to the classical reproductive roles, this gene is expressed in tracheobronchial epithelial cells and its expression has been linked to squamous differentiation. We reconstructed the evolutionary history of the European rabbit RFLB locus using the tools of comparative genomics and molecular evolution. We found that the European rabbit possess a RFLB locus which is unique among mammals in that there are five tandemly arranged relaxin gene copies, which contrast with the single relaxin copy gene found in most mammals. In addition we also found that the ancestral pre-duplication gene was subject to the action of positive selection, and several amino acid sites were identified under the action of natural selection including the sites B12 and B13 which are part of the receptor recognition and binding site.

New Insights into Ligand-Receptor Pairing and Coevolution of Relaxin Family Peptides and Their Receptors in Teleosts

“…While RXFP1 genes in mammals and teleosts have evolved in similar ways, the gene coding for the hormone relaxin, rln, has been subject to purifying and neutral evolution in teleosts, but has been the target of strong positive selection in mammals (see Figure 5(c), Table S3). In accordance with two recent studies showing the strong role of selection on the relaxin locus [25, 26], we find that approximately 50% of the codons in mammalian RLN show evidence of positive selection, whereas no sites in teleost rln do. Additionally, the qPCR expression pattern of rxfp1 in zebrafish shows broad but low levels of expression across multiple tissues, including gonad and brain.…”

“…It is interesting that the RLN/INSL peptides diversified their reproductive functions in mammals, owing to local duplications at the relaxin locus [23, 25, 26, 29], while teleosts underwent a massive diversification of the genes believed to be involved in neuroendocrine regulation ( rln3 / insl5 - rxpf3/4 ). Overall, we find evidence that many of these “additional” receptor genes in teleosts have characteristics of the RLN3-RXFP3 system, that is, slow evolution and predominant expression in the brain, while the primary receptors for the two Insl5 paralogs in teleosts remain obscure.…”

The comparative landscape of duplications in Heliconius melpomene and Heliconius cydno

“…There are now many examples in which gene duplicates provide the genetic fuel for adaptation, and have been shown to be under positive selection (Beisswanger and Stephan, 2008; Arroyo et al , 2012; Blount et al , 2012). Here, we are specifically interested in speciation.…”

Evolution of the Relaxin/Insulin-Like Gene Family in Anthropoid Primates

“…The number and nature of genes in these three genomic loci are well conserved in most mammalian lineages, with the exception of the RFLB locus (Park et al 2008; Hoffmann and Opazo 2011; Arroyo, Hoffmann, Good, et al 2012; Arroyo, Hoffmann, Opazo 2012a, 2012b). This locus possess a complex duplicative history characterized by small-scale duplications and differential gene retention, where the relative age of many genes is not consistent with their phyletic distribution (Hoffmann and Opazo 2011; Arroyo, Hoffmann, Good, et al 2012; Arroyo, Hoffmann, Opazo 2012a, 2012b).…”

“…This locus possess a complex duplicative history characterized by small-scale duplications and differential gene retention, where the relative age of many genes is not consistent with their phyletic distribution (Hoffmann and Opazo 2011; Arroyo, Hoffmann, Good, et al 2012; Arroyo, Hoffmann, Opazo 2012a, 2012b). For example, the INSL4 gene, also called placentin, is restricted to catarrhine primates but derives from a duplication event in the last common ancestor of placental mammals (Bieche et al 2003; Park et al 2008; Park, Semyonov, et al 2008; Arroyo, Hoffmann, Good, et al 2012; Arroyo, Hoffmann, Opazo 2012b).…”