Evolution of the Relaxin/Insulin-like Gene Family in Placental Mammals: Implications for Its Early Evolution

Abstract

The relaxin (RLN) and insulin-like (INSL) gene family is a group of genes involved in a variety of physiological roles that includes bone formation, testicular descent, trophoblast development, and cell differentiation. This family appears to have expanded in vertebrates relative to non-vertebrate chordates, but the relative contribution of whole genome duplications (WGDs) and tandem duplications to the observed diversity of genes is still an open question. Results from our comparative analyses favor a model of divergence post vertebrate WGDs in which a single-copy progenitor found in the last common ancestor of vertebrates experienced two rounds of WGDs before the functional differentiation that gave rise to the RLN and INSL genes. One of the resulting paralogs was subsequently lost, resulting in three proto-RLN/INSL genes on three separate chromosomes. Subsequent rounds of tandem gene duplication and divergence originated the set of paralogs found on a given cluster in extant vertebrates. Our study supports the hypothesis that differentiation of the RLN and INSL genes took place independently in each RLN/INSL cluster after the two WGDs during the evolutionary history of vertebrates. In addition, we show that INSL4 represents a relatively old gene that has been apparently lost independently in all Euarchontoglires other than apes and Old World monkeys, and that RLN2 derives from an ape-specific duplication.

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

“…Copy number variation is also minimal in the RFLB locus in most mammalian species with the exception of primates ( Fig. 1; Park et al 2008a;Arroyo et al 2012;Hoffmann and Opazo 2011). In most mammals the RFLB locus contains two genes: a single copy of a relaxin-like gene, labeled as either RLN or RLN2, and a single copy of an ortholog of the human INSL6 gene, but primates show additional variation in the number and nature of genes in this locus ( Fig.…”

“…The number and nature of genes in these three loci is well conserved in most mammalian groups. The RFLA locus contains an ortholog of the human INSL5 gene, which has remained as a single-copy gene in all species surveyed, and the RFLC locus contains orthologs of the human INSL3 and RLN3 genes, which have also remained as single-copy genes in all species surveyed (Park et al 2008a, Arroyo et al 2012, Hoffmann and Opazo 2011. Copy number variation is also minimal in the RFLB locus in most mammalian species with the exception of primates ( Fig.…”

“…In most mammals the RFLB locus contains two genes: a single copy of a relaxin-like gene, labeled as either RLN or RLN2, and a single copy of an ortholog of the human INSL6 gene, but primates show additional variation in the number and nature of genes in this locus ( Fig. 1; Bièche et al 2003;Park et al 2008a, b;Arroyo et al 2012;Hoffmann and Opazo 2011). For example, haplorhines primates, the group that includes tarsiers, New World monkeys, Old World monkeys and apes, also posses a copy of INSL4 at this locus (Bièche et al 2003;Park et al 2008a, b;Arroyo et al 2012), and apes also posses duplicated RLN1 and RLN2 paralogs.…”

“…Morris Goodman (1981Goodman ( , 1982 postulated that in the first stages of functional differentiation the amino acid changes that remodel the molecule could be driven to fixation by positive Darwinian selection, whereas at later stages the previously fixed changes would be preserved by purifying selection so as to maintain the newly acquired physiological role. In this regard the relaxin gene family represents an interesting model system to explore the interplay between gene duplication and functional differentiation in originating a group of genes with a variety of physiological functions (Sherwood 2004;Wilkinson et al 2005;Arroyo et al 2012;Hoffmann and Opazo 2011).…”

The Power of an Evolutionary Perspective in Studies of Endocrinology

“…The gene number increases with genome size, and morphological complexity is mostly generated by expanding the sizes of gene families rather than due to a growth of the number of unique gene types, hence multicellular organisms employ large sets of similar gene products while exhibiting extraordinary biodiversity. The elements of endocrine systems often group into families (e.g., hormones and their specific receptors), whose members have diverged to various extents in regulation and function (Danks et al 2011;Hoffmann and Opazo 2011;Irwin 2010;Kim et al 2011;Sundström, Dreborg and Larhammar 2010). Gene duplication is the most important mechanism for generating new genes and new biochemical processes and has facilitated the evolution of biodiversity and complexity (Li 2006;Ohno 1970).…”