Evolution of the relaxin-like peptide family

BMC Evol Biol. 2005 Feb 12:5:14. doi: 10.1186/1471-2148-5-14.


Background: The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 peptides of high structural but low sequence similarity; relaxin-1, 2 and 3, and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, INSL6 remain uncharacterised. The evolution of this family has been contentious; high sequence variability is seen between closely related species, while distantly related species show high similarity; an invertebrate relaxin sequence has been reported, while a relaxin gene has not been found in the avian and ruminant lineages.

Results: Sequence similarity searches of genomic and EST data identified homologs of relaxin-like peptides in mammals, and non-mammalian vertebrates such as fish. Phylogenetic analysis was used to resolve the evolution of the family. Searches were unable to identify an invertebrate relaxin-like peptide. The published relaxin cDNA sequence in the tunicate, Ciona intestinalis was not present in the completed C. intestinalis genome. The newly discovered relaxin-3 is likely to be the ancestral relaxin. Multiple relaxin-3-like sequences are present in fugu fish (Takifugu rubripes) and zebrafish (Danio rerio), but these appear to be specific to the fish lineage. Possible relaxin-1 and INSL5 homologs were also identified in fish and frog species, placing their emergence prior to mammalia, earlier than previously believed. Furthermore, estimates of synonymous and nonsynonymous substitution rates (dN/dS) suggest that the emergence of relaxin-1, INSL4 and INSL6 during mammalia was driven by positive Darwinian selection, hence these peptides are likely to have novel and in the case of relaxin-1, which is still under positive selection in humans and the great apes, possibly still evolving functions. In contrast, relaxin-3 is constrained by strong purifying selection, demonstrating it must have a highly conserved function, supporting its hypothesized important neuropeptide role.

Conclusions: We present a phylogeny describing the evolutionary history of the relaxin-like peptide family and show that positive selection has driven the evolution of the most recent members of the family.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Dogs
  • Evolution, Molecular*
  • Humans
  • Insulin / classification*
  • Insulin / genetics
  • Mice
  • Molecular Sequence Data
  • Phylogeny*
  • Rats
  • Relaxin / classification*
  • Relaxin / genetics*
  • Sequence Alignment
  • Sequence Analysis, Protein


  • Insulin
  • Relaxin

Associated data

  • GENBANK/A34936
  • GENBANK/AB000201
  • GENBANK/AF233687
  • GENBANK/AF233688
  • GENBANK/AF254739
  • GENBANK/AF317625
  • GENBANK/BK005152
  • GENBANK/BK005251
  • GENBANK/L34838
  • GENBANK/S45940
  • GENBANK/S79879
  • GENBANK/S85964
  • GENBANK/X00948
  • GENBANK/Z27224
  • GENBANK/Z27228
  • GENBANK/Z27237
  • GENBANK/Z27245
  • GENBANK/Z27246