Corticotropin-releasing hormone family evolution: five ancestral genes remain in some lineages

  1. Dan Larhammar2
  1. 1Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade do Algarve, Campus de Gambelas, Faro, Portugal
  2. 2Department of Neuroscience, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  1. Correspondence should be addressed to D Larhammar; Email: Dan.Larhammar{at}
  1. Figure 1

    Sequence alignment of the five deduced CRH family mature peptides in human, coelacanth, spotted gar, and elephant shark. The peptides were identified based on consensus proteolytic cleavage sites (Supplementary Data 1). Amino acids that have been maintained across all peptides are annotated with ‘*’. Positions shown marked with ‘:’ or “#” are the amino acids conserved within the CRH1/CRH2/UCN1 and UCN2/UCN3 subfamilies, respectively. Positions shown with ‘.’ are common to CRH1 and CRH2. The consensus peptide sequence for each subfamily is represented below and annotated in bold: upper case letters represent total conservation, small case letters indicate partial conservation and, gaps indicate nonconserved region. A full colour version of this figure is available at (

  2. Figure 2

    Phylogenetic relationship of the CRH family members in vertebrates. The phylogenetic tree was constructed using the mature peptide sequences (the most conserved regions of the peptide precursors) with the maximum likelihood (ML) method. Accession numbers of the sequences are shown in Table 1 and the sequence alignment is shown in Supplementary Fig. 1. The smelt (Osmerus mordax) Crh sequences were obtained from NCBI (Crha, ACO09991.1; Crhb ACO10011.1). The peptide subfamilies descendants of the two ancestral peptide clades are circled and annotated with colors: CRH1/CRH2/UCN1 in pink and UCN2/UCN3 in green. Only the sequences of Atlantic salmon Crha1 and Crhb1 are represented as their duplicates produce identical peptides. A full colour version of this figure is available at

  3. Figure 3

    Gene synteny analysis of the CRH1/CRH2/UCN1 and UCN2/UCN3 paralogons. Chromosomal locations of the CRH family members and neighboring genes in five different vertebrate clades are shown. The numbers to the left and right of the chromosome lines refer to chromosome or scaffold number. Gene positions (Mb) are given below each gene. The order of the genes on the chromosomes has been reshuffled and members of the same gene family were aligned to highlight the similarities both between species and between the chromosomes within each species, i.e. paralogon. The gene abbreviations stand for: CACNA2D, voltage-dependent calcium channel subunit alpha2delta family; CAMK/PCNK, Ca2+/calmodulin-dependent protein kinase family; GATA, GATA transcription factor family; HCK/LCK/BLK/LYN, tyrosine protein kinases; NCOA, nuclear receptor coactivator family; PLXNA, plexin A family; STMN, stathmin; XKR, X Kell blood group precursor-related family. A full colour version of this figure is available at

  4. Figure 4

    Proposed evolutionary duplication scheme for the vertebrate CRH family members and their receptors. The putative ancestral vertebrate genome regions that contained the ancestral CRH1/CRH2/UCN1 gene, the ancestral UCN2/UCN3 gene, and the ancestral CRHR gene are shown according to (Putnam et al. 2008). The tetraploidization events are marked as 1R, 2R, and 3R (teleost specific). Genes that were most likely lost soon after each tetraploidization are shown as white circles. The ucn2 gene in zebrafish and the CRH2 genes in chicken and human are represented as a color circles with a cross because they were lost in these particular species, but they exist in other species in these lineages. Similarly, for zebrafish crhr1 and crhr2 and for the elephant shark CRHR genes, data were retrieved from our previous study (Cardoso et al. 2014). The identity of the cyclostome CRH family remains to be confirmed and they are represented by dashed circles and CRHR members were obtained from (Cardoso et al. 2014). The tree was drawn respecting the proposed divergence times (million years ago) of the vertebrate lineages represented according to the mean of different studies given by Elasmobranchii-Euteleostomi (±488 MYA); Actinopterygii-Sarcopterygii (±436 MYA); Latimeria-Tetrapoda (±413 MYA); Lepisosteiformes-Teleostei (±325 MYA); and Aves-Mammalian (±320 MYA). Agnatha-Gnathostomes (±500 MYA) was taken from (Kuraku & Kuratani 2006). A full colour version of this figure is available at

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