Research paperEvolution of the growth hormone, prolactin, prolactin 2 and somatolactin family
Introduction
The growth hormone (GH), prolactin (PRL), prolactin 2 (PRL2) and somatolactin (SL) genes in vertebrates constitute a gene family within the large superfamily of class-1 helical cytokines (Huising et al., 2006). The four members share a common exon organization and the proteins display a characteristic conserved amino-acid framework with four cysteine residues forming two disulfide bridges that stabilize their tertiary four-helical structure (Pérez-Sánchez et al., 2002, Power, 2005, Whittington and Wilson, 2013). The four proteins share only about 25–30% amino acid sequence identity, and each one can display considerable variation in evolutionary rate across taxa, both among mammals (Wallis, 2014, Wallis, 2001, Wallis, 2000, Wallis et al., 2005) and teleost fishes (Ryynänen and Primmer, 2006). Nevertheless, the conserved cysteine framework, the exon organization of the genes and the binding properties define them as a monophyletic family within the cytokine superfamily (Huising et al., 2006). Despite sequence information from a vast number of species, it has remained unclear how the gene family was formed by gene duplications, and different proposals have been discussed extensively over the years (Bole-Feysot et al., 1998, Forsyth and Wallis, 2002, Kawauchi and Sower, 2006). The identification of only one family member, a GH-like sequence, in the jawless sea lamprey (Petromyzon marinus) (Kawauchi et al., 2002) was seen as evidence that the gene duplications that gave rise to GH, PRL and SL took place in an ancestor of jawed vertebrates (Gnathostomata), before their radiation (Kawauchi et al., 2002, Kawauchi and Sower, 2006). Subsequently lineage-specific gains and losses of genes occurred in both the ray-finned fish (Actinopterygii) and lobe-finned fish (Sarcopterygii) lineages. This includes the duplications and diversification of GH in primates (Papper et al., 2009, Wallis and Wallis, 2006), and PRL in rodents (Alam et al., 2006, Wiemers et al., 2003) and ruminants (Larson et al., 2006, Ushizawa et al., 2007b), producing the placental lactogens (PL) and prolactin-related proteins (Forsyth and Wallis, 2002). After the first identification of somatolactin in the olive flounder (Paralichthys olivaceus) (Ono et al., 1990) and Atlantic cod (Gadus morhua) (Rand-Weaver et al., 1991), this member of the hormone family has been identified in a multitude of teleost species (Benedet et al., 2008) as well as in the white sturgeon (Acipenser transmontanus) and the African lungfish (Protopterus annectens) (Amemiya et al., 1999, May et al., 1999). The latter findings demonstrated that all three hormones, including somatolactin, were present before the divergence of lobe-finned fishes and ray-finned fishes.
More recent discoveries complicate this view of the family’s evolution. We have previously reported the existence of PRL2 in teleost genomes and we noted that it likely emerged through the duplication of a large chromosome block (Ocampo Daza et al., 2009). The PRL2 gene had already been discovered in the green spotted pufferfish (Tetraodon nigroviridis) genome and named PRLb as part of the analysis of the draft genome sequence (Huising et al., 2006). Subsequently PRL2 was identified in a variety of vertebrate classes and characterized biologically with regard to tissue expression and receptor activation in several independent studies: The PRL2 gene was identified in elephant shark (Callorhinchus milii), Russian sturgeon (Acipenser gueldenstaedti) (Huang et al., 2009) and chicken (Gallus gallus) (Wang et al., 2010), showing that both PRL and PRL2 must have been present in a jawed vertebrate ancestor. This implies that the divergences between GH, the ancestral PRL/PRL2, and SL took place even earlier.
These findings lead to several important questions regarding the origin and diversification of this family of hormones. The origin of the first member is of special interest. Recent studies identified a putative GH-like homolog in the lancelet Branchiostoma japonicum and claimed to demonstrate its growth-promoting and osmoregulatory abilities (Li et al., 2017, Li et al., 2014). This was the first identification of a putative GH family gene and protein hormone in an invertebrate species, and led the authors to suggest that GH is the ancestral member, with PRL and SL emerging in the vertebrate lineage. Additionally, it is not clear whether the GH gene identified in the sea lamprey also represents the ancestor of all four genes in jawed vertebrates, or if there have been losses in this lineage.
Furthermore, the two types of SL, called SLa and SLb, first identified in cyprinid and salmonid fishes, have been suggested to have resulted from the basal teleost tetraploidization (3R) (Jaillon et al., 2004, Meyer and van de Peer, 2005). However, published analyses of sequence-based phylogeny (Benedet et al., 2008, Zhu et al., 2004) and conserved synteny (Fukamachi and Meyer, 2007) have been inconclusive.
In order to resolve these key questions, it becomes essential to determine whether the gene duplications that gave rise to GH, PRL, PRL2 and SL genes resulted from the two rounds of basal vertebrate tetraploidization (1R and 2R) (Dehal and Boore, 2005, Holland et al., 2008, Nakatani et al., 2007, Putnam et al., 2008). This may also shed light on the relationships of lamprey GH regardless of whether cyclostomes have undergone both 1R and 2R, or only 1R (Lagman et al., 2013, Mehta et al., 2013, Werner, 2013). The involvement of 1R and 2R in the emergence of the growth hormone family has not yet been thoroughly investigated, although it has been previously proposed (Forsyth and Wallis, 2002) and discussed in some detail (Huang et al., 2009, Ocampo Daza et al., 2009, Wang et al., 2010). The time points of the origin of the family and the gene duplications will be essential to understand the origin and evolution of many neuroendocrine functions mediated by the pituitary in vertebrates. These time points may subsequently be correlated with the time points for the corresponding receptor gene duplications to provide much needed context for comparative and evolutionary studies of hormone-receptor binding preferences. We recently reported that the growth hormone receptor and prolactin receptor genes GHR and PRLR arose as a result of a local gene duplication in a jawed vertebrate ancestor, and subsequently both genes were duplicated in the basal teleost tetraploidization (Ocampo Daza and Larhammar, 2017).
In the present study, we have combined comprehensive phylogenetic and chromosomal synteny analyses in order to shed light on the evolution of the growth hormone, prolactin, prolactin 2, and somatolactin family of hormones. This has posed a series of challenges, not only due to the low sequence identity and differential evolutionary rates between the family members as well as between species or lineages, but also because of differential losses in some lineages and, as we have come to realize during the course of this work, the dynamic evolutionary history of the chromosome regions harboring the GH, PRL, PRL2 and SL genes.
Section snippets
Sequence identification in vertebrate genome databases
GH, PRL, PRL2 and SL gene predictions were identified in the Ensembl genome browser (http://www.ensembl.org) and the National Center for Biotechnology Information (NCBI) genome resource (https://www.ncbi.nlm.nih.gov/genome/) by using gene orthology prediction and protein family functions (Fernández-Suárez and Schuster, 2010) as well as extensive TBLASTN searches (Altschul et al., 1990). For all such searches, hits were considered informative if expect values (E-values) were lower than 1e−30.
Nomenclature
For the human, mouse, chicken, Xenopus, and zebrafish genes, the approved gene symbols have been used, following the appropriate gene nomenclature guidelines for each species. Thus, we have applied the approved stem symbols GH for growth hormone genes, SL for somatolactin genes, PRL for “classical” prolactin genes, and PRL2 for the recently described PRL paralog genes. The numeral “1” was added to the PRL stem symbol only where duplicates of PRL could be confused for PRL2 genes, e.g. PRL1.2 and
Evolution of the GH, PRL, PRL2 and SL family
The evolution of the growth hormone family of genes has been extensively investigated over the years, including discussions of varying evolutionary rates in different vertebrate lineages (Ryynänen and Primmer, 2006, Wallis, 2001); the duplication and diversification of GH and PRL genes in some species (Soares, 2004, Wallis, 2014); as well as evolutionary aspects of receptor interactions (Chen et al., 2011, Ellens et al., 2013, Fukamachi and Meyer, 2007). In this study, we have investigated the
Acknowledgments
This work was supported by grants from the Swedish Research Council and Carl Trygger’s Foundation.
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