Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions - PubMed (original) (raw)

Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions

J W Thornton. Proc Natl Acad Sci U S A. 2001.

Abstract

The evolution of novelty in tightly integrated biological systems, such as hormones and their receptors, seems to challenge the theory of natural selection: it has not been clear how a new function for any one part (such as a ligand) can be selected for unless the other members of the system (e.g., a receptor) are already present. Here I show-based on identification and phylogenetic analysis of steroid receptors in basal vertebrates and reconstruction of the sequences and functional attributes of ancestral proteins-that the first steroid receptor was an estrogen receptor, followed by a progesterone receptor. Genome mapping and phylogenetic analyses indicate that the full complement of mammalian steroid receptors evolved from these ancient receptors by two large-scale genome expansions, one before the advent of jawed vertebrates and one after. Specific regulation of physiological processes by androgens and corticoids are relatively recent innovations that emerged after these duplications. These findings support a model of ligand exploitation in which the terminal ligand in a biosynthetic pathway is the first for which a receptor evolves; selection for this hormone also selects for the synthesis of intermediates despite the absence of receptors, and duplicated receptors then evolve affinity for these substances. In this way, novel hormone-receptor pairs are created, and an integrated system of increasing complexity elaborated. This model suggests that ligands for some "orphan" receptors may be found among intermediates in the synthesis of ligands for phylogenetically related receptors.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Phylogeny of the steroid receptor gene family. A reduced version is shown of the single most parsimonious phylogeny of 73 receptor sequences when the relative weight of gene duplications/losses to amino acids w > 3. (Length = 3,209 aa changes + 8 duplications + 0 losses. For unreduced phylogeny, see Fig. 7, which is published as supplemental data.) Support for each clade is shown as the number of extra steps required for the labeled node not to appear in the most parsimonious tree (19); all support values are insensitive to_w_ except *, shown for w = 10. Blue circles indicate gene duplications within the steroid receptor family; red squares mark the lamprey–gnathostome divergence; and unmarked nodes represent other speciation events. Ancestral steroid receptors are indicated. Italicized node labels correspond to Fig. 3. Tree length = 3,209 aa changes, eight duplications, zero losses; consistency index = 0.628; retention index = 0.870.

Figure 2

Figure 2

Steroid receptors diversified by large-scale genome expansions. Paralogous members of gene families with two or more members on the same chromosomes as the human 3-ketosteroid receptors are shown, without regard to map order.

Figure 3

Figure 3

Divergence rates of steroid receptor sequences after gene duplications indicate that the first steroid receptor was an estrogen receptor. Grouped bars show the ratio of the rate of amino acid replacement on the upper branch to that in the lower. White bars, rate ratio based on the relative rate test; black bars, ratio of parsimony branch lengths; hatched bars, ratio of maximum likelihood branch lengths. Outgroups for relative rate tests, from top to bottom, are estrogen-related receptors (ERRs), tetrapod ERs, lamprey PR, and lamprey GR. *, statistically significant departure from unity, P < 0.001. Parsimony and likelihood branch lengths are proportional to the number of weighted amino acid changes on paralogous branches that descend from duplication of an ancestral steroid receptor to an equivalent speciation event, with labels corresponding to nodes in Fig. 1.

Figure 4

Figure 4

Maximum likelihood reconstructions of ancestral sequences indicate that the first steroid receptor was an estrogen receptor and the first 3-ketosteroid receptor was not an androgen receptor. (a) Aligned amino acids forming the ligand-binding pocket of the ancestral steroid receptor (AncSR1), the ancestral 3-ketosteroid receptor (AncSR2), and five human steroid receptors, based on homology to human steroid receptors with solved structures. Colors and residue numbers refer to the positions shown in b. Filled circles (●) indicate amino acids identical to AncSR1; small dots are identical to AncSR2 but not AncSR1. Red, amino acids making direct hydrogen bonds with ligands (32, 33); blue, residues critical to discriminate androgens from C21 steroids in the androgen receptor (35). Amino acid numbers of homologous positions in the crystallized human receptors are at right; parentheses indicate positions that do not contact ligand in the indicated receptor. (b) Schematic of the ligand-binding pocket of ancestral steroid receptors with generic steroid hormone, based on homology to the crystal structures of human ERα and human PR (32, 33). Red and blue residues as in a. Yellow circles marked “R” indicate substituents that vary among steroid hormones.

Figure 5

Figure 5

Reconstruction of ligand-binding characteristics of ancestral steroid receptors indicates that the ancestral 3-ketosteroid receptor did not bind corticoids. Substituents at critical positions of the ligands that each vertebrate receptor binds were coded as characters (Right). Character states at ancestral nodes were reconstructed on the reduced phylogeny of steroid receptor paralogs with a parsimony-based algorithm, and the inferred structures of the ligands bound by each ancestral receptor are shown (Left); colored groups correspond to characters in the matrix. ?, substituent groups that could not be unambiguously reconstructed; NA, not applicable. P, progesterone; E2, estradiol; T, testosterone; B, corticosterone; F, cortisol; Aldo, aldosterone.

Similar articles

Cited by

References

    1. Dawkins R. The Blind Watchmaker. New York: W. W. Norton; 1986.
    1. Kauffman S A. The Origins of Order: Self-Organization and Selection in Evolution. Oxford: Oxford Univ. Press; 1993.
    1. Thornton J W, DeSalle R. Syst Biol. 2000;49:183–201. - PubMed
    1. Ohno S. Evolution by Gene Duplication. Berlin: Springer; 1970.
    1. Fryxell K J. Trends Genet. 1996;12:364–369. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources