Lynch, V. J. et al. Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals. Proc. Natl Acad. Sci. USA 105, 14928-14933

Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2008; 105(39):14928-33. DOI: 10.1073/pnas.0802355105
Source: PubMed

ABSTRACT Evolutionary change in gene regulation can result from changes in cis-regulatory elements, leading to differences in the temporal and spatial expression of genes or in the coding region of transcription factors leading to novel functions or both. Although there is a growing body of evidence supporting the importance of cis-regulatory evolution, examples of protein-mediated evolution of novel developmental pathways have not been demonstrated. Here, we investigate the evolution of prolactin (PRL) expression in endometrial cells, which is essential for placentation/pregnancy in eutherian mammals and is a direct regulatory target of the transcription factor HoxA-11. Here, we show that (i) endometrial PRL expression is a derived feature of placental mammals, (ii) the PRL regulatory gene HoxA-11 experienced a period of strong positive selection in the stem-lineage of eutherian mammals, and (iii) only HoxA-11 proteins from placental mammals, including the reconstructed ancestral eutherian gene, are able to up-regulate PRL from the promoter used in endometrial cells. In contrast, HoxA-11 from the reconstructed therian ancestor, opossum, platypus, and chicken are unable to up-regulate PRL expression. These results demonstrate that the evolution of novel gene expression domains is not only mediated by the evolution of cis-regulatory elements but can also require evolutionary changes of transcription factor proteins themselves.

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    • "Similarly, the N-terminal motif of the Daphnia Antennapedia protein has also been implicated in the evolution of their specific appendage morphology (Shiga et al., 2002). Lynch et al. (2008) presented evidence that modification to HoxA-11 was essential in the evolution of mammalian pregnancy, as the modified protein has acquired a novel regulatory relationship with the prolactin gene. These studies have revealed that the evolution of morphology is driven not only by the molecular evolution of cisregulatory elements but also by the evolution of protein coding sequences. "
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    Developmental Biology 11/2013; 385(2). DOI:10.1016/j.ydbio.2013.11.010 · 3.55 Impact Factor
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    • "Therefore, it is particularly intriguing to understand the role of Hox cluster duplications in the evolution of vertebrate body plans and novelty (Holland et al. 1994; Malaga-Trillo and Meyer 2001; Wagner et al. 2003; Prohaska and Stadler 2004). For example, the posterior (5 0 ) Hox genes including paralog groups (PGs) Hox13, Hox12, and Hox11 have been implicated in the evolution of a variety of tetrapod novelties such as the autopod/ thumb in humans (Shubin et al. 1997), flippers in cetaceans (Wang et al. 2009), and genital/urogenital organs in various tetrapods (Warot et al. 1997; Lynch et al. 2008; Sifuentes- Romero et al. 2010). With respect to the TSGD, there are several examples of asymmetric evolution and functional divergence of duplicate gene paralogs, or " ohnologs " when derived from WGD (Wolfe 2000; Byrne and Wolfe 2005), that are associated with novel features in both non-Hox and Hox genes. "
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    ABSTRACT: Vertebrates have experienced two rounds of whole-genome duplication (WGD) in the stem lineages of deep nodes within the group and a subsequent duplication event in the stem lineage of the teleosts-a highly diverse group of ray-finned fishes. Here, we present the first full Hox gene sequences for any member of the Acipenseriformes, the American paddlefish, and confirm that an independent WGD occurred in the paddlefish lineage, approximately 42 Ma based on sequences spanning the entire HoxA cluster and eight genes on the HoxD gene cluster. These clusters comprise different HOX loci and maintain conserved synteny relative to bichir, zebrafish, stickleback, and pufferfish, as well as human, mouse, and chick. We also provide a gene genealogy for the duplicated fzd8 gene in paddlefish and present evidence for the first Hox14 gene in any ray-finned fish. Taken together, these data demonstrate that the American paddlefish has an independently duplicated genome. Substitution patterns of the "alpha" paralogs on both the HoxA and HoxD gene clusters suggest transcriptional inactivation consistent with functional diploidization. Further, there are similarities in the pattern of sequence divergence among duplicated Hox genes in paddlefish and teleost lineages, even though they occurred independently approximately 200 Myr apart. We highlight implications on comparative analyses in the study of the "fin-limb transition" as well as gene and genome duplication in bony fishes, which includes all ray-finned fishes as well as the lobe-finned fishes and tetrapod vertebrates.
    Genome Biology and Evolution 07/2012; 4(9):825-41. DOI:10.1093/gbe/evs067 · 4.23 Impact Factor
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    • "Thus the relatively large average size (King and Wilson 1975; Tuch et al. 2008) and low pleiotropy of mutations in cis-regulatory regions may explain how with fewer mutations these structures can contribute substantially to phenotypic evolution. It is probable that genetic adaptation involves a combined effect of protein-coding and cis-regulatory changes (Hanikenne et al. 2008; Lynch et al. 2008; Tuch et al. 2008). For example, after gene duplication and subfunctionalization, protein-coding mutations could fine-tune some protein function and cis-regulatory mutations could specify regulatory expression for this function (Zhang 2003). "
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    ABSTRACT: A long-standing debate in evo-devo research concerns the relative role of protein-coding and cis-regulatory regions in adaptation. Recent studies of genetic adaptation have revealed that the number of substitutions contributing to phenotypic variation is lower in cis-regulatory than in structural regions, which has led to the idea that cis-regulatory regions are less important in phenotypic adaptation. However, the number of substitutions is not the only important factor, the "size" of the adaptive contribution of these substitutions is important too. A geometrical reasoning predicts that, given their lesser pleiotropic effects, cis-regulatory substitutions should have a larger average adaptive contribution than protein-coding substitutions. Thus it is possible that even with a lower number of adaptive mutations, cis-regulatory regions may contribute at the same level or even more than protein-coding regions.
    Evolution 11/2011; 65(11):3332-5. DOI:10.1111/j.1558-5646.2011.01412.x · 4.61 Impact Factor
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