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


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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    • "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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    • "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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