Convergent Evolution of Endometrial Prolactin Expression in Primates, Mice, and Elephants Through the Independent Recruitment of Transposable Elements

Abstract

Prolactin (PRL) is a multifunctional signaling molecule best known for its role in regulating lactation in mammals. Systemic PRL is produced by the anterior pituitary, but extrapituitary PRL has also been detected in many tissues including the human endometrium. Prolactin is essential for pregnancy in rodents and one of the most dramatically induced genes in the endometrium during human pregnancy. The promoter for human endometrial Prl is located about 5.8 kb upstream of the pituitary promoter and is derived from a transposable element called MER39. Although it has been shown that prolactin is expressed in the pregnant endometrium of a few mammals other than humans, MER39 has been described as primate specific. Thus, in an effort to understand mechanisms of prolactin regulatory evolution, we sought to determine how uterine prolactin is transcribed in species that lack MER39. Using a variety of complementary strategies, including reverse transcriptase-polymerase chain reaction, 5' rapid amplification of cDNA ends, and whole-transcriptome sequencing, we show that endometrial Prl expression is not a shared character of all placental mammals, as it is not expressed in rabbits, pigs, dogs, or armadillos. We show that in primates, mice, and elephants, prolactin mRNA is transcribed in the pregnant endometrium from alternative promoters, different from the pituitary promoter and different from each other. Moreover, we demonstrate that the spider monkey promoter derives from the long terminal repeat (LTR) element MER39 as in humans, the mouse promoter derives from the LTR element MER77, and the elephant promoter derives from the lineage-specific LINE retrotransposon L1-2_LA. We also find surprising variation of transcriptional start sites within these transposable elements and of Prl splice variants, suggesting a high degree of flexibility in the promoter architecture even among closely related species. Finally, the three groups shown here to express endometrial prolactin-the higher primates, the rodents, and the elephant-represent three of the four lineages that showed adaptive evolution of the Prl gene in an earlier study (Wallis M. 2000. Episodic evolution of protein hormones: molecular evolution of pituitary prolactin. J Mol Evol. 50:465-473), which supports our findings and suggests that the selective forces responsible for accelerated Prl evolution were in the endometrium. This is the first reported case of convergent evolution of gene expression through the independent recruitment of different transposable elements, highlighting the importance of transposable elements in gene regulatory, and potentially adaptive, evolution.

Transformation of a transposon into a derived prolactin promoter with function during human pregnancy

“…An arrow indicates that a region has promoter activity; size of arrow indicates strength of promoter. Note that strength of mouse promoter has not been tested but location has been determined; rabbits do not express decidual prolactin, so their MER20/ MER39 region is assumed here to lack a promoter (5). Also note that the presence of decidual prolactin transcripts has not been tested in lemurs.…”

“…In a recent paper we showed that the prolactin gene was independently recruited into uterine expression in primates, mice, and elephants by the co-option of different transposable elements, highlighting the frequency at which TEs can be recruited and their importance in gene regulatory innovation (5). Here we trace the evolutionary history and function of transposable elements in one of these groups-the primates-to understand precisely how uterine prolactin expression evolved via these elements, and why.…”

A review of inter- and intraspecific variation in the eutherian placenta

“…Prolactin (Prl) for example, a gene involved in regulating lactation in placental mammals, has many alternative transcripts [33]. Placental mammals such as dogs and armadillos show no evidence of a myometrial Prl transcript, while humans, some New World monkeys, mice and elephants all express Prl transcripts; however, each species expresses different splice variants with alternative transcription start sites [34]. Another gene that has multiple alternative transcripts across the placental mammals is the gene encoding aromatase (CYP19).…”

Sameness, novelty, and nominal kinds

“…Consider the expression of prolactin (PRL) in the endometrium of elephants, rodents, and primates but not in the endometrium of rabbits, pigs, dogs, armadillos, or opossums (Emera et al 2012). Three independent origins of endometrial PRL expression are associated with insertions from four families of transposable elements (TEs) that occurred at different times during mammalian evolution (Lynch et al 2008;Emera et al 2012).…”

“…Three independent origins of endometrial PRL expression are associated with insertions from four families of transposable elements (TEs) that occurred at different times during mammalian evolution (Lynch et al 2008;Emera et al 2012). Some insertions were not associated with endometrial expression for many millions of years (Emera and Wagner 2012a).…”