Ancient Transposable Elements Transformed the Uterine Regulatory Landscape and Transcriptome during the Evolution of Mammalian Pregnancy

Abstract

SUMMARY A major challenge in biology is determining how evolutionarily novel characters originate; however, mechanistic explanations for the origin of new characters are almost completely unknown. The evolution of pregnancy is an excellent system in which to study the origin of novelties because mammals preserve stages in the transition from egg laying to live birth. To determine the molecular bases of this transition, we characterized the pregnant/gravid uterine transcriptome from tetrapods to trace the evolutionary history of uterine gene expression. We show that thousands of genes evolved endometrial expression during the origins of mammalian pregnancy, including genes that mediate maternal-fetal communication and immunotolerance. Furthermore, thousands of cis-regulatory elements that mediate decidualization and cell-type identity in decidualized stromal cells are derived from ancient mammalian transposable elements (TEs). Our results indicate that one of the defining mammalian novelties evolved from DNA sequences derived from ancient mammalian TEs coopted into hormone-responsive regulatory elements distributed throughout the genome.

Transposable elements are the primary source of novelty in primate gene regulation

“…This suggests that even modest changes in gene regulation produce significant differences, and confirms that cis-regulatory evolution plays a central role in primate diversification (Davidson 2001(Davidson , 2006Wray 2007;Ho et al 2009;Tsankov et al 2010;Martin et al 2012;Coolon et al 2014;Martin and Reed 2014;Guo et al 2015;Lynch et al 2015;Villar et al 2015;Adachi et al 2016;Landeen et al 2016;Lesch et al 2016;Zhang and Reed 2016).…”

“…Similarly, the recruitment of novel regulatory networks in the uterus was likely mediated by ancient mammalian TEs (Lynch et al 2011(Lynch et al , 2015. Conversely, neocortical enhancers do not exhibit strong evidence of transposon co-option (Emera et al 2016).…”

“…Although previous studies have suggested a role for transposable elements (TEs) in the evolution of gene regulation, validating the functional contribution of TEs in mammalian gene regulation remains a challenge (McClintock 1950(McClintock , 1984Britten and Davidson 1969;Davidson and Britten 1979;Jordan et al 2003;Bejerano et al 2006;Wang et al 2007;Bourque et al 2008;Sasaki et al 2008;Markljung et al 2009;Kunarso et al 2010;Lynch et al 2011Lynch et al , 2015Schmidt et al 2012;Chuong et al 2013Chuong et al , 2016Jacques et al 2013;Xie et al 2013;del Rosario et al 2014;Sundaram et al 2014;Du et al 2016;Rayan et al 2016;Ward et al 2017).…”

Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes

“…A rapidly growing body of literature shows in different model systems Thompson et al 2016). Co-option of LTR sequences may have clear biological implications, as shown for human innate immunity (Chuong et al 2016), mammalian development (Chuong et al 2013;Lynch et al 2015;Nishihara et al 2016), evolution of mammalian gene regulatory networks (Xie et al 2010;Sundaram et al 2014), or RNA interference in mice (Flemr et al 2013). Our study represents a remarkable case of ERVL LTRs that function as gene-remodeling platforms that stochastically sculpt gene expression and function in oocytes and zygotes.…”

Potential impact of primate-specific SVA retrotransposons during the evolution of human cognitive function

“…23,24 BRCA1 is also known to have a strong role in the control of brain size, 25,26 especially in regions responsible for learning, memory, muscle control and balance. Interestingly, structurally related PGR (progesteronedependent transcription factor) binding sites were shown to be enriched in ancient mammalian TEs linked to evolution of pregnancy, 27 and LTR and Alu elements were also shown to be strongly associated with genes relevant to reproduction. 4 Moderate expression of the majority of behavioral-SVA-associated genes in male germ cells (in contrast to less than 10% though strongly, expressed in oocyte) could make this cell type a particular source of trans-mobilized SVA elements which are inheritable and passed on to following generations.…”