Abstract
Acquisition of cis-elements is a major driving force for rewiring a gene regulatory network. Several kinds of transposable elements (TEs), mostly retrotransposons that propagate via a copy-and-paste mechanism, are known to possess transcription factor binding motifs and have provided source sequences for enhancers/promoters. However, it remains largely unknown whether retrotransposons have spread the binding sites of master regulators of morphogenesis and accelerated cis-regulatory expansion involved in common mammalian morphological features during evolution. Here, I demonstrate that thousands of binding sites for estrogen receptor α (ERα) and three related pioneer factors (FoxA1, GATA3 and AP2γ) that are essential regulators of mammary gland development arose from a spreading of the binding motifs by retrotransposons. The TE-derived functional elements serve primarily as distal enhancers and are enriched around genes associated with mammary gland morphogenesis. The source TEs occurred via a two-phased expansion consisting of mainly L2/MIR in a eutherian ancestor and endogenous retrovirus 1 (ERV1) in simian primates and murines. Thus the build-up of potential sources for cis-elements by retrotransposons followed by their frequent utilization by the host (co-option/exaptation) may have a general accelerating effect on both establishing and diversifying a gene regulatory network, leading to morphological innovation.
Highlights
Mammals share various common morphological features, but the evolutionary process responsible for the establishment of the cis-regulatory systems involved in their development is largely unknown
The proportion of Transposable elements (TEs) in protein coding sequences (CDSs) and conserved non-coding elements (CNEs) that are under purifying selection was found to be only 0.4% and 3.7%, respectively (Figure 1B), suggesting a general view that most TEs rarely contribute to putative functional sequences in spite of their large fraction in the genome (48%)
At least two-thirds of the binding sites were derived from non-TE sequences, it should be noted that larger percentages of them are represented by MIR SINE, L2 LINE, and endogenous retrovirus (ERV1 and ERVL) sequences relative to CDSs/CNEs and even to the human genome
Summary
Mammals share various common morphological features, but the evolutionary process responsible for the establishment of the cis-regulatory systems involved in their development is largely unknown. Several TE copies under purifying selection have acquired enhancer/promoter functions for developmental genes involved in morphological evolution in mammals [7,8,9,10,11]. These examples, explain only a small fraction of the TE population, and it remains unknown how large numbers of TEs have been co-opted and have contributed to the evolution of morphological novelties in mammals
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