Co-option of an endogenous retrovirus (LTR7-HERVH) in early human embryogenesis: becoming useful and going unnoticed.

Abstract

While it is straightforward to understand why most mutations affecting functional sequence are harmful, how genomic changes result in new beneficial traits is harder to understand. Domestication of transposable elements (TEs) is an important source of both new genes and new regulatory systems as, for their own propagation, TEs need to have transcription factor binding sites and functional products that predispose to their recruitment. But are such predispositions to gain-of-function sufficient? Here we consider the case of the endogenous retrovirus, HERVH. Knockdown data supports HERVH having roles in pluripotency, self-renewal and defence against transpositionally-active retroelements in the early human embryo. We clarify the pluripotent cell types associated with HERVH expression and, in the process, note a key unresolved issue, framed by the unwanted transcript hypothesis: how can some cell types have 2% of their transcripts being HERVH-derived but survive the multiplicity of cellular devices that suppress foreign transcripts, be this by transcriptional repression or post-transcriptional filtering? We note a common coupling between novelty generation and suppression evasion. For example, pluripotency-associated KLF4 binding is thought to compete with transcriptional suppressor binding. Similarly, HERVH has a strong splice site enabling efficient novel chimeric transcript formation, the resulting exon-intron junctions enabling evasion of the unwanted transcript filters that recognize low or absent intron presence. We conclude that to better understand domestication, a focus on predispositions to avoidance of unwanted transcripts filters, as well as predispositions to gain of functions, is necessary. The same insights will be valuable for transgene design (eg for gene therapy) and instructive of gain-of-function in tumours, as HERVH is known to be involved in onco-exaptation events.