High-Throughput Sequencing is a Crucial Tool to Investigate the Contribution of Human Endogenous Retroviruses (HERVs) to Human Biology and Development

Abstract

Human Endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that represent a large fraction of our genome. Their transcriptional activity is finely regulated in early developmental stages and their expression is modulated in different cell types and tissues. Such activity has an impact on human physiology and pathology that is only partially understood up to date. Novel high-throughput sequencing tools have recently allowed for a great advancement in elucidating the various HERV expression patterns in different tissues as well as the mechanisms controlling their transcription, and overall, have helped in gaining better insights in an all-inclusive understanding of the impact of HERVs in biology of the host.

HERV-K(HML7) Integrations in the Human Genome: Comprehensive Characterization and Comparative Analysis in Non-Human Primates

“…As expected from their general defective structure, the great majority of HML7 proviruses lost most of the functional domains normally predicted in retroviral sequences and, among the one with highest integrity as identified by RetroTector, none present intact ORFs due to the introduction of internal stop codons and frameshifts ( Table 3 ). However, one should consider that these predictions were based on the proviral sequences identified in human genome assembly; it is hence possible that individual human genomes still hold HML7 loci with residual coding potential, deserving further investigations in transcriptomic data [ 41 ]. Concerning typical Class II structural features, as in the other HERV-K groups, HML7 elements also present two Gag NC Zinc-fingers as well as a dUTPase domain at the N-terminal of Pro.…”

“…Overall, the comprehensive characterization of the HML7 group composition, localization, and dynamics of diffusion in primates here presented provides for the first time an exhaustive genomic description of this poorly investigated group. This opens the field to the study of individual HML7 elements’ specific variation within human population, their residual transcriptional activity in the different tissues and—by consequence—their eventual modulation in diseased conditions, to unveil unknown contributions of the group to human evolution and physiopathology [ 41 ]. The latter can be multifaceted and are however the result of complex interactions with the different tissues/cellular systems rather than on a general mechanism of HERV activation.…”

Human Endogenous Retroviruses (HERVs) and Mammalian Apparent LTRs Retrotransposons (MaLRs) Are Dynamically Modulated in Different Stages of Immunity

“…LTR-retrotransposons accumulated several mutations over time, and solitary LTRs were generated by recombination occurrences [ 3 , 4 , 5 ]. Despite that, both solo LTRs and proviral MaLRs/HERVs can contribute to human biology and development [ 6 , 7 , 8 ]. Indeed, the sequence of solo- and proviral LTRs includes enhancers, promoters, and polyadenylation signals that may modify the expression of neighboring cellular genes [ 6 , 9 , 10 ].…”

“…Despite that, both solo LTRs and proviral MaLRs/HERVs can contribute to human biology and development [ 6 , 7 , 8 ]. Indeed, the sequence of solo- and proviral LTRs includes enhancers, promoters, and polyadenylation signals that may modify the expression of neighboring cellular genes [ 6 , 9 , 10 ]. Moreover, some HERV loci maintain intact retroviral ORFs and are expressed in human tissues [ 6 , 11 , 12 ].…”

Editorial Overview: Endogenous Retroviruses in Development and Disease

“…To make the problem harder, many of these loci are polymorphic within populations and are likely to differ, for any individual, from those present in the current reference genomes. The review by Pisano et al [ 1 ] in this issue describes these problems in depth and discusses how well current sequencing methods can address them.…”