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

Abstract

Endogenous Retroviruses (ERVs) are ancient relics of infections that affected the primate germ line and constitute about 8% of our genome. Growing evidence indicates that ERVs had a major role in vertebrate evolution, being occasionally domesticated by the host physiology. In addition, human ERV (HERV) expression is highly investigated for a possible pathological role, even if no clear associations have been reported yet. In fact, on the one side, the study of HERV expression in high-throughput data is a powerful and promising tool to assess their actual dysregulation in diseased conditions; but, on the other side, the poor knowledge about the various HERV group genomic diversity and individual members somehow prevented the association between specific HERV loci and a given molecular mechanism of pathogenesis. The present study is focused on the HERV-K(HML7) group that—differently from the other HERV-K members—still remains poorly characterized. Starting from an initial identification performed with the software RetroTector, we collected 23 HML7 proviral insertions and about 160 HML7 solitary LTRs that were analyzed in terms of genomic distribution, revealing a significant enrichment in chromosome X and the frequent localization within human gene introns as well as in pericentromeric and centromeric regions. Phylogenetic analyses showed that HML7 members form a monophyletic group, which based on age estimation and comparative localization in non-human primates had its major diffusion between 20 and 30 million years ago. Structural characterization revealed that besides 3 complete HML7 proviruses, the other group members shared a highly defective structure that, however, still presents recognizable functional domains, making it worth further investigation in the human population to assess the presence of residual coding potential.

Comprehensive identification and characterization of the HERV-K (HML-9) group in the human genome

“…The assembled LTR14C-HERVK14C-LTR14C in the current work is from the Dfam database. Additionally, the expected distribution of the HML-9 loci on each chromosome was predicted according to the formula e = Cl × n/Tl (e is the number of integrations expected in the chromosome, Cl represents the ungapped length of the chromosome, n is the total number of actual HML-9 loci identified in the human genome, and Tl represents the sum ungapped length of all chromosomes) [ 49 ]. The difference between the expected number of integrations and the actual number of HML-9 loci was analyzed via the chi-square (χ 2 ) test, and statistical significance was estimated according to the p value.…”

Human endogenous retroviruses in development and disease

“…Software tools have also been developed specifically to assist in the identification and characterization of ERVs, such as RetroTector [17] , [18] . Benefit from the new resources in genetics, several works collected and analyzed the coordinates of specific HERV families, including HERV-K (HML-2) [19] , HERV-K (HML-6) [20] , HERV-K (HML-7) [21] , HERV-K (HML-10) [22] , and HERV-W [23] . Furthermore, a recent study provided a reference of global population diversity in HERV-K proviruses at all currently known polymorphic loci in the human genome and revealed notable differences in the prevalence of HERV-Ks in different global populations and in the total number of HERV-Ks currently known to be polymorphic within a person’s genome [24] .…”

Comprehensive identification and characterization of HERV-K (HML-9) group in the human genome

“…Until now, the characterization and identi cation of HML1-8, and HML10 groups have been carried out [9,42,51,[53][54][55][56][57][58]. However, there are only very few incomplete characterizations and research for HML-9 at present.…”

“…The assembled LTR14C-HERVK14C-LTR14C sequence was used as a query. Additionally, the expected distribution of the HML-9 loci in each chromosome were predicted according to the formula: e = Cl * n / Tl (e is the number of integrations expected in the chromosome, Cl represents the ungapped length of the chromosome, n is the total number of actual HML-9 loci identi ed in the human genome, and Tl represents the sum ungapped length of all chromosome) [42]. The variation of the expected integrations was compared to the actual number of HML-9 loci through a chi-square (χ 2 ) test, and its statistical signi cance was estimated through the p-value.…”