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. 2021 May 14;10(5):439.
doi: 10.3390/biology10050439.

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

Nicole Grandi  1 , Maria Paola Pisano  1 , Eleonora Pessiu  1 , Sante Scognamiglio  1 , Enzo Tramontano  1   2
Affiliations

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

Nicole Grandi et al. Biology (Basel). .

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.

Keywords: HERV; HERV-K; HML7; endogenous retroviruses; retrotransposons.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chromosomal distribution of HML7 loci. In the upper part of the figure, HML7 proviruses (red arrows) and solitary LTRs (blue lines) have been visualized on the human karyotype (source: www.ensembl.org (accessed on 30 March 2021)). In the lower part of the figure, the observed chromosomal distribution of HML7 elements was statistically compared to the expected one, showing significant decrease in chromosome 15 and enrichment in chromosome X integrations.
Figure 2
Figure 2
Structural characterization of HML7 proviral loci. The identified HML7 proviruses have been aligned with the Dfam proviral reference, and all insertions and deletions ≥1 nucleotide have been annotated.
Figure 3
Figure 3
Phylogenetic tree of HML7 proviral loci. The identified HML7 proviruses were analyzed with the maximum likelihood method, including also the Dfam reference proviral sequences of all HERV-K groups (HML1 to HML10). Phylogenies have been statistically tested through the bootstrap method with 100 replicates. The monophyletic group formed by the HML7 proviruses and including the HML7 group Dfam reference (black dot) is highlighted with blue branches.
Figure 4
Figure 4
Time of integration of HML7 proviral loci in primate genomes. Temporal overview of the colonization of primate species by HML7 elements, based on the combination of time of integration estimation and comparative genomics analysis of each human locus in non-human primates. Each node indicates a speciation event, and the correspondent time is indicated in the line below. HML7 loci whose insertion occurred in centromeric or pericentromeric regions are marked with a * (Xq11.1) or a + (3q11.2, Yp11.2, 2q11.2 and 12q12), respectively, and their localization in non-human primates could possibly be affected by the lower comparability of constitutive heterochromatin. 1 Based on multiple approaches of divergence calculation; see materials and methods for further details.
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