Human-Specific Integrations of the HERV-K Endogenous Retrovirus Family

Abstract

Several distinct families of endogenous retrovirus-like sequences (HERVs) exist in the genomes of humans and other primates. One of these families, the HERV-K group, contains members that encode functional proteins and that have been implicated in the etiology of insulin-dependent diabetes mellitus (IDDM). Because of potential functional and disease relevance, it is important to determine if there are HERV-K-associated genetic differences between individuals. In this study, we have investigated the divergence and evolutionary age of HERV-K long terminal repeats (LTRs). Thirty-seven LTRs, taken primarily from random human clones in GenBank, were aligned and grouped into nine clusters with decreasing sequence divergence. Cluster 1 sequences are 8.6% divergent, on average, whereas cluster 9 LTRs, represented by the LTRs of the fully sequenced HERV-K10 clone, show an average of only 1.1% divergence from each other. The evolutionary age of 18 LTRs from different clusters was then investigated by genomic PCR to determine presence or absence of the retroviral element in different primate species. LTRs from clusters of higher divergence were detected in monkeys and apes, whereas LTRs in clusters with lower divergence were acquired later in evolution. Notably, LTRs of cluster 9 were found only in humans at all nine loci examined. Genomic Southern analysis with an oligonucleotide probe specific for cluster 9 LTRs suggests that HERV-K elements with this type of LTR expanded independently in the genomes of humans and the great apes. This is the first report of endogenous retroviral integrations that are specific to humans and indicates that some HERVs have amplified much later than previously thought. These elements may still be actively transposing and may therefore represent a source of genetic variation linked to disease development.

Retroviruses and primate evolution

“…Moreover, these subgroups can be further subdivided into smaller "subsubgroups." (43,44) Below I will use the term "superfamily" to designate the major groups of HERVs, such as HERV-K or HERV-H. The smaller groups like HERV-K (HML-1) or HERV-K (HML-6) will be referred to as "families," and still smaller subdivisions of the families will be termed consecutively "subfamilies" and "branches."…”

“…(58,59) As judged from sequence divergence, some HERVs might have been integrated into the genome earlier than 60 MYr ago, that is prior to the divergence of prosimians and New World monkeys. (21,44,47) Therefore, some HERV families might be present in prosimians but not yet detected, possibly due to low sequence homology. The extent of amplification of various HERV families in the genomes of primates is very different (Fig.…”

CTRL+INSERT: retrotransposons and their contribution to regulation and innovation of the transcriptome

“…Indeed, retrotransposons are frequently detected across all genomic assays, suggesting that they can contribute to both regulation and transcription in the human genome. Compared to protein-coding genes, retrotransposon sequences are much less conserved, and they can differ substantially between species [11][12][13][14][15][16]. While this may suggest that they are not essential for human life, they nevertheless show some biochemical activity [3].…”

Evolutionary Medicine of Retroviruses in the Human Genome

“…HERV-K is a case of beneficial endogenous retroviruses and has been integrated stepwise during primate evolution. 37 It is known that HIV-1 infection stimulates a T cell response to HERV-K antigens because of protein similarity. 38 Monde et al showed that gag proteins encoded by HERV-K changed the size and morphology of HIV particles, and these changes caused significant diminishing of the release efficiency and infectivity of HIV viruses.…”