Cross-Sectional Dating of Novel Haplotypes of HERV-K 113 and HERV-K 115 Indicate These Proviruses Originated in Africa before Homo sapiens

Abstract

The human genome, human endogenous retroviruses (HERV), of which HERV-K113 and HERV-K115 are the only known full-length proviruses that are insertionally polymorphic. Although a handful of previously published papers have documented their prevalence in the global population; to date, there has been no report on their prevalence in the United States population. Here, we studied the geographic distribution of K113 and K115 among 156 HIV-1+ subjects from the United States, including African Americans, Hispanics, and Caucasians. In the individuals studied, we found higher insertion frequencies of K113 (21%) and K115 (35%) in African Americans compared with Caucasians (K113 9% and K115 6%) within the United States. We also report the presence of three single nucleotide polymorphism sites in the K113 5′ long terminal repeats (LTRs) and four in the K115 5′ LTR that together constituted four haplotypes for K113 and five haplotypes for K115. HERV insertion times can be estimated from the sequence differences between the 5′ and 3′ LTR of each insertion, but this dating method cannot be used with HERV-K115. We developed a method to estimate insertion times by applying coalescent inference to 5′ LTR sequences within our study population and validated this approach using an independent estimate derived from the genetic distance between K113 5′ and 3′ LTR sequences. Using our method, we estimated the insertion dates of K113 and K115 to be a minimum of 800,000 and 1.1 million years ago, respectively. Both these insertion dates predate the emergence of anatomically modern Homo sapiens.

Reconstitution of the Ancestral Glycoprotein of Human Endogenous Retrovirus K and Modulation of Its Functional Activity by Truncation of the Cytoplasmic Domain

“…Recently, however, recognition that the HERV-K108 glycoprotein has residual functional activity plus the in silico generation of consensus prototypic HERV-K(HML-2) sequences have added considerably to our basic understanding of the virus and its proteins (20,21,39). The data presented here describe a strategy to overcome the poor expression and document efforts to reconstitute a HERV-K(HML-2) Env protein coded for by the HERV-K113 element that originally entered the human germ line as an infectious retrovirus more than 800,000 years ago (33,54). This provirus is one of the most studied elements.…”

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

“…K109 and K113, also likely candidates for replication competence (76,77,79,80), had RPKM values below our limit of detection or were not able to be analyzed in this study, respectively. K113 is the most recent germ line integration known (10,76), with an allele frequency of ϳ16% in the population (10,76); thus, it is not yet fixed in the human population. As such, it is possible that K113 is not present in the genome of the PBL donor.…”

“…These results suggest that Tat treatment, in addition to activating, also represses HERV-K (HML-2) expression. Interestingly, of these activated proviruses, K108 and K115 (considered among the most likely candidates to remain replication competent in modern humans) (76)(77)(78)(79) are significantly activated by Tat treatment. K109 and K113, also likely candidates for replication competence (76,77,79,80), had RPKM values below our limit of detection or were not able to be analyzed in this study, respectively.…”

“…Interestingly, of these activated proviruses, K108 and K115 (considered among the most likely candidates to remain replication competent in modern humans) (76)(77)(78)(79) are significantly activated by Tat treatment. K109 and K113, also likely candidates for replication competence (76,77,79,80), had RPKM values below our limit of detection or were not able to be analyzed in this study, respectively. K113 is the most recent germ line integration known (10,76), with an allele frequency of ϳ16% in the population (10,76); thus, it is not yet fixed in the human population.…”

The role of human endogenous retroviral long terminal repeat sequences in human cancer (Review)

“…Only a few sequence polymorphisms have been described, partly due to the difficulty in identifying them against the background of closely similar proviruses. Using specific PCR primers spanning 5'LTRs of K115 and K113, Jha et al (45) reported the presence of three single nucleotide polymorphism sites in the K113 5'LTR and four in the K115 5'LTR that together constituted four haplotypes for K113. At present, there is little convincing evidence that any sequence polymorphism of a HERV provides susceptibility to human disease.…”