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. 2004 Apr 6;101(14):4894-9.
doi: 10.1073/pnas.0307800101. Epub 2004 Mar 25.

Long-term reinfection of the human genome by endogenous retroviruses

Robert Belshaw  1 , Vini Pereira, Aris Katzourakis, Gillian Talbot, Jan Paces, Austin Burt, Michael Tristem
Affiliations

Long-term reinfection of the human genome by endogenous retroviruses

Robert Belshaw et al. Proc Natl Acad Sci U S A. .

Abstract

Endogenous retrovirus (ERV) families are derived from their exogenous counterparts by means of a process of germ-line infection and proliferation within the host genome. Several families in the human and mouse genomes now consist of many hundreds of elements and, although several candidates have been proposed, the mechanism behind this proliferation has remained uncertain. To investigate this mechanism, we reconstructed the ratio of nonsynonymous to synonymous changes and the acquisition of stop codons during the evolution of the human ERV family HERV-K(HML2). We show that all genes, including the env gene, which is necessary only for movement between cells, have been under continuous purifying selection. This finding strongly suggests that the proliferation of this family has been almost entirely due to germ-line reinfection, rather than retrotransposition in cis or complementation in trans, and that an infectious pool of endogenous retroviruses has persisted within the primate lineage throughout the past 30 million years. Because many elements within this pool would have been unfixed, it is possible that the HERV-K(HML2) family still contains infectious elements at present, despite their apparent absence in the human genome sequence. Analysis of the env gene of eight other HERV families indicated that reinfection is likely to be the most common mechanism by which endogenous retroviruses proliferate in their hosts.

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Figures

Fig. 1.
Fig. 1.
Bayesian estimate of the phylogenies for the internal region and LTRs (those of the same element are linked by lines). Posterior probabilities for the internal region are shown above the branches except (for clarity) in the human-specific clade. Internal branches are thickened if they were also recovered in a strict consensus of the most parsimonious trees. Thick terminal branches in the LTR tree represent 5′ LTRs, and thin terminal branches represent 3′ LTRs. Boxes represent elements whose 5′ and 3′ LTRs do not cluster together, with a thick box showing that they are polyphyletic in both Bayesian and MP trees, and a thin box showing that they are paraphyletic in both, or monophyletic in one. Filled circles denote elements containing the 292-bp deletion spanning the pol-env junction [Type I HERV-K(HML2) subgroup], which is absent in all other elements [Type II HERV-K(HML2) subgroup]. The clade created by segmental duplication of the host genome is also indicated, as are the branches indicating probable changes in the distribution of elements among primates.
Fig. 2.
Fig. 2.
Phylogenetic profile obtained by using phylpro. The darkened line shows the profile for sequence 12c22 only. Negative peaks for groups A and B (members of which have almost identical profiles) are indicated. The vertical dashed lines extend from the break-point positions identified by lard for 12c22 and the two other group A elements (HKY model, with κ and α estimated from neighbor joining trees for each triplet). P values are calculated from seq-gen using 100 replicates from a Bayesian tree (HKY model: κ, α and base frequencies taken from the tree). The window size in phylpro extends to include 100 variable positions either side of the sliding point. The ordinate shows the linear correlation score of uncorrected pairwise distances from the two windows.
Fig. 3.
Fig. 3.
Phylogeny of the internal region. The estimated number of stop codons acquired on each branch is shown (with R representing a reversal) and the dN/dS ratio is indicated by the line thickness. Superscript letters show the five potential acquisitions of stop codons on internal branches discussed in the text. Note that a short branch may represent insufficient changes for a reliable estimate to be made for that branch.
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