Rate of recombinational deletion among human endogenous retroviruses

Abstract

The fate of most human endogenous retroviruses (HERVs) has been to undergo recombinational deletion. This process involves homologous recombination between the flanking long terminal repeats (LTRs) of a full-length element, leaving a relic structure in the genome termed a solo LTR. We examined loci in one family, HERV-K(HML2), and found that the deletion rate decreased markedly with age: the rate among recently integrated loci was almost 200-fold higher than that among loci whose insertion predated the divergence of humans and chimpanzees (8 x 10(-5) and 4 x 10(-7) recombinational deletion events per locus per generation, respectively). One hypothesis for this finding is that increasing mutational divergence between the flanking LTRs reduces the probability of homologous recombination and thus the rate of solo LTR formation. Consistent with this idea, we were able to replicate the observed rates by a simulation in which the probability of recombinational deletion was reduced 10-fold by a single mutation and 100-fold by any additional mutations. We also discuss the evidence for other factors that may influence the relationship between locus age and the rate of deletion, for example, host recombination rates and selection, and highlight the consequences of recombinational deletion for dating recent HERV integrations.

FIG. 1.

Comparison of the observed and simulated proportions of full-length proviruses in different age categories. Large dots (shown with confidence limits) representing the observed data have been placed at the midpoints of the provirus age groups. Small dots represent the means for 1,000 generations in the simulation. Note that the proportions for loci older than 6 million years are abruptly and massively elevated because we excluded deletions that occurred before 6 mya (we examined only loci that are represented by full-length proviruses in the chimpanzee genome). Simulated deletion probabilities per generation were 10⁻⁴, 10⁻⁵, and 10⁻⁶ for 0, 1, and >1 mutations, respectively.