Mutation Rate Variation and Other Challenges in 2-LTR Dating of Primate Endogenous Retrovirus Integrations

The time of integration of germline-targeting Long Terminal Repeat (LTR) retroposons, such as endogenous retroviruses (ERVs), can be estimated by assessing the nucleotide divergence between the LTR sequences flanking the viral genes. Due to the viral replication mechanism, both LTRs are identical at the moment of integration, when the provirus becomes part of the host genome. After that time, proviral sequences evolve within the host DNA. When the mutation rate is known, nucleotide divergence between the LTRs would then be a measure of time elapsed since integration. Though frequently used, the approach has been complicated by the choice of host mutation rate and, to a lesser extent, by the method selected to estimate nucleotide divergence. As a result, outcomes can be incompatible with, for instance, speciation events identified from the fossil record. The review will give an overview of research reporting LTR-retroposon dating, and a summary of important factors to consider, including the quality, assembly, and alignment of sequences, the mutation rate of foreign DNA in host genomes, and the choice of a distance estimation method. Primates will here be the focus of the analysis because their genomes, ERVs, and fossil record have been extensively studied. However, most of the factors discussed have a wide applicability in the vertebrate field.