Structural polymorphism and population-variable coding capacity of HERV-K(HML-2) in human pangenomes

Endogenous retroviruses, including the HERV-K(HML-2) clade, make up around 8% of the human genome. This particular group of retroviruses has been linked to various conditions such as cancer, ALS, and embryogenesis. Most studies focusing on HERV expression, especially HML-2, have utilized short-read sequencing techniques. However, the high similarity among different HML-2 proviruses often results in these short reads being unable to uniquely identify individual loci.

To overcome this limitation, researchers compared haplotype-resolved long-read genome assemblies from 292 individuals. This approach revealed structural polymorphism at several loci previously considered fixed. At certain positions, multiple copies of proviral sequences were found in tandem arrays, with one instance showing up to six proviral copies at a single site on the 8q11.23 chromosome.

Additionally, a previously unknown full-length provirus was identified at this location on one haplotype, while all other 583 haplotypes carried a single long terminal repeat (LTR). The study discovered that standard reference genomes do not accurately represent the coding capacity present in many individuals, as some carry intact open reading frames in their proviruses, despite disruptive mutations present in the reference sequences.

Consequently, short-read genotypes left unresolved 32.5% of the tested donor-variant pairs, particularly at sites where viral reading frames are associated. This research highlights the importance of considering the structural and coding alleles carried by each individual when interpreting HML-2 expression.