Impact of endogenous intronic retroviruses on major histocompatibility complex class II diversity and stability

Abstract

The major histocompatibility complex (MHC) represents a multigene family that is known to display allelic and gene copy number variations. Primate species such as humans, chimpanzees (Pan troglodytes), and rhesus macaques (Macaca mulatta) show DRB region configuration polymorphism at the population level, meaning that the number and content of DRB loci may vary per haplotype. Introns of primate DRB alleles differ significantly in length due to insertions of transposable elements as long endogenous retrovirus (ERV) and human ERV (HERV) sequences in the DRB2, DRB6, and DRB7 pseudogenes. Although the integration of intronic HERVs resulted sooner or later in the inactivation of the targeted genes, the fixation of these endogenous retroviral segments over long time spans seems to have provided evolutionary advantage. Intronic HERVs may have integrated in a sense or an antisense manner. On the one hand, antisense-oriented retroelements such as HERV-K14I, observed in intron 2 of the DRB7 genes in humans and chimpanzees, seem to promote stability, as configurations/alleles containing these hits have experienced strong conservative selection during primate evolution. On the other hand, the HERVK3I present in intron 1 of all DRB2 and/or DRB6 alleles tested so far integrated in a sense orientation. The data suggest that multigenic regions in particular may benefit from sense introgressions by HERVs, as these elements seem to promote and maintain the generation of diversity, whereas these types of integrations may be lethal in monogenic systems, since they are known to influence transcript regulation negatively.

FIG. 1.

Organization of the HLA-DR region and the nomenclature of DRB loci, lineages, and alleles.

FIG. 2.

Composition of HERV inserts in the HLA-DRB2 and HLA-, Patr-, and Mamu-DRB6 introns. The illustration is drawn to scale, with lengths of introns given in base pairs, except for intron 3 of Mamu-DRB6*0118, in which the lengths before and after the insertion of 7,206 bp are designated. All HERVs and other insertions discussed in the text are in scale and color coded. Orientation of the inserts is specified by arrows. Black bars within HERV segments indicate that the respective retroviral sequence is discontinuous (Table 1 and 3).

FIG. 3.

Phylogenetic analysis of intron 1-4 sequences of diverse HLA-, Patr-, and Mamu-DRB alleles.

FIG. 4.

Phylogenetic analysis of HERVK3I sequences of intron 1 of different DRB alleles. The DRB inserts are compared to two published HERVK3I sequences (ID 31865 and AF079797).

FIG. 5.

Composition of HERV-K14I sequences in intron 2 of HLA- and Patr-DRB7. The illustration is drawn to scale, with exon and intron lengths given in bp. The orientation of the inserts is designated by arrows. HERVs and LTRs are in scale and color coded. Black bars within HERV segments indicate that the respective retroviral sequence is discontinuous (Table 4).

FIG. 6.

Phylogenetic analysis of intron 2 sequences of diverse HLA-, Patr-, and Mamu-DRB alleles.