Impact of endogenous intronic retroviruses on MHC class II diversity and stability

Department of Comparative Genetics & Refinement, Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands

^* To whom correspondence should be addressed. Email: doxiadis{at}bprc.nl.

	Abstract

The Major Histocompatibility Complex (MHC) represents a multigene family that is known to display allelic as well as gene copy number variation. 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 lengths due to insertions of transposable elements as long endogenous retroviral (ERV/HERV) sequences in DRB2, DRB6, and DRB7 pseudogenes. Although 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 antisense manner. On the one hand, antisense-oriented retroelements such as HERV-K14I, observed in intron 2 of 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, HERVK3I present in intron 1 of all DRB2 and/or DRB6 alleles tested so far integrated in 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.