Long-Term Balancing Selection in LAD1 Maintains a Missense Trans-Species Polymorphism in Humans, Chimpanzees, and Bonobos

Abstract

Balancing selection maintains advantageous genetic and phenotypic diversity in populations. When selection acts for long evolutionary periods selected polymorphisms may survive species splits and segregate in present-day populations of different species. Here, we investigate the role of long-term balancing selection in the evolution of protein-coding sequences in the Homo-Pan clade. We sequenced the exome of 20 humans, 20 chimpanzees, and 20 bonobos and detected eight coding trans-species polymorphisms (trSNPs) that are shared among the three species and have segregated for approximately 14 My of independent evolution. Although the majority of these trSNPs were found in three genes of the major histocompatibility locus cluster, we also uncovered one coding trSNP (rs12088790) in the gene LAD1. All these trSNPs show clustering of sequences by allele rather than by species and also exhibit other signatures of long-term balancing selection, such as segregating at intermediate frequency and lying in a locus with high genetic diversity. Here, we focus on the trSNP in LAD1, a gene that encodes for Ladinin-1, a collagenous anchoring filament protein of basement membrane that is responsible for maintaining cohesion at the dermal-epidermal junction; the gene is also an autoantigen responsible for linear IgA disease. This trSNP results in a missense change (Leucine257Proline) and, besides altering the protein sequence, is associated with changes in gene expression of LAD1.

Detecting balancing selection in genomes: limits and prospects

“…; Teixeira et al . ). These studies have been particularly comprehensive, as they investigated signatures of BS acting at various temporal scales.…”

How reticulated are species?

“…In some cases, incomplete lineage sorting occurs as a result of balancing selection maintaining polymorphisms: when speciation occurs, both daughter species may maintain the same “trans‐specific” polymorphisms, even though with recombination, the signal of ancestral origin may erode over time . Good examples of shared polymorphisms between humans and apes are MHC and ABO blood group loci , among other genes. In the species complex including the major mosquito vector, Anopheles gambiae , a very large chromosomal inversion, 2La (22 Mb in length, 8.5% of the total genome size) is maintained as a balanced polymorphism that has persisted across several speciation events .…”

Understanding rare and common diseases in the context of human evolution

“…Several studies searching for the occurrence of trans-species polymorphism have shown that advantageous variants in the human population may have been inherited from distant ancestral species [142–145]. For example, functional diversity in ABO blood group has been maintained across primates for millions of years, probably due to host–pathogen coevolution [142].…”