Long-term persistence of both functional and non-functional alleles at the leukocyte immunoglobulin-like receptor A3 (LILRA3) locus suggests balancing selection

Abstract

The leukocyte immunoglobulin-like receptor (LILR) family consists of 13 loci, and a number of variations have been identified in these genes. Some polymorphisms of the LILR genes are reported to be associated with susceptibility to diseases such as rheumatoid arthritis and multiple sclerosis. LILRA3, one of the LILR genes, exhibits a presence or absence variation due to a 6.7-kb deletion in various populations. In this study, variation screening of the LILRA3 gene revealed high allele frequency of the 6.7-kb LILRA3 deletion (71%) in Japanese, in contrast to the frequency reported for the other populations. In addition, we identified a splice acceptor mutation in intron 1 with allele frequency of 19%, resulting in three alternatively spliced isoforms. Surprisingly, all of these isoforms were found to contain premature termination codons (PTCs) in the exon 3. Taken together, approximately 80% of Japanese lack functional LILRA3 alleles. The maximum likelihood coalescent analysis suggested that two major lineages, functional alleles and PTC-containing alleles, have been maintained for 2.75 million years in humans. These results prompted us to hypothesize that balancing selection had maintained both the functional and non-functional alleles at the LILRA3 locus. This hypothesis is consistent with the observation that the 6.7-kb LILRA3 deletion is detected worldwide in the presence of functional LILRA3 alleles.

Multiple sclerosis associates with LILRA3 deletion in Spanish patients

“…To simplify and facilitate the analysis of LILRA3 genotypes in a clinical context, we designed a single-tube PCR that amplifies both the wild-type and the deleted LILRA3 alleles, which are then distinguished by their different electrophoretic mobilities in regular agarose gels ( Figure 1). This method simplifies further the approach used by Hirayasu et al 41 by using a single reverse PCR primer.…”

“…Intriguingly, mutations causing LILRA3 deficiency are common in the Japanese population, who have a low MS incidence rate and a high frequency of non-classical forms. 41 Establishing whether the association of MS with LILRA3 deletion is primary or secondary to LD of this defect with another, as yet unidentified, risk locus, requires further studies on polymorphisms located in the LILR gene complex and functional studies on LILRA3 itself, still hampered by a lack of specific antibodies. Presence or absence in the genome of each KIR gene was determined as described earlier.…”

Haplotype sorting using human fosmid clone end-sequence pairs

“…A study of a German cohort suggests that deletions of this locus may be associated with risk of multiple sclerosis (Koch et al 2005). The deletion is known to exist at a high frequency in Japanese populations where haplotypes from this locus form two distinct clades (Hirayasu et al 2006). The ability to obtain contiguous sequence from haplotypes carrying the deletion and insertion configuration may clarify the role of this locus in human evolution and disease.…”

Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations

“…12 In addition, nonfunctional alleles containing premature stop codons have been detected in East Asians. 13 These nonfunctional alleles are estimated to have been maintained for a long time in humans, suggesting that balancing selection has been acting on this locus. 13 By contrast, the copy number of LILRA6 observed in an individual ranges from one to six, which can be explained by the deletion or duplication of this gene.…”