Inter- and Intralocus Recombination Drive MHC Class IIB Gene Diversification in a Teleost, the Three-Spined Stickleback Gasterosteus aculeatus

Abstract

The mutational mechanism underlying the striking diversity in MHC (major histocompatibility complex) genes in vertebrates is still controversial. In order to evaluate the role of inter- and intragenic recombination in MHC gene diversification, we examined patterns of nucleotide polymorphism across an exon/intron boundary in a sample of 31 MHC class IIB sequences of three-spined stickleback (Gasterosteus aculeatus). MHC class IIB genes of G. aculeatus were previously shown to be under diversifying (positive) selection in mate choice and pathogen selection experiments. Based on recoding of alignment gaps, complete intron 2 sequences were grouped into three clusters using maximum-parsimony analysis. Two of these groups had >90% bootstrap support and were tentatively assigned single locus status. Intron nucleotide diversity within and among loci was low (p-distance within and among groups = 0.016 and 0.019, respectively) and fourfold lower than the rate of silent mutations in exon 2, suggesting that noncoding regions are homogenized by frequent interlocus recombination. A substitution analysis using GENECONV: revealed as many intergenic conversion events as intragenic ones. Recombination between loci may explain the occurrence of sequence variants that are particularly divergent, as is the case in three-spined stickleback, with nucleotide diversity attaining dN = 0.39 (peptide-binding residues only). For both MHC class II loci we also estimated the amount of intragenic recombination as population rate (4N(e)r) under the coalescent and found it to be approximately three times higher compared to point mutations (Watterson estimate per gene, 4N(e)mu). Nonindependence of molecular evolution across loci and frequent recombination suggest that MHC class II genes of bony fish may follow different evolutionary dynamics than those of mammals. Our finding of widespread recombination suggests that phylogenies of MHC genes should not be based on coding segments but rather on noncoding introns.

Contrasting evolutionary histories of MHC class I and class II loci in grouse—effects of selection and gene conversion

“…The scarce available information suggests that both types of recombination may occur at a similar rate within class II B (Reusch and Langefors, 2005). In addition, high similarity among sequences derived from different MHC loci (apparent paralogs) suggests that inter-locus gene conversion may be an important evolutionary mechanism in fish (Reusch and Langefors, 2005;Aguilar and Garza, 2007) and birds (Edwards et al, 1995;Wittzell et al, 1999a, b;Burri et al, 2008). In grouse, we found that ca.…”

“…Although the evidence for inter-locus recombination at MHC is now wellestablished in different vertebrate taxa (Hughes and Nei, 1989;Cardenas et al, 2005;Zagalska-Neubauer et al, 2010), including galliforms (Strand et al, 2013), the relative rates of inter-and intralocus gene conversion at MHC are difficult to assess. The scarce available information suggests that both types of recombination may occur at a similar rate within class II B (Reusch and Langefors, 2005). In addition, high similarity among sequences derived from different MHC loci (apparent paralogs) suggests that inter-locus gene conversion may be an important evolutionary mechanism in fish (Reusch and Langefors, 2005;Aguilar and Garza, 2007) and birds (Edwards et al, 1995;Wittzell et al, 1999a, b;Burri et al, 2008).…”

“…While de novo MHC sequence variation is generated by point mutation, gene conversion can generate new haplotypes by transferring sections of DNA within and across duplicated MHC loci (Spurgin et al, 2011). Gene conversion (either intra-or inter-locus) is now recognized to have a crucial role in generating and maintaining MHC diversity in many vertebrates (Reusch and Langefors, 2005;Schaschl et al, 2006), including birds (Chaves et al, 2010;Spurgin et al, 2011;Promerová et al, 2013).…”

“…Furthermore, recombination is expected to be different depending on the number of loci. For example, species such as the greater prairie chicken with a single class I locus and two class II loci can only show signs of intralocus gene conversion within the single class I locus, while both intraand inter-locus gene conversion can occur at class II where there are two loci (Reusch and Langefors, 2005). In addition, the rate of intralocus gene conversion may depend on the strength of selective pressures, as stronger balancing selection might favour new alleles produced by gene conversion (Wegner, 2008).…”

Contrasting responses to selection in class I and class IIα major histocompatibility-linked markers in salmon

“…However, pathogen-driven balancing selection (through overdominance, negative frequency dependence or temporal/spatial heterogeneity in pathogen phenotype) is thought by many to be the main force driving MHC evolution (Klein and O'Huigin, 1994;Parham and Ohta, 1996;Edwards and Hedrick, 1998;Hedrick and Kim, 2000;Jeffery and Bangham, 2000). Evidence of selection on MHC genes has traditionally come from four sources (Hughes and Yeager, 1998): (a) long persistence times for MHC alleles compared with neutral expectation (often resulting in trans-specific polymorphism) (Figueroa et al, 1988;Lawlor et al, 1988;McConnell et al, 1988;Klein et al, 2007); (b) frequency distributions of MHC alleles in natural populations that are more even than that expected under a neutral model (Hedrick and Thompson, 1983;Markow et al, 1993); (c) high levels of nonsynonymous versus synonymous substitutions in codons for peptide binding residues (Hughes and Nei, 1988, 1989; and (d) homogenization of introns with concurrent diversification of exons at MHC loci (Cereb et al, 1997;Reusch and Langefors, 2005).…”