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. 2013 Jun;3(6):1552-68.
doi: 10.1002/ece3.567. Epub 2013 Apr 22.

Duplication and population dynamics shape historic patterns of selection and genetic variation at the major histocompatibility complex in rodents

Jamie C Winternitz  1 , John P Wares
Affiliations

Duplication and population dynamics shape historic patterns of selection and genetic variation at the major histocompatibility complex in rodents

Jamie C Winternitz et al. Ecol Evol. 2013 Jun.

Abstract

Genetic variation at the major histocompatibility complex (MHC) is vitally important for wildlife populations to respond to pathogen threats. As natural populations can fluctuate greatly in size, a key issue concerns how population cycles and bottlenecks that could reduce genetic diversity will influence MHC genes. Using 454 sequencing, we characterized genetic diversity at the DRB Class II locus in montane voles (Microtus montanus), a North American rodent that regularly undergoes high-amplitude fluctuations in population size. We tested for evidence of historic balancing selection, recombination, and gene duplication to identify mechanisms maintaining allelic diversity. Counter to our expectations, we found strong evidence of purifying selection acting on the DRB locus in montane voles. We speculate that the interplay between population fluctuations and gene duplication might be responsible for the weak evidence of historic balancing selection and strong evidence of purifying selection detected. To further explore this idea, we conducted a phylogenetically controlled comparative analysis across 16 rodent species with varying demographic histories and MHC duplication events (based on the maximum number of alleles detected per individual). On the basis of phylogenetic generalized linear model-averaging, we found evidence that the estimated number of duplicated loci was positively related to allelic diversity and, surprisingly, to the strength of purifying selection at the DRB locus. Our analyses also revealed that species that had undergone population bottlenecks had lower allelic richness than stable species. This study highlights the need to consider demographic history and genetic structure alongside patterns of natural selection to understand resulting patterns of genetic variation at the MHC.

Keywords: Balancing selection; Microtus montanus; gene duplication; major histocompatibility complex; population dynamics; purifying selection.

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Figures

Figure 1
Figure 1
Neighbor-joining (NJ) phylogeny and Bayesian estimated posterior probabilities for all 21 M. montanus (Mimo-DRB) alleles using a tree shrew (Tupaia belangeri) sequence as an outgroup (GenBank accession no. GU825729). We constructed the NJ phylogeny with the Kimura-two parameter nucleotide distance considering all sites. Node numbers indicate bootstrap support ≥50 (5000 replicates) and numbers in parentheses indicate Bayesian posterior probabilities above 80%. Scale bar indicates the genetic distance. Alleles are partitioned hierarchically into two groups representing two putative loci.
Figure 2
Figure 2
Alignment of 21 identified amino acid sequences of the partial DRB exon 2 of the montane vole, Microtus montanus (Mimo-DRB). A dot indicates congruence with the amino acid sequence of Mimo-DRB*01. Gray shading denotes antigen binding sites (ABS) according to Brown et al. (1993) and astericks at the bottom of the table denote ABS according to Bondinas et al. (2007).
Figure 3
Figure 3
Trans-species polymorphism of the MHC class II DRB gene in 16 rodent species. The DRB tree on the right is a neighbor-joining phylogeny of all 21 M. montanus DRB alleles (in black) compared with 45 DRB sequences from 15 different rodent species, using a tree shrew (Tupaia belangeri) and white-tailed deer sequence (Odocoiles virginianus) as outgroups. GenBank ascension numbers are given after each species name. M. montanus alleles (Mimo-DRB colored black) cluster among its nearest relatives, the bank vole (Myodes glareolus) and root vole (Microtus oeconomus). The scale bar indicates genetic distance in units of nucleotide substitutions per site. The species tree on the left was derived from the mammal supertree (Bininda-Emonds et al. 2007) and depicts the evolutionary divergence between species, with the scale bar indicating Myr. Numbers at the tips indicate the putative number of DRB loci for each species. M. montanus is boxed.
Figure 4
Figure 4
Evidence of balancing selection at the antigen binding sites (ABS) (Brown et al. 1993) and negative selection at non-ABS across 16 rodent species and Tupaia. (A) The ratio of nonsynonymous to synonymous substitutions per site (dN/dS) was calculated at non-ABS (open bar) and ABS (filled bar) sites separately for each species. Significant departures from neutrality (dN/dS) = 1 at the ABS were determined with codon based Z-tests using the Nei-Gojobori method with Jukes-Cantor correction in Mega 5.05. Variance was computed using the bootstrap method (1000 replicates). Asterisks denote significance at P < 0.05 (See Table S2 for P-values). Dotted line indicates neutrality (dN/dS) = 1 and open circles indicates species with cyclic population dynamics. (B) Evidence of purifying selection at non-ABS across 16 rodent species and Tupaia. We performed codon-based Z-tests as above. The test statistic (dS-dN) was calculated for non-ABS (open bar) and ABS (filled bar) sites separately for each species. Astericks denote significance at P < 0.05 and open triangles indicate species with duplicated DRB genes (See Table S2 for P-values).
Figure 5
Figure 5
Interspecific trait effects on signals of selection and nucleotide diversity at the DRB in 16 rodent species. (A) Relationship between population dynamics categorized as stable, cyclic, and bottlenecked, and DRB allelic richness. N indicates sample size and error bars indicate 95% confidence intervals. (B) Relationship between the number of DRB loci per species and average nucleotide divergence (π, black diamonds) and strength of purifying selection (dS–dN at non antigen binding sites, open squares). For the secondary y-axis, zero indicates equal rates of synonymous and nonsynonymous substitutions, while positive values indicate negative selection for amino-acid changing substitutions. The black dotted line is the linear best fit for π, and the gray dotted line is the linear best fit for “purifying selection.”
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References

    1. Aars J, Dallas JF, Piertney SB, Marshall F, Gow JL, Telfer S, et al. Widespread gene flow and high genetic variability in populations of water voles Arvicola terrestris in patchy habitats. Mol. Ecol. 2006;15:1455–1466. - PubMed
    1. Aguilar A, Roemer G, Debenham S, Binns M, Garcelon D, Wayne RK. High mhc diversity maintained by balancing selection in an otherwise genetically monomorphic mammal. Proc. Natl Acad. Sci. USA. 2004;101:3490–3494. - PMC - PubMed
    1. Altizer S, Harvell D, Friedle E. Rapid evolutionary dynamics and disease threats to biodiversity. Trends Ecol. Evol. 2003;18:589–596.
    1. Apanius V, Penn D, Slev PR, Ruff LR, Potts WK. The nature of selection on the major histocompatibility complex. Crit. Rev. Immunol. 1997;17:179–224. - PubMed
    1. Axtner J, Sommer S. Gene duplication, allelic diversity, selection processes and adaptive value of mhc class ii drb genes of the bank vole, Clethrionomys glareolus. Immunogenetics. 2007;59:417–426. - PubMed