Genome-wide mapping in a house mouse hybrid zone reveals hybrid sterility loci and Dobzhansky-Muller interactions

Abstract

Mapping hybrid defects in contact zones between incipient species can identify genomic regions contributing to reproductive isolation and reveal genetic mechanisms of speciation. The house mouse features a rare combination of sophisticated genetic tools and natural hybrid zones between subspecies. Male hybrids often show reduced fertility, a common reproductive barrier between incipient species. Laboratory crosses have identified sterility loci, but each encompasses hundreds of genes. We map genetic determinants of testis weight and testis gene expression using offspring of mice captured in a hybrid zone between M. musculus musculus and M. m. domesticus. Many generations of admixture enables high-resolution mapping of loci contributing to these sterility-related phenotypes. We identify complex interactions among sterility loci, suggesting multiple, non-independent genetic incompatibilities contribute to barriers to gene flow in the hybrid zone.

Keywords: evolutionary biology; genomics; hybrid incompatibilities; hybrid zone; mouse; reproductive isolation; speciation.

Figure 1.. Manhattan plot of GWAS results.

Single SNPs associated with (A) relative testis weight, (B) testis expression principal component 1, and (C) expression of transcripts located on other chromosomes (trans). Dashed lines indicate significance thresholds based on: permutations for autosomes (labeled 5% perm A), permutations for X chromosome (labeled 5% perm X), false discovery rate <0.1 (labeled 10% FDR), and 95^th percentile of significant transcript association counts across SNPs (labeled 95%). DOI: http://dx.doi.org/10.7554/eLife.02504.005

Figure 1—figure supplement 1.. Geographic location of and genetic makeup of mapping population.

(A) Location of sampling area (black box) in European house mouse hybrid zone. (B) Sampling locations for parents of mice in the mapping population. (C) Structure analysis of mapping population. Individuals (vertical bands) are arranged by geographic origin and average percentage alleles from Mus musculus musculus. DOI: http://dx.doi.org/10.7554/eLife.02504.007

Figure 1—figure supplement 2.. Principal components analysis of genome-wide gene expression in testis.

(A) Plot of principal component 1 (PC1) vs PC2 scores. Individuals with relative testis weight and/or sperm count below the pure subspecies range are indicated in blue (‘low fertility’). Individuals with relative testis weight and sperm count within one standard deviation of the mean in pure subspecies individuals are indicated in red (‘fertile range’). (B) Plot of relative testis weight vs PC1 score. Correlation coefficient (Pearson's) and p value are indicated. (C) Plot of hybrid index (% musculus alleles on autosomes) vs PC2 score. Correlation coefficient (Pearson's) and p value are indicated. DOI: http://dx.doi.org/10.7554/eLife.02504.008

Figure 2.. Significant GWAS regions and interactions in hybrid zone mice.

Results for (A) relative testis weight and (B) testis expression principal component 1 in hybrid zone mice. In (A) orange and yellow boxes in outer rings (outside grey line) indicate quantitative trait loci (QTL) identified for testis weight and other sterility phenotypes in previous studies (see Table 1 for details). Green boxes indicate significant GWAS regions for relative testis weight. Green lines represent significant genetic interactions between regions; shade and line weight indicate the number of significant pairwise interactions between SNPs for each region pair. In (B) orange boxes in outer rings indicate QTL for testis-related phenotypes (testis weight and seminiferous tubule area) identified in previous studies, yellow boxes indicate QTL for other sterility phenotypes and red boxes indicate trans eQTL hotspots (see Table 2 for details). Green boxes indicate significant GWAS regions for relative testis weight. Purple boxes indicate significant GWAS regions for testis expression PC1. Lines represent significant genetic interactions between regions; color and line weight—as specified in legend—indicate the number of significant pairwise interactions between SNPs for each region pair. Plot generated using circos (Krzywinski et al., 2009). DOI: http://dx.doi.org/10.7554/eLife.02504.011

Figure 2—figure supplement 1.. Genetic interactions associated with hybrid sterility in hybrid zone mice and in F₂ hybrids.

Orange boxes in outer rings indicate QTL for testis-related phenotypes (testis weight and seminiferous tubule area) identified in previous studies, yellow boxes indicate QTL for other sterility phenotypes, and red boxes indicate trans eQTL hotspots (see Table 2 for details). Green boxes indicate significant GWAS regions for relative testis weight. Purple boxes indicate significant GWAS regions for testis expression PC1. Lines represent significant genetic interactions identified in hybrid zone mice for relative testis weight (in green) and expression PC1 (in purple), which are concordant with genetic interactions identified by mapping expression traits in F2 hybrids (Turner et al., 2014). Plot generated using circos (Krzywinski et al., 2009). DOI: http://dx.doi.org/10.7554/eLife.02504.014

Figure 3.. Phenotypic effects of testis-weight loci and interactions.

Histograms showing maximum deviations from the population mean for (A) single SNPs and (B) two-locus interactions. Dashed vertical lines indicate minimum values observed in pure subspecies males. (C) Examples of phenotypic means by two-locus genotype for autosomal–autosomal and X–autosomal interactions. Genotypes are indicated by one letter for each locus: D—homozygous for the domesticus allele, H—heterozygous, M—homozygous musculus. DOI: http://dx.doi.org/10.7554/eLife.02504.015

Figure 4.. Mapping power in simulations.

Each panel illustrates results from a single genetic architecture model for (A) 100 autosomal–autosomal SNP pairs and (B) 100 X—autosomal SNP pairs. Each point represents the percentage of data sets generated from a single SNP pair in which locus 1 (domesticus sterile allele; green), locus 2 (musculus sterile allele; purple), or both loci (orange) were identified by association mapping (≥1 SNP significant by permutation based threshold within 10 Mb of ‘causal’ SNP). The x axis indicates the percentage of individuals with partial or full sterility phenotypes. Curves were fit using second order polynomials. In (A), locus 1 indicates the SNPs with musculus alleles sterile and locus 2 indicates the SNPs with domesticus alleles sterile. In (B), locus 1 is the X-linked SNP and locus 2 is the autosomal SNP. DOI: http://dx.doi.org/10.7554/eLife.02504.016

Figure 4—figure supplement 1.. Mapping simulation methods.

Schematics of (A) choice of ‘causal’ SNP pairs from the genotype data, (B) phenotype distributions for simulations, (C) generation of simulated phenotype data sets, (D) association mapping. In (B) histogram shows the empirical distribution of relative testis weight in the mapping population, in standard deviation units. DOI: http://dx.doi.org/10.7554/eLife.02504.018

Figure 4—figure supplement 2.. Distances of significant SNPs to causal SNP in simulations.

Distributions are shown at two scales for autosomal and X-linked loci. DOI: http://dx.doi.org/10.7554/eLife.02504.019