Genetic incompatibilities are widespread within species

Abstract

The importance of epistasis—non-additive interactions between alleles—in shaping population fitness has long been a controversial topic, hampered in part by lack of empirical evidence1,2,3,4. Traditionally, epistasis is inferred on the basis of non-independence of genotypic values between loci for a given trait. However, epistasis for fitness should also have a genomic footprint5,6,7. To capture this signal, we have developed a simple approach that relies on detecting genotype ratio distortion as a sign of epistasis, and we apply this method to a large panel of Drosophila melanogaster recombinant inbred lines8,9. Here we confirm experimentally that instances of genotype ratio distortion represent loci with epistatic fitness effects; we conservatively estimate that any two haploid genomes in this study are expected to harbour 1.15 pairs of epistatically interacting alleles. This observation has important implications for speciation genetics, as it indicates that the raw material to drive reproductive isolation is segregating contemporaneously within species and does not necessarily require, as proposed by the Dobzhansky–Muller model, the emergence of incompatible mutations independently derived and fixed in allopatry. The relevance of our result extends beyond speciation, as it demonstrates that epistasis is widespread but that it may often go undetected owing to lack of statistical power or lack of genome-wide scope of the experiments.

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Figure 1: Locus pairs showing significant GRD across the DSPR lines of Drosophila.
Figure 2: From missing genotypes to epistasis.
Figure 3: Model for unlinked loci with segregating pairs of incompatible alleles.

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Acknowledgements

We are grateful to T. Long, S. Macdonald and E. King for creating the DSPR and sharing the RILs and founder strains with us. We thank C. Jones, B. de Bivort, T. Sackton, S. D. Kocher, J. Grenier and N.E. Soltis for comments and discussions. We thank X. Shi for technical assistance. This work was supported by grants: NIH GM065169 and GM084236 to D.L.H., HD059060 to A.G.C., and Harvard Society of Fellows Fellowship and Harvard Milton Funds to J.F.A. R.B.C.-D. was supported by a Harvard Prize Fellowship.

Author information

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Authors

Contributions

J.F.A. conceived the idea of the project, R.B.C.-D. and J.F.A. conceived and designed experiments and analyses. R.B.C.-D. and J.F.A. conducted bioinformatics and statistical analyses; R.B.C.-D., J.F.A. and J.Z. performed experiments; J.Z. carried out molecular work; A.G.C. and D.L.H. gave analytical and conceptual advice throughout the project.

Corresponding author

Correspondence to Julien F. Ayroles.

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The authors declare no competing financial interests.

Additional information

All code used and generated for this study is available upon request.

Extended data figures and tables

Extended Data Figure 1 Description of the DSPR and validation scheme.

a, Geographic distribution of the DSPR founding strains (orange, panel A; red, panel B). b, Construction of the recombinant inbred lines. For each panel all founder strains were crossed in a round-robin design (line 1 ♀ × line 2 ♂, line 2 ♀ × line 3 ♂,…, line 8 ♀ × line 1 ♂) to produce F1s, and the F1s were then allowed to mate free to produce an F2 population. In each panel A and B, these F2 populations were split into two independent population to create panels A1, A2 and B1, B2. Each was allowed to recombine freely for 50 generations, in very large population. After 50 generations, for each replicate panel, about 400 isofemale lines were inbred for 25 generations to create the 4 panels of RILs used in this study. c, Crossing scheme used to validate epistatic effects. A pair of founder segregating incompatible alleles was selected and crossed to produce F1s; we then intercrossed the F1 progeny to produce a large F2 population, segregating all possible allelic combinations between alleles at loci 1 and 2. We then counted the progeny each pair produced by intercrossing a large number of F2s which were later genotyped at sites near to the predicted interacting loci.

Extended Data Figure 2 Principal component analysis of all three DSPR RIL panels.

Green, panel A-2; blue, panel B-1; and red, panel B-2. No evidence of population structure is shown.

Extended Data Figure 3 D′ distribution for significant GRD.

Data are plotted across DSPR panels. On the x axis, D′ is a measure of the disequilibrium between interacting alleles. The red curve corresponds to a smooth curve fit using non-parametric density estimation. An outlier box-plot is presented above the histogram (the lozenge represent the mean and 95% CI, the edge of the rectangle represent the 25% and 75% percentile, the vertical bar within the median, the dots are possible outlier and the red bracket represents the shortest length that contain 50% of the data).

Extended Data Figure 4 Epistasis plot for each validated instance of GRD.

On the y axes are the productivity measurements that correspond to each genotypic class across both chromosomes. The x axes correspond to the genotypes on one of the chromosomes, the other genotype is represented by the colour indicated inside the plot (for example, genotype AA,bb in panel a is found in the lower left corner, where AA is read from the x axis and bb from the blue colour). a, GRD between chromosomes 2R and 3R (tagged by SNPs 2R:4806926, on the X axis and 3R:5870973, coloured lines) shows strong negative epistasis due to the low fitness of the aa;bb genotype. The additive-by-additive genetic effect is equal to −13.75 (in the sense of refs 5 and 29). b, GRD between chromosomes 3L and X (tagged by SNPs 3L: 11510853, on the X axis and X: 16483812, coloured lines) also shows negative epistasis. Here the additive-by-additive genetic effect equals −5.94.

Extended Data Figure 5 The accumulation of post-zygotic reproductive isolation through time (note log scale on axes).

Approximate divergence times of commonly studied Drosophila species are indicated by green circles, and the red circle indicates a reasonable expectation for divergence times of stocks used to found the DSPR (10,000 years). The horizontal red area indicates a very approximate ‘speciation threshold’, and indicates that many species pairs that are commonly studied substantially exceed this threshold.

Extended Data Table 1 List of all significant inter-chromosomal GRD identified in the DSPR
Extended Data Table 2 List of significant inter-chromosomal GRD in the Arabidopsis MAGIC panel and maize NAM panel

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Corbett-Detig, R., Zhou, J., Clark, A. et al. Genetic incompatibilities are widespread within species. Nature 504, 135–137 (2013). https://doi.org/10.1038/nature12678

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