Genomic Networks of Hybrid Sterility

Leslie M Turner,Bret A Payseur,Diethard Tautz,Michael A White,John H Willis

doi:10.1371/journal.pgen.1004162

Abstract

Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci (“Dobzhansky-Muller incompatibilities”). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is difficult. With subspecies in the early stages of speciation, an array of genetic tools, and detailed knowledge of reproductive biology, house mice (Mus musculus) provide a model system for dissecting hybrid incompatibilities. Male hybrids between M. musculus subspecies often show reduced fertility. Previous studies identified loci and several X chromosome-autosome interactions that contribute to sterility. To characterize the genetic basis of hybrid sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven ‘hotspots,’ seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL—but not cis eQTL—were substantially lower when mapping was restricted to a ‘fertile’ subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. The integrated mapping approach we employed is applicable in a broad range of organisms and we advocate for widespread adoption of a network-centered approach in speciation genetics.

Highlights

To understand patterns of biodiversity, it is essential to characterize the processes by which new species arise and are maintained in nature, including ecological specialization, population differentiation and reproductive isolation
Hybrid defects are caused by negative interactions between genes that have undergone evolutionary change within each subgroup
We combined mapping of gene expression levels in testis with previous results mapping male sterility traits in hybrid house mice. This new approach to finding genetic causes of reproductive barriers enabled us to identify a large number of hybrid incompatibilities, involving genomic regions with known roles in hybrid sterility and previously unknown regions

Summary

Introduction

To understand patterns of biodiversity, it is essential to characterize the processes by which new species arise and are maintained in nature, including ecological specialization, population differentiation and reproductive isolation. Divergence in gene regulation is expected to contribute to reproductive isolation between nascent species, and studies with F1 hybrids support this prediction [8,9,10,11,12,13]. These two approaches – genetic mapping and measurement of genome-wide expression patterns in hybrids – have yet to be combined directly in the context of speciation. Hybrid sterility and hybrid inviability frequently result from negative epistasis between mutations at interacting genes [14,15,16] This ‘‘Dobzhansky-Muller model’’ predicts that disruptions in gene networks should be common in hybrids. A network perspective should provide insights into the genetics of reproductive isolation that are difficult to obtain using a gene-by-gene approach

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Conclusion