The search for sexually antagonistic genes: Practical insights from studies of local adaptation and statistical genomics

Abstract

Sexually antagonistic (SA) genetic variation--in which genotypes favoured in one sex are disfavoured in the other--is predicted to be common and has been documented in several animal and plant populations, yet we currently know little about its pervasiveness among species or its population genetic basis. Recent applications of genomics in studies of SA genetic variation have highlighted considerable methodological challenges to the identification and characterisation of SA genes, raising questions about the feasibility of genomic approaches for inferring SA selection. The related fields of local adaptation and statistical genomics have previously dealt with similar challenges, and lessons from these disciplines can therefore help overcome current difficulties in applying genomics to study SA genetic variation. Here, we integrate theoretical and analytical concepts from local adaptation and statistical genomics research--including FST and FIS statistics, genome-wide association studies (GWAS), pedigree analyses, reciprocal transplant studies, and evolve-and-resequence (E&R) experiments--to evaluate methods for identifying SA genes and genome-wide signals of SA genetic variation. We begin by developing theoretical models for between-sex FST and FIS, including explicit null distributions for each statistic, and using them to critically evaluate putative signals of sex-specific selection in previously published datasets. We then highlight new statistics that address some of the limitations of FST and FIS, along with applications of more direct approaches for characterising SA genetic variation, which incorporate explicit fitness measurements. We finish by presenting practical guidelines for the validation and evolutionary analysis of candidate SA genes and discussing promising empirical systems for future work. Impact SummaryGenome sequences carry a record of the evolutionary and demographic histories of natural populations. Research over the last two decades has dramatically improved our ability to detect genomic signals of adaptation by natural selection, including several widely-used methods for identifying genes underlying local adaptation and quantitative trait variation. Yet the application of these methods to identify sexually antagonistic (SA) genes--wherein variants that are adaptive for one sex are maladaptive for the other--remains under-explored, despite the potential importance of SA selection as a mechanism for maintaining genetic variation. Indeed, several lines of evidence suggest that SA genetic variation is common within animal and plant populations, underscoring the need for analytical methods that can reliably identify SA genes and genomic signals of SA genetic variation. Here, we integrate statistics and experimental designs that were originally developed within the fields of local adaptation and statistical genomics and apply them to the context of sex-specific adaptation and SA genetic variation. First, we evaluate and extend statistical methods for identifying signals of SA variation from genome sequence data alone. We then apply these methods to re-analyse previously published datasets on allele frequency differences between sexes--a putative signal of SA selection. Second, we highlight more direct approaches for identifying SA genetic variation, which utilise experimental evolution and statistical associations between individual genetic variants and fitness. Third, we provide guidelines for the biological validation, evolutionary analysis, and interpretation of candidate SA polymorphisms. By building upon the strong methodological foundations of local adaptation and statistical genomics research, we provide a roadmap for rigorous analyses of genetic data in the context of sex-specific adaptation, thereby facilitating insights into the role and pervasiveness of SA variation in adaptive evolution.