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. 2024 Aug 19;13:e96652. doi: 10.7554/eLife.96652

Table 2. Outstanding questions for Haldane’s rule and sex-biased hybrid dysfunction.

Consideration Questions in need of addressing
Model development in exploring sex-biased hybrid dysfunction How can models of classic Haldane’s rule be extended to provide predictions for sex-biased hybrid dysfunction in taxa lacking heteromorphic sex chromosomes?
What new models can be developed to explain sex-biased hybrid dysfunction in taxa with homomorphic GSD, ESD, haplodiploidy, and hermaphroditism?
Relative influence of factors causing Haldane’s rule What is the balance across sexual systems of forces that reinforce and oppose hybrid dysfunction biased toward a particular sex?
Which mechanisms most commonly explain exceptions to classic Haldane’s rule, and how do they link to phylogeny?
Associating sex-biased hybrid dysfunction with developmental timing over life history Under what circumstances do alternative mechanisms for sex-biased hybrid dysfunction affect predictions differently for sterility than for inviability?
Is sex-biased hybrid dysfunction truly more prevalent for sterility than for inviability, and if so, why?
To what extent does sex bias in pre-zygotic reproductive isolation associate with sex bias in post-zygotic hybrid dysfunction?
Connecting to other features of reproductive isolation How do predictions for sex-biased hybrid dysfunction intersect with parent-of-origin asymmetries (Darwin’s corollary to Haldane’s rule)?
What is the extent and biological significance of within-species genetic variation for sex-biased hybrid dysfunction?
Approaches and methodologies to investigate sex-biased hybrid dysfunction What is the relative contribution of divergence in regulatory and coding sequence to sex-biased hybrid dysfunction, and how do they conform to alternate theoretical expectations?
How might inference of different rates of accumulation of sex-biased hybrid dysfunction from ‘speciation clock’ analysis inform alternate explanatory models?
How might taxa with multiple sex chromosomes, neo-sex chromosomes, and autosomal paleo-sex chromosomes be exploited to inform alternate models for sex-biased hybrid dysfunction?
How can analysis of hybrid zones and hybrid populations differentiate among alternative explanations for sex-biased hybrid dysfunction?
What do experimental manipulations of sex using hormone treatments, transgenic alterations, and karyotype perturbations indicate for general causes of sex-biased hybrid dysfunction?
How can alternative causes of sex-biased hybrid dysfunction be distinguished by testing for differences in the ontogenetic timing at which dysfunctional development manifests?