Haldane's rule: hybrid sterility affects the heterogametic sex first because sexual differentiation is on the path to species differentiation.

Prevention of recombination is needed to preserve both phenotypic differentiation between species and sexual phenotypic differentiation within species. For species differentiation (speciation), isolating barriers preventing recombination may be pre-zygotic (gamete transfer barriers), or post-zygotic (either a developmental barrier resulting in hybrid inviability, or a chromosomal-pairing barrier resulting in hybrid sterility). The sterility barrier is usually the first to appear and, although often initially only manifest in the heterogametic sex (Haldane's rule), is finally manifest in both sexes. For sexual differentiation, the first and only barrier is chromosomal-pairing, and always applies to the heterogametic sex. For regions of sex chromosomes affecting sexual differentiation there must be something analogous to the process generating the hybrid sterility seen when allied species cross. Explanations for Haldane's rule have generally assumed that the chromosomal-pairing barrier initiating evolutionary divergence into species is due to incompatibilities between gene products ("genic), or sets of gene products ("polygenic), rather than between chromosomes per se ("chromosomal"). However, if chromosomal incompatibilities promoting incipient sexual differentiation could also contribute to the process of incipient speciation, then a step towards speciation would have been taken in the heterogametic sex. Thus, incipient speciation, manifest as hybrid sterility when "varieties" are crossed, would appear at the earliest stage in the heterogametic sex, even in genera with homomorphic sex chromosomes (Haldane's rule for hybrid sterility). In contrast, it has been proposed that Haldane's rule for hybrid inviability needs differences in dosage compensation, so could not apply to genera with homomorphic sex chromosomes.