Species-specific positive selection of the male-specific lethal complex that participates in dosage compensation in Drosophila

Abstract

In many taxa, males and females have unequal ratios of sex chromosomes to autosomes, which has resulted in the invention of diverse mechanisms to equilibrate gene expression between the sexes (dosage compensation). Failure to compensate for sex chromosome dosage results in male lethality in Drosophila. In Drosophila, a male-specific lethal (MSL) complex of proteins and noncoding RNAs binds to hundreds of sites on the single male X chromosome and up-regulates gene expression. Here we use population genetics of two closely related Drosophila species to show that adaptive evolution has occurred in all five protein-coding genes of the MSL complex. This positive selection is asymmetric between closely related species, with a very strong signature apparent in Drosophila melanogaster but not in Drosophila simulans. In particular, the MSL1 and MSL2 proteins have undergone dramatic positive selection in D. melanogaster, in domains previously shown to be responsible for their specific targeting to the X chromosome. This signature of positive selection at an essential protein-DNA interface of the complex is unexpected and suggests that X chromosomal MSL-binding DNA segments may themselves be changing rapidly. This highly asymmetric, rapid evolution of the MSL genes further suggests that misregulated dosage compensation may represent one of the underlying causes of male hybrid inviability in Drosophila, wherein the fate of hybrid males depends on which species' X chromosome is inherited.

Fig. 1.

MSL1 and MSL2 play a key role in assembly and targeting of the dosage compensation complex to the male X chromosome. (A) Five known protein components and two known RNAs comprising the MSL complex. The five MSL proteins are drawn to scale with known domains highlighted. MSL1 serves as a scaffold for the entire MSL complex. MSL1 binds to MSL2, and together they bind to the X chromosome. Amino acids 85–186 of MSL1 are necessary and sufficient for binding to amino acids 1–190 of MSL2. Together, amino acids 1–265 of MSL1 and amino acids 1–190 of MSL2 are sufficient for targeting to high-affinity binding sites on the male X chromosome (30, 33, 34). Targeting of MSL1 is abolished by deletion of amino acids 1–26 (32). MSL1 also binds to other components of the MSL complex, including MSL3 [which contains a chromobarrel domain (61) that binds RNA (62)] and MOF [which contains a chromobarrel domain (61), a zinc finger, and an acetyltransferase domain with specific activity for histone H4 (10, 63)]. MLE encodes ATPase and RNA/DNA helicase activities (64). (B) Schematic model of the assembly of the MSL complex onto the male X chromosome that highlights the central scaffolding role of MSL1 and MSL2.

Fig. 2.

Positive selection of the MSL complex and X chromosomal MSL-binding sites might result in hybrid incompatibility. (A) Two-locus D–M model for hybrid incompatibility between closely related species. Loci A and B interact in the ancestral species. During (reproductive or recombinational) isolation, there is a neutral fixation of the a and b alleles in the two populations, which is tolerated because the new alleles (a and b) are still compatible with the old alleles (B and A, respectively). However, this fixation results in hybrid incompatibility because of negative epistatic interactions between the new a and b alleles. This model can explain the onset of incompatibilities even under neutral evolution (56). (B) In the case of positive selection (bold arrows) driving the interaction of the A and B loci, only one lineage may evolve to the new a and b alleles, resulting in incompatibility with the other lineage, which still preserves the ancestral A and B alleles. (C) MSL1 and MSL2 could represent the A and B loci in the D–M model, with the positive selection (bold arrows) at their interaction interface resulting in hybrid inviability. Under this model, male hybrids containing either the D. melanogaster or D. simulans X chromosomes would be inviable because the protein composition is expected to be the same in both cases. (D) Model for hybrid incompatibility with MSL1–MSL2 and the X chromosomal MSL-binding sites, as A and B loci, respectively. Positive selection (bold arrows) in D. melanogaster has resulted in rapid evolution of the MSL1–MSL2 genes and (we infer) the X chromosomal MSL-binding sites. In male hybrids, D. simulans MSL1 and MSL2 are unable to recognize “newly evolved” MSL-binding sites on the D. melanogaster X chromosome resulting in mislocalization of the MSL complex in hybrids with a D. melanogaster X chromosome (44). However, hybrids with a D. simulans X chromosome localize the MSL complex normally (45) because the D. melanogaster MSL1 and MSL2 proteins retain an ancestral DNA-binding ability. (E) Known male hybrid incompatibility in D. melanogaster crosses to D. simulans. Male inviability occurs when a D. melanogaster X chromosome is combined with a hybrid autosomal background (43).