Dosage sensitivity and exon shuffling shape the landscape of polymorphic duplicates in Drosophila and humans

Despite polymorphic duplicate genes' importance for the early stages of duplicate gene evolution, they are less studied than old gene duplicates. Two essential questions thus remain poorly addressed: how does dosage sensitivity, imposed by stoichiometry in protein complexes or by X chromosome dosage compensation, affect the emergence of complete duplicate genes? Do introns facilitate intergenic and intragenic chimaerism as predicted by the theory of exon shuffling? Here, we analysed new data for Drosophila and public data for humans, to characterize polymorphic duplicate genes with respect to dosage, exon-intron structures and allele frequencies. We found that complete duplicate genes are under dosage constraint induced by protein stoichiometry but potentially tolerated by X chromosome dosage compensation. We also found that in the intron-rich human genome, gene fusions and intragenic duplications extensively use intronic breakpoints generating in-frame proteins, in accordance with the theory of exon shuffling. Finally, we found that only a small proportion of complete or partial duplicates are at high frequencies, indicating the deleterious nature of dosage or gene structural changes. Altogether, we demonstrate how mechanistic factors including dosage sensitivity and exon-intron structure shape the short-term functional consequences of gene duplication.