Drosophila duplication hotspots are associated with late-replicating regions of the genome

Abstract

Duplications play a significant role in both extremes of the phenotypic spectrum of newly arising mutations: they can have severe deleterious effects (e.g. duplications underlie a variety of diseases) but can also be highly advantageous. The phenotypic potential of newly arisen duplications has stimulated wide interest in both the mutational and selective processes shaping these variants in the genome. Here we take advantage of the Drosophila simulans-Drosophila melanogaster genetic system to further our understanding of both processes. Regarding mutational processes, the study of two closely related species allows investigation of the potential existence of shared duplication hotspots, and the similarities and differences between the two genomes can be used to dissect its underlying causes. Regarding selection, the difference in the effective population size between the two species can be leveraged to ask questions about the strength of selection acting on different classes of duplications. In this study, we conducted a survey of duplication polymorphisms in 14 different lines of D. simulans using tiling microarrays and combined it with an analogous survey for the D. melanogaster genome. By integrating the two datasets, we identified duplication hotspots conserved between the two species. However, unlike the duplication hotspots identified in mammalian genomes, Drosophila duplication hotspots are not associated with sequences of high sequence identity capable of mediating non-allelic homologous recombination. Instead, Drosophila duplication hotspots are associated with late-replicating regions of the genome, suggesting a link between DNA replication and duplication rates. We also found evidence supporting a higher effectiveness of selection on duplications in D. simulans than in D. melanogaster. This is also true for duplications segregating at high frequency, where we find evidence in D. simulans that a sizeable fraction of these mutations is being driven to fixation by positive selection.

Figure 1. Proportion of duplications in low-, medium-, and high-frequency overlapping different genomic contexts in D. simulans.

A duplication is said to be intergenic if it overlaps exclusively intergenic sequence, to be intronic if it overlaps exclusively intronic sequence, to be a partial gene duplication if it encompasses exonic or exonic and intronic sequence, and to be a complete duplication if it encompasses a complete gene structure. The numbers in the columns refer to the number of duplications observed in each class.

Figure 2. Comparison of the proportion of duplications in low-, medium-, and high-frequency overlapping different genomic contexts in D. simulans and D. melanogaster.

Figure 3. Replication timing of duplications overlapping between D. simulans and D. melanogaster.

The first panel shows the replication timing data for the whole genome as determined by Schwaiger and colleagues . The second panel compares the distribution of replication timing values for duplications that overlap and that do not overlap between the two species. The third panel is similar to the second but considers only duplications smaller than 5 kb (in both species). The numbers on the top of the three panels refer to the observed median replication times. ^** indicates a significantly lower replication timing (p<<0.01).