Mutational bias shaping fly copy number variation: implications for genome evolution

Abstract

Copy number variants (CNVs) underlie several genomic disorders and are a major source of genetic innovation. Consequently, any bias affecting their placement in the genome will impact our understanding of human disease and genome evolution. Here we report a mutational bias affecting CNVs that generates different probabilities of duplication and deletion across the genome in association with DNA replication time. We show that this mutational bias has important consequences for genome evolution by leading to different probabilities of gene duplication for different classes of genes and by linking the probability of gene duplication with the transcriptional activity of genes.

Figure 1. Relationship between the differential distribution of duplication and deletion densities and replication time

(a) Density of duplications and deletions along chromosome 2L. CNV data was produced by Emerson and colleagues [3]. The red blocks correspond to deletion-HDRs and the grey blocks to duplication-HDRs. HDRs correspond to the chromosome regions with the 10% most extreme CNV density values (after excluding pericentromeric regions). (b) Replication time profiles of duplication-HDRs and deletion-HDRs. The boxplots represent the distribution of replication time values for duplication-HDRs (in grey), non-HDRs (in white) and deletion-HDRs (in red). The width of the boxplot is proportional to the number of observations in each group. (c) Association between replication time and duplication density and deletion density. For each interval of duplication and deletion density (as defined by the histogram in grey) we calculated the mean observed replication time (red dots). The curve was produced using the R function ‘scatter.smooth’ [24]. In (b) and (c) replication time data was produced by Schwaiger and colleagues [12].

Figure 2. A mechanistic model based on the interplay between DNA replication and DNA repair

Schematic representation of how gene density, DNA repair pathways and types of CNVs are expected to vary along the S-phase of the cell cycle (i.e., during DNA replication). Although late-replicating regions are indicated by low numbers we chose to depict the cell cycle as progressing left to right (with late-replication on the right).