Copy Number Variants and Segmental Duplications Show Different Formation Signatures

In addition to variation in terms of single nucleotide polymorphisms (SNPs), whole regions ranging from several kilobases up to a megabase in length differ in copy number among individuals. These differences are referred to as Copy Number Variants (CNVs) and extensive mapping of these is underway. Recent studies have highlighted their great prevalence in the human genome. Segmental Duplications (SDs) are long (>1kb) stretches of duplicated DNA with high sequence identity. They are generally thought to be the result of CNVs reaching fixation in the population. To elucidate likely mechanisms of formation of these features, we examine in detail patterns of co-occurrence of different genomic features with both CNVs and SDs. First, we analyzed the co-localization of SDs and find that SDs are significantly co-localized with each other, resulting in a power-law distribution, which suggests a preferential attachment mechanism, i.e. existing SDs are likely to be involved in creating new ones nearby. This finding is further bolstered by an observation that young SDs most strongly co-localize with SDs that are closest in age and less strongly with older SDs. In line with this, we observe significant association of CNVs with SDs, but this association is weaker than may be expected. Second, we look at the relationship of CNVs/SDs with various types of repeats. We we find that the previously recognized association of SDs with Alu elements is significantly stronger for older SDs and is sharply decreasing for younger ones. While it might be expected that the patterns should be similar for SDs and CNVs, we find, surprisingly, no association of CNVs with Alu elements. This trend is consistent with the decreasing correlation between Alu elements and younger SDs – the activity of Alu elements has been decreasing and by now it they seem no longer active. Furthermore, we find a striking association of SDs with processed pseudogenes suggesting that they may also have mediated SD formation. In line with the trend for Alu elements, this association is decreasing for recent SDs and is quite weak for CNVs. Moreover, find strong association with microsatellites for both SDs and CNVs that suggests a role for satellites in the formation of both. Finally, a manual analysis of a small number of CNV breakpoints is suggestive of an alternative mechanism. In summary, we find striking differences in formation signatures of CNVs and SDs that can partly be explained by a decrease in Alu activity. …