To estimate the strength of purifying selection acting on CNVs in different functional categories, we fitted a population genetic model of demography and selection37 to the site frequency spectrum of deletions and duplications in the CEU population, corrected for incomplete ascertainment (Supplementary Methods). We observed the strongest purifying selection acting on exonic CNVs, then intronic CNVs then intergenic CNVs (Fig. 5a). Stronger purifying selection at intronic CNVs than intergenic CNVs has also been observed in Drosophila38 and intronic deletions can be pathogenic if they interfere with proper splicing39. Differences in the ascertainment and in the precision of estimates of key population genetic parameters between CNV and published base substitution data sets render direct comparison of average fitness coefficients between CNVs and substitutions potentially misleading.
