Promoter CpG density is predictive of downstream gene loss-of-function intolerance

The aggregation and joint analysis of large numbers of exome sequences has recently made it possible to derive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoF-intolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich promoters (top 10% CpG density) have a 66.4% probability of being highly LoF-intolerant, using the LOEUF metric from gnomAD. This is in contrast to 7.6% of genes downstream of the most CpG-poor (bottom 10% CpG density) promoters. Combining promoter CpG density with exonic and promoter conservation explains 32.4% of the variation in LOEUF, and the contribution of CpG density exceeds the individual contributions of exonic and promoter conservation. We leverage this to train a simple and easily interpretable predictive model that outperforms other existing predictors and allows us to classify 1,796 genes - which currently lack reliable LOEUF estimates - as highly LoF-intolerant or not. These predictions have the potential to aid in the interpretation of novel patient variants. Moreover, our results reveal that high CpG density is not merely a generic feature of human promoters, but is preferentially encountered at the promoters of the most selectively constrained genes, calling into question the prevailing view that CpG islands are not subject to selection.