Promoter CpG Density Predicts Downstream Gene Loss-of-Function Intolerance

Area of Science:

• Genomics
• Human Genetics
• Molecular Biology

Background:

• Large-scale exome sequencing enables estimation of gene intolerance to loss-of-function (LoF) variation.
• Previous research has not fully explored the relationship between LoF intolerance and regulatory elements like CpG promoters.

Purpose of the Study:

• To investigate the association between genic LoF intolerance and promoter CpG density across the human genome.
• To develop a predictive model for LoF intolerance using CpG density and conservation metrics.
• To identify previously unascertained genes as highly LoF intolerant.

Main Methods:

• Analysis of exome sequence data and LoF intolerance metrics (LOEUF from gnomAD).
• Correlation analysis between promoter CpG density and genic LoF intolerance.
• Development and validation of a predictive model incorporating CpG density and conservation data.

Main Results:

• A strong, widespread coupling exists between genic LoF intolerance and promoter CpG density.
• Genes with CpG-rich promoters are significantly more likely to be LoF intolerant (67.2%) compared to those with CpG-poor promoters (7.4%).
• Promoter CpG density, combined with conservation, explains a substantial portion (33.4%) of LoF intolerance variation, outperforming conservation alone.

Conclusions:

• Promoter CpG density is a key predictor of genic LoF intolerance.
• The developed model accurately classifies LoF intolerance for unascertained genes, aiding clinical variant interpretation.
• The preferential association of high CpG density with constrained genes challenges existing views on selection acting on CpG islands.