A simple way of estimating the segregating load arising from rare, deleterious mutations across a set of genes comes from comparing the ratios of NonSyn to Syn variants in different frequency ranges. The NonSyn to Syn ratio among rare (<0.5%) variants is typically in the range 1-2 and among common variants in the range 0.5-1.5, suggesting that 25-50% of rare NonSyn variants are deleterious. However, the segregating rare load among gene groups in KEGG pathways20 varies substantially (Fig. S11a; Table S13). Certain groups (e.g., ECM-receptor interaction, DNA replication and pentose phosphate pathway) show a substantial excess of rare coding mutations, which is only weakly correlated with the average degree of evolutionary conservation. Pathways and processes showing an excess of rare functional variants vary between continents (Fig. S11b). Moreover, the excess of rare NonSyn variants is typically higher in populations of European and East Asian ancestry (for example, the ECM-receptor interaction pathway load is strongest in EUR). Other groups of genes (for example, those associated with allograft rejection) actually have a high NonSyn:Syn ratio in common variants, potentially indicating the effects of positive selection.
