Figure 5. Deleterious effect of the ultra-rare PTVs are also associated with lifespan.

(a) Survival of UKB subjects with 5 ultra-rare PTVs per exome. The inset shows association between lifespan and the properties of genes harboring ultra-rare PTV: evolutionary constraint quantified by $dN/dS$ ratios (the ratio of substitution rates at non-synonymous and synonymous sites) in human-chimpanzee orthologs; indispensability score (IS) as in Khurana et al., 2013; genome-wide haploinsufficiency score (GHIS) as in Steinberg et al. (2015); (relative) number of tissues expressing the gene; observed/expected (oe) score; prediction for variants being loss-of-function (LOF, see LOF-gene) and triggering NMD (see NMD-gene). Orange and blue areas in (a) designate survival windows for subjects dying earlier in life (young) and later in life (old) and this color scheme is the same as that in the plots B-D. Difference in (B) GHIS scores, (C) percent of tissues expressing gene affected by variants, and (D) oe scores, and (e) proportion of predicted loss-of-function ($LOF\mathrm{\_}gene$) variants for individuals with same PTV number but differing in lifespan (i.e. dying younger (47.4 − 58.9 years) or older (73.8 − 78.5 years)). p-Values in (b) and (d) were calculated by Student t-test, p-value in (c) and (e) were calculated by Wilcoxon rank-sum test. NMD - nonsense-mediated decay, IS - indispensability score, GHIS - genome-wide haploinsufficiency score, LOF - loss of function, PTV - protein-truncating variant (defined as stop codon gains, frameshifts, canonical splice acceptor/donor sites variant).