The Phase 1 data enable us to compare, for different genomic features and variant types, the effects of purifying selection on evolutionary conservation19, the allele frequency distribution and the level of differentiation between populations. At the most highly conserved coding sites, 85% of nonsynonymous (NonSyn) variants and over 90% of STOP gain and splice-disrupting variants are below 0.5% in frequency , compared to 65% of synonymous (Syn) variants (Fig. 4a). In general, the rare variant excess tracks the level of evolutionary conservation for variants of most functional consequence, but varies systematically between types (e.g., for a given level of conservation enhancer variants have a higher rare variant excess than variants in transcription factor motifs). However, STOP gains and, to a lesser-extent, splice-site disrupting changes, show elevated rare-variant excess whatever the conservation of the base in which they occur, as such mutations can be highly deleterious whatever the level of sequence conservation. Interestingly, the least conserved splice-disrupting variants show rare-variant load similar to synonymous and non-coding regions suggesting that these alternative transcripts are under very weak selective constraint. Sites at which
