A sequence of SVA retrotransposon insertions in ASIP shaped human pigmentation

Retrotransposons comprise about 45% of the human genome 1 , but their contributions to human trait variation and evolution are only beginning to be explored 2 , 3 . Here, we find that a sequence of SVA retrotransposon insertions in an early intron of the ASIP (agouti signaling protein) gene has probably shaped human pigmentation several times. In the UK Biobank ( n = 169,641), a recent 3.3-kb SVA insertion polymorphism associated strongly with lighter skin pigmentation (0.22 [0.21–0.23] s.d.; P = 2.8 × 10 −351 ) and increased skin cancer risk (odds ratio = 1.23 [1.18–1.27]; P = 1.3 × 10 −28 ), appearing to underlie one of the strongest common genetic influences on these phenotypes within European populations 4 – 6 . ASIP expression in skin displayed the same association pattern, with the SVA insertion allele exhibiting 2.2-fold (1.9–2.6) increased expression. This effect had an unusual apparent mechanism: an earlier, nonpolymorphic, human-specific SVA retrotransposon 3.9 kb upstream appeared to have caused ASIP hypofunction by nonproductive splicing, which the new (polymorphic) SVA insertion largely eliminated. Extended haplotype homozygosity indicated that the insertion allele has risen to allele frequencies up to 11% in European populations over the past several thousand years. These results indicate that a sequence of retrotransposon insertions contributed to a species-wide increase, then a local decrease, of human pigmentation. Genomic analysis identifies an SVA retrotransposon insertion in an intron of ASIP as a likely causal variant influencing human pigmentation. This insertion appears to mitigate the effects of an older, nonpolymorphic SVA insertion in the same intron.