Retrotransposons comprise about 45% of the human genome¹, 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^4,5,6. 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.

逆转录转座子约占人类基因组的 45% ¹ ，但它们对人类性状变异和进化的贡献才刚刚开始被探索^2,3 。在这里，我们发现ASIP （agouti 信号蛋白）基因早期内含子中的 SVA 逆转录转座子插入序列可能多次塑造了人类色素沉着。在英国生物银行 ( n = 169,641) 中，最近的 3.3-kb SVA 插入多态性与较浅的皮肤色素沉着 (0.22 [0.21–0.23] sd; P = 2.8 × 10 ⁻³⁵¹ ) 和皮肤癌风险增加 (比值比 = 1.23 [1.18–1.27]； P = 1.3 × 10 ⁻²⁸ )，似乎是欧洲人群中对这些表型最强烈的常见遗传影响之一^4,5,6 。皮肤中的ASIP表达显示出相同的关联模式，其中 SVA 插入等位基因的表达增加了 2.2 倍（1.9-2.6）。这种效应有一个不寻常的明显机制：一个早期的、非多态性的、人类特异性的 SVA 逆转录转座子 3.9 kb 上游似乎通过非生产性剪接导致了ASIP功能减退，而新的（多态性）SVA 插入在很大程度上消除了 ASIP 功能减退。扩展的单倍型纯合性表明，在过去几千年中，插入等位基因在欧洲人群中的等位基因频率已上升至 11%。这些结果表明，一系列逆转录转座子插入导致人类色素沉着在物种范围内增加，然后局部减少。