A sequence of SVA retrotransposon insertions in ASIP shaped human pigmentation.
Nat Genet
; 56(8): 1583-1591, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-39048794
ABSTRACT
Retrotransposons comprise about 45% of the human genome1, but their contributions to human trait variation and evolution are only beginning to be explored2,3. 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 populations4-6. 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pigmentação da Pele
/
Retroelementos
/
Proteína Agouti Sinalizadora
Limite:
Humans
Idioma:
En
Revista:
Nat Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Estados Unidos