Skin pigmentation is a classic example of a polygenic trait that has experienced directional selection in humans. Genome-wide association studies have identified well over a hundred pigmentation-associated loci, and genomic scans in present-day and ancient populations have identified selective sweeps for a small number of light pigmentation-associated alleles in Europeans. It is unclear whether selection has operated on all of the genetic variation associated with skin pigmentation as opposed to just a small number of large-effect variants. Here, we address this question using ancient DNA from 1,158 individuals from West Eurasia covering a period of 40,000 y combined with genome-wide association summary statistics from the UK Biobank. We find a robust signal of directional selection in ancient West Eurasians on 170 skin pigmentation-associated variants ascertained in the UK Biobank. However, we also show that this signal is driven by a limited number of large-effect variants. Consistent with this observation, we find that a polygenic selection test in present-day populations fails to detect selection with the full set of variants. Our data allow us to disentangle the effects of admixture and selection. Most notably, a large-effect variant atSLC24A5was introduced to Western Europe by migrations of Neolithic farming populations but continued to be under selection post-admixture. This study shows that the response to selection for light skin pigmentation in West Eurasia was driven by a relatively small proportion of the variants that are associated with present-day phenotypic variation.

Soy foods may protect against breast cancer in Asian but not in Western populations. We examined if the levels of various markers of breast cancer risk and inflammation, as well as the effects of soy food consumption on these markers, differ between Asian and non-Asian premenopausal women in two soy intervention trials. One study randomized 220 women to a 2-year intervention and the other one randomized 96 women in a cross-over design to examine the effects of consumption of 2 daily soy servings on nipple aspirate fluid (NAF) volume, estrogens in serum, NAF, and urine, insulin-like growth factor-1 (IGF-1), IGF binding protein 3, and inflammatory markers in serum, and mammographic densities. Mixed linear models were applied to assess ethnic differences in biomarkers and response to the soy diet. Serum C-reactive protein, serum leptin, NAF volume, and NAF estrone-sulfate were lower, while urinary isoflavones were higher in Asian than in non-Asian women. A significant interaction (pinteraction=0.05) between ethnicity and soy diet was observed for IGF-1 but not for other biomarkers. The current findings suggest possible ethnic differences in levels of biomarkers for breast cancer risk but little evidence that Asian women respond differently to soy foods than non-Asian women.

11Skin pigmentation is a classic example of a polygenic trait that has experienced directional 12 selection in humans. Genome-wide association studies have identified well over a hundred 13 pigmentation-associated loci, and genomic scans in present-day and ancient populations have 14 identified selective sweeps for a small number of light pigmentation-associated alleles in 15Europeans. It is unclear whether selection has operated on all the genetic variation associated 16 with skin pigmentation as opposed to just a small number of large-effect variants. Here, we 17 address this question using ancient DNA from 1158 individuals from West Eurasia covering a 18 period of 40,000 years combined with genome-wide association summary statistics from the UK 19Biobank. We find a robust signal of directional selection in ancient West Eurasians on skin 20 pigmentation variants ascertained in the UK Biobank, but find this signal is driven mostly by a 21 limited number of large-effect variants. Consistent with this observation, we find that a 22 polygenic selection test in present-day populations fails to detect selection with the full set of 23 variants; rather, only the top five show strong evidence of selection. Our data allow us to 24 disentangle the effects of admixture and selection. Most notably, a large-effect variant at 25SLC24A5 was introduced to Europe by migrations of Neolithic farming populations but 26 continued to be under selection post-admixture. This study shows that the response to selection 27 for light skin pigmentation in West Eurasia was driven by a relatively small proportion of the 28 variants that are associated with present-day phenotypic variation. 29 30 Significance 31 Some of the genes responsible for the evolution of light skin pigmentation in Europeans show 32 signals of positive selection in present-day populations. Recently, genome-wide association 33 studies have highlighted the highly polygenic nature of skin pigmentation. It is unclear whether 34 selection has operated on all of these genetic variants or just a subset. By studying variation in 35 over a thousand ancient genomes from West Eurasia covering 40,000 years we are able to study 36 both the aggregate behavior of pigmentation-associated variants and the evolutionary history of 37 individual variants. We find that the evolution of light skin pigmentation in Europeans was 38 driven by frequency changes in a relatively small fraction of the genetic variants that are 39 associated with variation in the trait today. 40 SLC45A2, TYR, and APBA2/OCA2). 51 52 Therefore, while the existence of selective sweeps at a handful of skin pigmentation loci is well-53 established, the evidence for polygenic selection-a coordinated shift in allele frequencies across 54 many trait-associated variants (11)-is less clear. Recently, genome-wide association studies 55 (GWAS) of larger samples and more diverse populations (12-15) have emphasized the polygenic 56 architecture of skin pigmentation. This raises the question of whether selection on skin 57 pigmen...