The National Academies Press

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4 Human Adaptations to Diet, Subsistence, and Ecoregion Are Due to Subtle Shifts in Allele Frequency--Angela M. Hancock, David B. Witonsky, Edvard Ehler, Gorka Alkorta-Aranburu, Cynthia Beall, Amha Gebremedhin, Rem Sukernik, Gerd Utermann, Jonathan Pritchard, Graham Coop, and Anna Di Rienzo
Pages 63-80

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From page 63... ... ‡‡ human populations use a variety of subsistence strategies to exploit an exceptionally broad range of ecoregions and dietary components. These aspects of human environments have changed dramatically during human evolution, giving rise to new selective pressures. Read the entire page →
From page 64... ... however, identifying the polymorphisms underlying adaptive phenotypes is challenging because current patterns of human genetic variation result not only from selective but also from demographic processes. Previous studies examined evidence of positive selection by scanning genome-wide snP data using approaches that are generally agnostic to the underlying selective pressures. Read the entire page →
From page 65... ... here, we develop and apply an approach that uses information about underlying selective pressures while also controlling for the important effect of population structure in shaping the spatial distribution of beneficial alleles. our approach allows us to detect subtle but concordant changes in allele frequencies across populations that live in the same geographic region but that differ in terms of ecoregion, main dietary component, or mode of subsistence. Read the entire page →
From page 66... ... statistic based on the location of each snP in the overall distribution of BFs. Because we rank each snP relative to snPs within the same allele frequency range and from the same ascertainment panel, this transformed rank statistic allows us to make comparisons across snP sets. Read the entire page →
From page 67... ... To this end, we examined the lower tails of the rank statistic distributions for each individual variable to determine which ones showed the strongest enrichment of genic and ns snPs. several ecoregion variables exhibited a significant excess of genic and ns snPs with low rank statistics, with the strongest signals observed for polar domain (Table 4.2) Read the entire page →
From page 68... ... Luyha Bantu (South) Mandenka Mandenka Yoruba Luyha Biaka Masaai Vasekela Vasekela Mbuti Amhara San San Basque Tuscan HGDP Bergamo Adygei Tuscan HGDP French Adygei Basque French Bergamo Tuscan HapMap Orcadian Sardinian Tuscan HapMap Orcadian Sardinian Russian Russian Druze Palestinian Mozabite Druze Palestinian Mozabite Bedouin Bedouin Balochi Gujarati Brahui Makrani Sindhi Brahui Pathan Pathan Gujarati Balochi Makrani Sindhi Kalash Burusho Burusho Kalash Hazara Hazara Lahu Naukan Yup'ik Uygur Maritime Chukchee Miaozu Dai Tujia Cambodian She Tu Han Yakut Dai Yizu Mongola Miaozu Cambodian Oroqen Yizu Lahu Daur Hezhen Naxi Daur Tu Japanese Japanese Han Yakut Tujia Xibo She Maritime Chukchee Uygur Naukan Yup'ik Mongola Hezhen Xibo Oroqen Naxi Melanesian Australian Aborigines Papuan Melanesian Australian Aborigines Papuan Surui Surui Pima Karitiana Piapoco & Curipaco Maya Maya Piapoco & Curipaco Karitiana Pima a given region that are part of the category of interest, and gray shading denotes transformed allele frequencies were computed by subtracting the mean allele members of the dichotomous category, and all other populations are denoted by vertical lines separate populations into one of seven major geographic regions Asia, oceania, and the Americas) Read the entire page →
From page 69... ... To this end, we calculated global FsT for each snP and compared these values with the minimum transformed rank statistics for ecoregion and subsistence. The correlations were extremely low (−0.024 and −0.034 for ecoregion and subsistence, Populations that specialize on cereals (left bar) Read the entire page →
From page 70... ... here, we focused on the individual variables with the strongest enrichment of genic relative to nongenic snPs: roots and tubers as the main dietary component and polar ecoregion. Because we found that proportionally more genic than nongenic snPs have strong correlations with environmental variables, an enrichment of signals for snPs in a particular gene set relative to nongenic snPs could simply reflect this global genic enrichment. Read the entire page →
From page 71... ... . We find that several snPs strongly correlated with subsistence, and main dietary component variables are associated with energy metabolism–related phenotypes [high-density lipoprotein cholesterol, electrocardiographic traits and QT interval (el-Gamal et al., 1995) Read the entire page →
From page 72... ... TABle 4.4 snPs with the strongest signals of selection Among Those Associated with Phenotypic Traits in GWAs information About Most significant environmental variable Disease/Trait Association Genetic region variable rank Trait P snP Type variable statistic Trait value Chr Position nearby Genes FADS2, FADS3 rs174570 ecoregion humid 2.00 × 10−5 lDl 4.00 × 10−13 11 61353788 tropical Total 2.00 × 10−10 ecoregion hDl cholesterol 4.00 × 10−6 TNXB, CREBL1 rs2269426 subsistence Fat, meat, 2.44 × 10−5 Plasma 3.00 × 10−6 6 32184477 milk eosinophil (MhC Class count iii) MADD, rs7395662 Foragers 5.92 × 10−5 hDl cholesterol 6.00 × 10−11 11 48475469 FOLH1 RPL21 rs10507380 Pastoral 4.07 × 10−4 electrocardiographic 8.00 × 10−6 13 26777526 traits MYC, rs9642880 Pastoral 4.57 × 10−4 Urinary bladder 9.00 × 10−12 8 128787250 BC042052 cancer KCNJ2 rs17779747 Main dietary roots and 1.11 × 10−4 QT interval 6.00 × 10−12 17 66006587 component tubers ZMAT4 rs2722425 roots and 2.20 × 10−4 Fasting plasma 2.00 × 10−8 8 40603396 tubers glucose KCNQ1 rs2237892 Cereals 1.49 × 10−4 Type 2 diabetes 1.70 × 10−42 11 2796327 noTes: Table contains snPs with an environmental rank less than 5 × 10−4 and a GWAs P value of less than 1 × 10−5. Read the entire page →
From page 73... ... . examples of more recent genetic adaptations that were integral for dietary specializations include variants near the lactase gene, which confer the ability for adults to digest fresh milk in agropastoral populations, and an increase in the num ber of amylase gene copies in horticultural and agricultural populations (Bersaglieri et al., 2004; Perry et al., 2007; Tishkoff et al., 2007b; enattah et al., 2008) Read the entire page →
From page 74... ... in fact, many of the gene sets significantly enriched for signals with the polar domain are directly relevant to energy metabolism and temperature homeostasis. Adaptations in these genes were probably critical in the establishment of stable human populations in the northernmost latitudes of europe and Asia. Read the entire page →
From page 75... ... in some ways our approach is similar to previous analyses based on FsT, but there are two important differences. First, we compare populations on the basis of environmental variables rather than their geographic origin, thus providing greater power to detect allele frequency differences that track the underlying selective pressure. Read the entire page →
From page 76... ... quencies across populations, we find a set of adaptive snPs that differs compared with previous analyses that were agnostic to the underlying selective pressure. Further, because the snPs we identify tend to have a global distribution and to show subtle, but consistent, differences in allele frequencies across populations, loci we identify are likely to represent cases of selection on standing variation. Read the entire page →
From page 77... ... Using these minimum rank statistics, we could ask questions about the evidence of selection for subsistence and for ecoregion overall. Assessing the Evidence for an Excess of Functional SNPs in the Tail of the Distribution To determine whether the lower tail of the rank statistic distribution contains an excess of snPs enriched for function, compared with that expected by chance, we calculated the proportions of genic and ns snPs relative to the proportion of nongenic snPs in the tail. Read the entire page →
From page 78... ... Canonical Pathway Analysis To determine whether there was an enrichment of signal for a particular canonical pathway, we used a method similar to that used to test for an excess of genic and ns snPs relative to nongenic snPs in the tails of the test statistic distribution. here, we compared the proportion of snPs from a given pathway with the proportion of all other genic snPs in the tail of the minimum rank distribution and of the transformed rank distri butions for the individual variables with the strongest genic enrichment. Read the entire page →
From page 79... ... A.M.h. was supported in part by American heart Association Graduate Fellowship 0710189Z and by nih Genetics and regulation Training Grant GM07197. Read the entire page →

From page 63...

... ‡‡ human populations use a variety of subsistence strategies to exploit an exceptionally broad range of ecoregions and dietary components. These aspects of human environments have changed dramatically during human evolution, giving rise to new selective pressures.