Sliding window analysis of pairwise nucleotide differences in the 5’ flanking region of the <i>TYR</i> gene.

<p>Average estimates of pairwise differences (π) at exons, introns and the complete 5’ flanking region are provided for reference. Pairwise differences in six regional population groups are shown separately. Approximate locations of previously known regulatory elements (TDE, TPE and h5’URS) are marked with red diamonds. A newly identified region with decreased genetic variability is marked with a blue diamond. Position numbers are shown relative to the first codon of the <i>TYR</i> gene. Sliding window size is 1500 bp and step size is 375 bp.</p

Global Patterns of Diversity and Selection in Human Tyrosinase Gene

<div><p>Global variation in skin pigmentation is one of the most striking examples of environmental adaptation in humans. More than two hundred loci have been identified as candidate genes in model organisms and a few tens of these have been found to be significantly associated with human skin pigmentation in genome-wide association studies. However, the evolutionary history of different pigmentation genes is rather complex: some loci have been subjected to strong positive selection, while others evolved under the relaxation of functional constraints in low UV environment. Here we report the results of a global study of the human tyrosinase gene, which is one of the key enzymes in melanin production, to assess the role of its variation in the evolution of skin pigmentation differences among human populations. We observe a higher rate of non-synonymous polymorphisms in the European sample consistent with the relaxation of selective constraints. A similar pattern was previously observed in the <i>MC1R</i> gene and concurs with UV radiation-driven model of skin color evolution by which mutations leading to lower melanin levels and decreased photoprotection are subject to purifying selection at low latitudes while being tolerated or even favored at higher latitudes because they facilitate UV-dependent vitamin D production. Our coalescent date estimates suggest that the non-synonymous variants, which are frequent in Europe and North Africa, are recent and have emerged after the separation of East and West Eurasian populations.</p> </div

Ancestral recombination graph of <i>TYR</i> haplotypes.

<p>The tree is rooted by the chimpanzee sequence and presents recombination history of 942 worldwide samples (1884 chromosomes). Haplogroup frequency by populations is shown below the tree. Haplogroup names are shaded in yellow. Green arrows show the origin of recombination prefixes, blue arrows show the origin of recombination suffixes. Recombination points are shown by rectangles. Numerical superscript prefixes to the left of rs identifiers correspond to the relative physical position of SNPs. SNPs which were out of the range of our re-sequencing alignment are marked with superscript suffixes to the right of respective rs identifiers and correspond to the following phylogenetic equivalents in our re-sequencing data: A – rs12799137, B – rs7108676, C – rs12799347, D – rs12417632, E and F – rs5021654, G – rs7934747, H – rs1126809. Non-synonymous mutations or their phylogenetic equivalents are shown in red font with amino-acid substitutions specified. 95% confidence intervals for the detected haplogroup frequencies are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074307#pone.0074307.s011" target="_blank">Table S6</a>.</p

Median-joining network of <i>TYR</i> haplotypes.

<p>The network is based on the analysis of sequence data of the first haplotype block of 8634 bp length in 81 samples (162 chromosomes), color-coded by the geographic region of origin of the samples. Chimpanzee sequence (white circle) was used as an outgroup and chimpanzee specific variants have been excluded from the network output.</p

Consensus maximum likelihood tree for a reduced number of populations with 10 migration events.

<p>Non-bold numbers are bootstrap estimates based on 100 iterations with a support greater than 70%. Quechua, Aymara and Collas form one clade and group with Chilean Andean speakers (Yaghan, Hulliche, Chono and Chilote). Gran Chaco populations (Toba, Wichí, Guaraní, Chané and Kaingang) form a clade with Brazilians (Suruí and Karitiana) and Colombians (Piapoco). Mixe and Pima from Mexico cluster outside all South Americans and Kaqchikel from Guatemala. Branch length refers to the amount of drift experienced but is also increased in populations with more individuals in the data set. Black arrows indicate migrations confirmed as significant by <i>f</i>4 test, while grey arrows indicate insignificant <i>f</i>4 results. Bold numbers represent admixture proportions for black arrows: Toba received 40% admixture proportion from Wichí. Gene flow among Chilean Andeans was strongly supported: Hulliche contributed 100% admixture to Chono and HA Andeans 16%. An ancestral population of Chilote and Chono contributed 37% to Chono and 20% to Chilote. Yaghan contributed 0.05% admixture proportion to Chono.</p

Comparison of variables between Collas and Wichí.

<p>*values correspond to the Commission Internationald'Eclairage L*a*b* system.</p>a<p>p≤0.001,</p>b<p>p<0.05.</p>c<p>Equally significant after correction for further independent variables:</p><p>Weight: corrected for height, age and gender; BMI: corrected for age and gender;</p><p>Systolic blood pressure/Cardiac output: corrected for time since last meal, its caloric amount, age and gender;</p><p>Log (Change in thorax breadth/depth): corrected for age and gender.</p

ADMIXTURE components of Argentinean Natives in a worldwide context.

<p>Populations are divided by six admixture proportions as K = 6 indicated the best fit for the data. The main proportions are derived from Yoruba (k3), Han Chinese (k4), Europeans (k6), Mexicans (Mixe/Pima, k2), Andean populations (k1) and Wichí (k5). Collas are indistinguishable from Aymara and Quechua, while Chilean Andeans mainly consist of Andean (k1) and Mixe/Pima (k2) characteristic admixture proportions. Gran Chaco populations (Kaingang, Chané, Guaraní and Toba) carry Wichí specific admixture proportions among others. The population name is displayed underneath the admixture plot while the sample origin is listed above (A: Argentina, B: Brazil, Bo: Bolivia, C: Colombia, Ch: Chile, G: Guatemala, M: Mexico, P:Paraguay) The population name is followed by a sign designating its study (°: HapMap, ∧: Reich <i>et al </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093314#pone.0093314-Reich1" target="_blank">[64]</a>, ‘: HGDP, “: Mao <i>et al </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093314#pone.0093314-Mao1" target="_blank">[63]</a>, *: this study).</p

Pathways determining hypoxia candidate genes for this study.

<p>Pathways determining hypoxia candidate genes for this study.</p

Hypoxia candidate genes in the 1% of iHS and XP-EHH results in Collas.

<p>Hypoxia candidate genes in the 1% of iHS and XP-EHH results in Collas.</p

<i>VEGFB</i> haplotype characterised by EHH >0.3 in study populations.

<p><i>VEGFB</i> haplotype characterised by EHH >0.3 in study populations.</p