KIR polymorphism modulates the avidity and specificity for HLA-C, as well as KIR abundance at the cell surface.

<p>(A) Binding of KIR2DL1-Fc fusion proteins to C2-bearing HLA-C allotypes. For each C2-bearing HLA-C allotype, the KIR2DL1 binding is the mean of the values obtained with 11 different KIR2DL1-Fc (2DL1*001, *003, *004, *007, *008, *012, *020, *021, *023 *024, *025). Each individual binding value was normalized to the binding of the W6/32 antibody before calculating the average. (B) Binding of KIR2DL1*022-Fc and KIR2DL2/3-Fc fusion proteins to C1-bearing HLA-B and -C allotypes. For each C1-bearing HLA-B and HLA-C allotype, the KIR2DL2/3 binding is the mean of the values obtained with 16 KIR2DL-Fc fusion proteins (2DL1*022; 2DL2*001,*003, *004, *006, 009 *011; and 2DL3*001, *005, *008, *009, *011, *013, *015, *016, *018). The proteins were tested against microbeads coated with one of nine C1 HLA-C or two C1 HLA-B allotypes. Each individual binding value was normalized to the binding to that of the W6/32 antibody before calculating the average. (C) Variable cell-surface expression of KIR2DL1. FLAG-tagged KIR2DL1 allotypes were transfected into HeLa cells. Cell-surface expression was detected using FLAG-specific antibody and analysis by flow cytometry. MFI = median fluorescence intensity. The experiment was performed in triplicate, error bars give the standard deviation. The difference between 2DL1*012 and 2DL1*026 is statistically significant as assessed by a two-tailed t-test.</p

The KhoeSan have high <i>KIR2DL1</i> diversity compared to other human populations.

<p>(A and B) The pie charts show the number and relative frequencies of <i>KIR2DL1</i> alleles in the KhoeSan of Southern Africa (A), and four other populations representing four continents (B): the Ga-Adangbe from Ghana in Western Africa [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005439#pgen.1005439.ref014" target="_blank">14</a>], Northern Ireland Caucasians from Europe [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005439#pgen.1005439.ref021" target="_blank">21</a>], Japanese from East Asia [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005439#pgen.1005439.ref024" target="_blank">24</a>] and Yucpa Amerindians from South America [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005439#pgen.1005439.ref020" target="_blank">20</a>]. The 'blank' is the frequency of <i>KIR</i> haplotypes that lack the <i>KIR2DL1</i> gene. (C) Also compared in the five populations are the frequencies of strong KIR2DL1, weak KIR2DL1, KIR2DL1 that are not inhibitory C2 receptors (inactive) and the absence of KIR2DL1 (blank). The definition and designation of these KIR2DL1 categories are given in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005439#pgen.1005439.s004" target="_blank">S4 Fig</a>.</p

The C2 frequency in the KhoeSan is unusually high.

<p>Each of the seven blue-shaded vertical bars gives the number of populations, of 140 considered [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005439#pgen.1005439.ref034" target="_blank">34</a>], that have a C2 frequency within the range covered by the bar, given on the horizontal axis. The frequency data are not significantly different from a normal distribution (grey line). The black-shaded dots on the curve give the frequencies for the KhoeSan and the four other populations for which <i>KIR2DL1</i> allele frequencies are given in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005439#pgen.1005439.g003" target="_blank">Fig 3</a>.</p

<i>KIR2DL1*022</i> and <i>2DL1*026</i> are of recent origin compared to other KhoeSan <i>KIR2DL1</i> alleles.

<p>(A) For each KhoeSan <i>KIR2DL1</i> allele, the number of centromeric <i>KIR</i> haplotypes on which the allele is present in the KhoeSan (number observed) is plotted against the number of different (distinct) haplotypes on which the allele is present. In total, 110 haplotypes were analyzed. Haplotypes that lack <i>KIR2DL1</i> are denoted ‘blank’. The r² was calculated from Pearson correlation of the alleles shown in blue. This analysis excluded <i>2DL1*022</i> and <i>*026</i> (shown in red). (B) Shows the allele content of centromeric <i>KIR</i> haplotypes containing either <i>2DL1*022</i> (purple) or <i>2DL1*026</i> (yellow). The observed number of each haplotype is given on the left. Also shown (in white) are the KhoeSan haplotypes that are the putative parents (Par?) of the derived <i>2DL*022-</i>containing and <i>2DL1*026</i>-containing haplotypes. The putative parents are the haplotypes that differ from the derived haplotypes by the least number of nucleotide substitutions. (C) Plot of haplotype frequency against linkage disequilibrium (LD). The analysis was conditioned so that <i>2DL2*003</i>-bearing haplotypes were analyzed. The figure illustrates the high level of linkage disequilibrium observed for haplotypes containing <i>2DL1*022</i> and <i>2DL1*026</i> suggesting they appeared more recently in the KhoeSan population than other <i>KIR2DL1</i> alleles.</p

A variant of KIR2DL1 originating in the KhoeSan is a C1-specific receptor and not a C2-specific receptor like other KIR2DL1.

<p>(A) This alignment of KIR2DL1 sequence differences shows the sites of polymorphism in the D1 domain (D1), the D2 domain (D2) and the transmembrane region (Tm). Dashes denote identity with the KIR2DL1*003 sequence, an asterisk denotes a termination codon. Sequences of the KhoeSan KIR2DL1 allotypes are highlighted in yellow. The names of allotypes with D1, D2 and Tm identical to an aligned sequence are listed in the column at the right. (B) Binding of KIR2DL1-Fc fusion proteins to microbeads coated with C1-bearing and seven C2-bearing HLA-C allotypes. Each binding value was normalized to that of the W6/32 antibody and these normalized values were averaged for the C1 (N = 9) and C2 (N = 7) allotype groups. The names of allotypes present in the KhoeSan are boldened. A dagger following the listed allotype indicates that the allotype represents a group of two or more alleles that encode identical ligand binding domains (see Panel A). (C) This alignment of KIR2DL2/3 sequence differences shows the sites of polymorphism in the D1 and D2 domains. Dashes denote identity with the KIR2DL2*001 sequence Sequences of the KhoeSan KIR2DL2/3 allotypes are highlighted in yellow. The names of allotypes with D1 and D2 identical to an aligned sequence are listed in the column at the right. (D) Binding of KIR2DL2/3-Fc fusion proteins to microbeads coated with C1-bearing and C2-bearing HLA-C allotypes. Each binding value was normalized to that of the W6/32 antibody and these normalized values were averaged for the C1 (N = 9) and C2 (N = 7) groups. The names of allotypes present in the KhoeSan are boldened. Groups of allotypes with identical D1 and D2 domains, and which are represented by a single KIR2DL2/3-Fc, are as shown in the column on the right of Panel A. A dagger following the listed allotype indicates that the allotype represents a group of two or more alleles that encode identical ligand binding domains (see Panel A).</p

Admixture times and proportions of ancestral populations for SCCS in (A) the model with two pulses of admixture and (B) the model with three pulses of admixture.

<p>Because the model features a continuous time parameter but discrete generation times, a single pulse occurring at a fractional time contributes migrants to the two adjacent discrete generation times. African, European, and Native American ancestries are displayed respectively in blue, red, and yellow. Rectangles show the proportion of each ancestry at each generation. Pie charts represent migrations, with the size of the pie representing the amounts of migrants at a given generation and the sectors representing the proportion of migrants coming from each source population. (C) Distribution of continuous ancestry tract lengths (dots) compared with predictions from the best-fit model (lines) for SCCS. Points in the shaded area are within one standard deviation of the predicted result. Kinks in the distribution are due to the finite length of chromosomes [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006059#pgen.1006059.ref016" target="_blank">16</a>]. (D) Inferred time to admixture and African ancestry proportions as functions of birth year in HRS African-Americans. (E) Proportions of African ancestry in African-Americans within the North, South, and West using region of birth, region of residence, and migration status; bootstrap <i>p</i>-values are calculated between disjoint sets of individuals.</p

Population Genetic Structure and Origins of Native Hawaiians in the Multiethnic Cohort Study

<div><p>The population genetic structure of Native Hawaiians has yet to be comprehensively studied, and the ancestral origins of Polynesians remain in question. In this study, we utilized high-resolution genome-wide SNP data and mitochondrial genomes of 148 and 160 Native Hawaiians, respectively, to characterize their population structure of the nuclear and mitochondrial genomes, ancestral origins, and population expansion. Native Hawaiians, who self-reported full Native Hawaiian heritage, demonstrated 78% Native Hawaiian, 11.5% European, and 7.8% Asian ancestry with 99% belonging to the B4 mitochondrial haplogroup. The estimated proportions of Native Hawaiian ancestry for those who reported mixed ancestry (i.e. 75% and 50% Native Hawaiian heritage) were found to be consistent with their self-reported heritage. A significant proportion of Melanesian ancestry (mean = 32%) was estimated in 100% self-reported Native Hawaiians in an ADMIXTURE analysis of Asian, Melanesian, and Native Hawaiian populations of K = 2, where K denotes the number of ancestral populations. This notable proportion of Melanesian admixture supports the “Slow-Boat” model of migration of ancestral Polynesian populations from East Asia to the Pacific Islands. In addition, approximately 1,300 years ago a single, strong expansion of the Native Hawaiian population was estimated. By providing important insight into the underlying population structure of Native Hawaiians, this study lays the foundation for future genetic association studies of this U.S. minority population.</p> </div

Pairwise genetic relatedness across US census regions among (A) African-Americans, (B) European-Americans, and (C) African-Americans and European-Americans.

<p>(D) Census-based prediction for African-Americans (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006059#sec008" target="_blank">Materials and Methods</a>). On each map, the line connecting two regions shows the average relatedness between individuals in those regions, and the thickness and opacity of the lines are on a linear scale between the minimum and maximum values shown above the map. Relatedness between regions with fewer than 10,000 possible pairs of individuals is not shown (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006059#sec008" target="_blank">Materials and Methods</a> for details). All numbers are in units of cM. (E) Decay of average IBD (shown in logarithmic scale) as a function of distance using IBD segments of length 18cM or longer from HRS (dots), compared to the analytical model (lines).</p

Inferred proportions of African, European, and Native American/Asian ancestry in three African-American cohorts with 95% confidence intervals based on sample bootstrap.

<p>These confidence intervals do not account for possible sampling biases.</p

Multi-Dimensional Scaling analysis of GWAS data.

<p>HGDP representative samples with European, East Asian and Oceanian ancestry and are plotted against Native Hawaiians with various degrees of self-reported ancestry in MDS dimensions.</p