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Additional file 3: Table S2. Shortlist of three candidate variants identified as plausible disease-causing variants.

Additional file 4: Table S3. Details of the candidate variant narrowed down using consecutive filters based on an autosomal recessive model of inheritance and low frequency.

Additional file 1: Table S1. Demographic model used to simulated SAC population

Additional file 2: Table S1. Summary of exome sequencing data for the patient and his parents.

Additional file 1: Figure S1. Timeline of symptoms presented by the index case.

Skin pigmentation is under strong directional selection in northern European and Asian populations. The indigenous KhoeSan populations of far southern Africa have lighter skin than other sub-Saharan African populations, potentially reflecting local adaptation to a region of Africa with reduced UV radiation. Here, we demonstrate that a canonical Eurasian skin pigmentation gene, SLC24A5, was introduced to southern Africa via recent migration and experienced strong adaptive evolution in the KhoeSan. To reconstruct the evolution of skin pigmentation, we collected phenotypes from over 400 ≠Khomani San and Nama individuals and high-throughput sequenced candidate pigmentation genes. The derived causal allele in SLC24A5, p.Ala111Thr, significantly lightens basal skin pigmentation in the KhoeSan and explains 8 to 15% of phenotypic variance in these populations. The frequency of this allele (33 to 53%) is far greater than expected from colonial period European gene flow; however, the most common derived haplotype is identical among European, eastern African, and KhoeSan individuals. Using four-population demographic simulations with selection, we show that the allele was introduced into the KhoeSan only 2,000 y ago via a back-to-Africa migration and then experienced a selective sweep (s = 0.04 to 0.05 in ≠Khomani and Nama). The SLC24A5 locus is both a rare example of intense, ongoing adaptation in very recent human history, as well as an adaptive gene flow at a pigmentation locus in humans.

Aicardi-Goutières syndrome (AGS) is an encephalopathy of early childhood. This disorder is genetically heterogeneous, with mutations in seven genes having been identified to be disease-causing. Most patients with AGS present with poordevelopmental outcome and reduced survival in the neonatal period or early infancy. Significant variability can be found in the onset and phenotypic severity of the condition, sometimes even within the same family. Here we describe two sisters of mixed ancestry from the Western Cape province of South Africa presenting with skin manifestations of autoimmune disease resembling those of systemic lupus erythematosus (SLE) on histology but with negative serology. The two affected individuals carried a homozygous c.1681_1682delAG; p. Ser561Phefs*61 mutation in exon 15 of SAMHD1 on chromosome 20. Both parents and the unaffected brother are heterozygous for this variant. The molecular investigation yielded a unifying diagnosis for an unusual combination of physical findings and differential phenotypic expression in the sisters. A confirmed diagnosis allowed for informed genetic counselling and targeted investigation and screening for complications such as glaucoma in the older sister.

Human genetic studies have long been vastly Eurocentric, raising a key question about the generalizability of these study findings to other populations. Because humans originated in Africa, these populations retain more genetic diversity, and yet individuals of African descent have been tremendously underrepresented in genetic studies. The diversity in Africa affords ample opportunities to improve fine-mapping resolution for associated loci, discover novel genetic associations with phenotypes, build more generalizable genetic risk prediction models, and better understand the genetic architecture of complex traits and diseases subject to varying environmental pressures. Thus, it is both ethically and scientifically imperative that geneticists globally surmount challenges that have limited progress in African genetic studies to date. Additionally, African investigators need to be meaningfully included, as greater inclusivity and enhanced research capacity afford enormous opportunities to accelerate genomic discoveries that translate more effectively to all populations. We review the advantages, challenges, and examples of genetic architecture studies of complex traits and diseases in Africa. For example, with greater genetic diversity comes greater ancestral heterogeneity; this higher level of understudied diversity can yield novel genetic findings, but some methods that assume homogeneous population structure and work well in European populations may work less well in the presence of greater heterogeneity in African populations. Consequently, we advocate for methodological development that will accelerate studies important for all populations, especially those currently underrepresented in genetics.

The functions of human NK cells in defense against pathogens and placental development during reproduction are modulated by interactions of killer cell Ig-like receptors (KIRs) with HLA-A, -B and -C class I ligands. Both receptors and ligands are highly polymorphic and exhibit extensive differences between human populations. Indigenous to southern Africa are the KhoeSan, the most ancient group of modern human populations, who have highest genomic diversity worldwide. We studied two KhoeSan populations, the Nama pastoralists and the ≠Khomani San hunter-gatherers. Comprehensive next-generation sequence analysis of HLA-A, -B, and -C and all KIR genes identified 248 different KIR and 137 HLA class I, which assort into ∼200 haplotypes for each gene family. All 74 Nama and 78 ≠Khomani San studied have different genotypes. Numerous novel KIR alleles were identified, including three arising by intergenic recombination. On average, KhoeSan individuals have seven to eight pairs of interacting KIR and HLA class I ligands, the highest diversity and divergence of polymorphic NK cell receptors and ligands observed to date. In this context of high genetic diversity, both the Nama and the ≠Khomani San have an unusually conserved, centromeric KIR haplotype that has arisen to high frequency and is different in the two KhoeSan populations. Distinguishing these haplotypes are independent mutations in KIR2DL1, which both prevent KIR2DL1 from functioning as an inhibitory receptor for C2+ HLA-C. The relatively high frequency of C2+ HLA-C in the Nama and the ≠Khomani San appears to have led to natural selection against strong inhibitory C2-specific KIR.

The functions of human natural killer (NK) cells in defense against pathogens and placental development during reproduction are modulated by interactions of killer cell immunoglobulin-like receptors (KIR) with HLA-A, -B and -C class I ligands. Both receptors and ligands are highly polymorphic and exhibit extensive differences between human populations. Indigenous to Southern Africa are the KhoeSan, the most ancient group of modern human populations, who have highest genomic diversity worldwide. We studied two KhoeSan populations, the Nama pastoralists and the ≠Khomani San hunter-gatherers. Comprehensive next-generation sequence analysis of HLA-A, -B and -C and all KIR genes identified 248 different KIR and 137 HLA class I, which assort into ~200 haplotypes for each gene family. All 74 Nama and 78 ≠Khomani San studied have different genotypes. Numerous novel KIR alleles were identified, including three arising by intergenic recombination. On average, KhoeSan individuals have 7–8 pairs of interacting KIR and HLA class I ligands, the highest diversity and divergence of polymorphic NK cell receptors and ligands observed to date. In this context of high genetic diversity, both the Nama and the Khomani San have an unusually conserved, centromeric KIR haplotype that has arisen to high frequency and is different in the two KhoeSan populations. Distinguishing these haplotypes are independent mutations in KIR2DL1, that both prevent KIR2DL1 from functioning as an inhibitory receptor for C2(+) HLA-C. The relatively high frequency of C2(+) HLA-C in the Nama and the ≠Khomani San appears to have led to natural selection against strong inhibitory C2-specific KIR.

Each panel shows individuals plotted by sequential combinations of the first five principle components, color-coded by sample herd. Here we see no obvious clustering based on herd membership. The eigenvalues of the first twenty principle components are plotted as an inset in the top left panel with the first five PCs highlighted in red. We see the decrease in eigenvalue levels off after principle component five.;Animals heterozygous or homozygous for the ‘G’ risk allele (red or violet) produce 45% less IL-12 than CC animals following pokeweed mitogen stimulation of whole blood (top panel). IL-12 production was not significantly associated with variation at SNP3195. Additionally, we observed no detectable difference in interferon gamma (INFγ) or interleukin 4 (IL-4) production relative to SNP2253 and SNP3195 genotype in this herd.

Each panel shows individuals plotted by sequential combinations of the first five principle components, color-coded by sample herd. Here we see no obvious clustering based on herd membership. The eigenvalues of the first twenty principle components are plotted as an inset in the top left panel with the first five PCs highlighted in red. We see the decrease in eigenvalue levels off after principle component five.;Animals heterozygous or homozygous for the ‘G’ risk allele (red or violet) produce 45% less IL-12 than CC animals following pokeweed mitogen stimulation of whole blood (top panel). IL-12 production was not significantly associated with variation at SNP3195. Additionally, we observed no detectable difference in interferon gamma (INFγ) or interleukin 4 (IL-4) production relative to SNP2253 and SNP3195 genotype in this herd.

BACKGROUND: Tuberculosis, which is caused by Mycobacterium tuberculosis, remains one of the leading causes of mortality worldwide. The C-type lectin DC-SIGN is known to be the major M. tuberculosis receptor on human dendritic cells. We reasoned that if DC-SIGN interacts with M. tuberculosis, as well as with other pathogens, variation in this gene might have a broad range of influence in the pathogenesis of a number of infectious diseases, including tuberculosis. METHODS AND FINDINGS: We tested whether polymorphisms in CD209, the gene encoding DC-SIGN, are associated with susceptibility to tuberculosis through sequencing and genotyping analyses in a South African cohort. After exclusion of significant population stratification in our cohort, we observed an association between two CD209 promoter variants (-871G and -336A) and decreased risk of developing tuberculosis. By looking at the geographical distribution of these variants, we observed that their allelic combination is mainly confined to Eurasian populations. CONCLUSIONS: Our observations suggest that the two -871G and -336A variants confer protection against tuberculosis. In addition, the geographic distribution of these two alleles, together with their phylogenetic status, suggest that they may have increased in frequency in non-African populations as a result of host genetic adaptation to a longer history of exposure to tuberculosis. Further characterization of the biological consequences of DC-SIGN variation in tuberculosis will be crucial to better appreciate the role of this lectin in interactions between the host immune system and the tubercle bacillus as well as other pathogens.