We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences present in these individuals but missing from the reference human genome. We aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the African-descended populations, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes while the rest appear to be intergenic.

Background Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. Objectives To test the hypothesis that some genes may contribute to the profound disparities in asthma. Methods We performed a genome-wide association study in two independent populations of African ancestry (935 African American asthma cases and controls from the Baltimore-Washington, D.C. area, and 929 African Caribbean asthmatics and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. Results Meta-analysis combining these two African-ancestry populations yielded three SNPs with a combined P-value <10-5 in genes of potential biological relevance to asthma and allergic disease: rs10515807, mapping to alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57×10-6); rs6052761, mapping to prion-related protein (PRNP) on chromosome 20pter-p12 (2.27×10-6); and rs1435879, mapping to dipeptidyl peptidase 10 (DPP10) on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of UK and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Conclusions Evidence for association was also examined in four additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease such as asthma in admixed populations, especially populations of African descent.

African descended populations exhibit an increased prevalence of asthma and allergies compared to Europeans. One approach to distinguish between environmental and genetic explanations for this difference is to study relationships of asthma risk to individual admixture. We aimed to determine the admixture proportions of a case-control sample from the Caribbean Coast of Colombia currently participating in genetic studies for asthma, and to test for population stratification and association between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 368 asthmatics and 365 non-asthmatics for 52 autosomal ancestry informative markers, six mtDNA haplogroups and nine haplogroups and five microsatellites in Y chromosome. Autosomal admixture proportions, population stratification, and associations between ancestry and the phenotypes were estimated by ADMIXMAP. The average admixture proportions among asthmatics were 42.8% European, 39.9% African and 17.2% Native American and among non-asthmatics they were 44.2% (P = 0.068), 37.6% (P = 0.007) and 18.1% (P = 0.050), respectively. In the total sample, the paternal contributions were 71% European, 25% African and 4.0% Native American and the maternal lineages were 56.8% Native American, and 20.2% African; 22.9% of the individuals carried other non-Native American mtDNA haplogroups. African ancestry was significantly associated with asthma (OR: 2.97; 95% CI: 1.08-8.08), high tIgE (OR: 1.9; 95% CI: 1.17-3.12) and socioeconomic status (OR = 0.64; 95% CI: 0.47-0.87). Significant population stratification was observed in this sample. Our findings indicate that genetic factors can explain the association between asthma and African ancestry and suggest that this sample is a useful resource for performing admixture mapping for asthma.

This article is available online at http://www.jlr.org Supplementary key words fatty acid desaturase • isolated population • genetic association Several changes in diet over the past century are hypothesized to have been maladaptive, thereby leading to an increase in the incidence of numerous chronic diseases in developed countries ( 1, 2 ). Many of these diseases (obesity, diabetes, asthma, allergies, arthritis and chronic joint disease, dementia, and cardiovascular disease) have a substantial infl ammatory component ( 3-6 ) with notable cooccurrences ( 7,8 ). Perhaps no changes in the modern diet have had a greater impact than the quantitative and qualitative changes in fat consumption. While the percentage of energy from fat ( ‫ف‬ 35%) is thought to be similar in ancestral and contemporary Western diets, the concentrations and ratios of the types of fat that humans eat ( 9, 10 ) have shifted, with marked increases in saturated and omega-6 ( 6) fatty acid consumption. Importantly, these changes have been suggested to alter human health and the incidence of chronic infl ammatory diseases ( 11-13 ).Long-chain serum polyunsaturated fatty acids (LC-PUFA; у 20 carbons), such as arachidonic acid (AA; C20:4 6), and their metabolic products orchestrate several critical events in immunity and infl ammation.Abstract Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and infl ammation through their capacity to be converted to potent infl ammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and fi ve ratios defi ning FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) ( P = 5.8 × 10؊ 7 -1.7 × 10 ؊ 8 ) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the -6 series ( P = 2.11 × 10 ؊ 13 -1.8 × 10 ؊ 20 ). The minor allele across all SNPs was consistently associated with decreased -6 PUFAs, with the exception of dihomo-␥ -linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our fi ndings in a geographically isolated population with a homogenous dietary environment suggest that variants in the ⌬ -5 desaturase enzymatic step likely regulate the effi ciency of conversion of medium-chain PUFAs to potentially infl ammatory PUFAs, such as AA. -Mathias, R. A., C. Vergara, L. Gao, N. Rafaels, T. Hand, M. Campbell, C. Bickel, P. Ivester, S. Sergeant, K. C. Barnes, and F. H. Chilton. FADS genetic variants and -6 polyunsaturated fatty acid metabolism in a homogeneous island population.