%0 Journal Article %J Am J Hum Genet %D 2018 %T Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana. %A Retshabile, Gaone %A Mlotshwa, Busisiwe C %A Williams, Lesedi %A Mwesigwa, Savannah %A Mboowa, Gerald %A Huang, Zhuoyi %A Rustagi, Navin %A Swaminathan, Shanker %A Katagirya, Eric %A Kyobe, Samuel %A Wayengera, Misaki %A Kisitu, Grace P %A Kateete, David P %A Wampande, Eddie M %A Maplanka, Koketso %A Kasvosve, Ishmael %A Pettitt, Edward D %A Matshaba, Mogomotsi %A Nsangi, Betty %A Marape, Marape %A Tsimako-Johnstone, Masego %A Brown, Chester W %A Yu, Fuli %A Kekitiinwa, Adeodata %A Joloba, Moses %A Mpoloka, Sununguko W %A Mardon, Graeme %A Anabwani, Gabriel %A Hanchard, Neil A %K Black People %K Botswana %K Cohort Studies %K Exome Sequencing %K Gene Pool %K Genetic Variation %K Genetics, Population %K Genome, Human %K Geography %K Humans %K Phylogeny %K Principal Component Analysis %X

Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana-a Southern African country that is regionally underrepresented in genomic databases. Using whole-exome sequencing data from 164 Batswana and comparisons with 150 similarly sequenced HIV-positive Ugandan children, we found that 13%-25% of variation observed among Batswana was not captured by public databases. Uncaptured variants were significantly enriched (p = 2.2 × 10) for coding variants with minor allele frequencies between 1% and 5% and included predicted-damaging non-synonymous variants. Among variants found in public databases, corresponding allele frequencies varied widely, with Botswana having significantly higher allele frequencies among rare (<1%) pathogenic and damaging variants. Batswana clustered with other Southern African populations, but distinctly from 1000 Genomes African populations, and had limited evidence for admixture with extra-continental ancestries. We also observed a surprising lack of genetic substructure in Botswana, despite multiple tribal ethnicities and language groups, alongside a higher degree of relatedness than purported founder populations from the 1000 Genomes project. Our observations reveal a complex, but distinct, ancestral history and genomic architecture among Batswana and suggest that disease mapping within similar Southern African populations will require a deeper repository of genetic variation and allelic dependencies than presently exists.

%B Am J Hum Genet %V 102 %P 731-743 %8 2018 May 03 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29706352?dopt=Abstract %R 10.1016/j.ajhg.2018.03.010 %0 Journal Article %J Eur J Hum Genet %D 2010 %T European admixture on the Micronesian island of Kosrae: lessons from complete genetic information. %A Bonnen, Penelope E %A Lowe, Jennifer K %A Altshuler, David M %A Breslow, Jan L %A Stoffel, Markus %A Friedman, Jeffrey M %A Pe'er, Itsik %K Chromosomes, Human, Y %K DNA, Mitochondrial %K Europe %K Female %K Gene Pool %K Genetic Markers %K Genetics, Population %K Genome, Human %K Geography %K Haplotypes %K Humans %K Inheritance Patterns %K Male %K Micronesia %K Pedigree %K Phylogeny %K Software %K Time Factors %X

The architecture of natural variation present in a contemporary population is a result of multiple population genetic forces, including population bottleneck and expansion, selection, drift, and admixture. We seek to untangle the contribution of admixture to genetic diversity on the Micronesian island of Kosrae. Toward this goal, we used a complete genetic approach by combining a dense genome-wide map of 100,000 single-nucleotide polymorphisms (SNPs) with data from uniparental markers from the mitochondrial genome and the nonrecombining portion of the Y chromosome. These markers were typed in approximately 3200 individuals from Kosrae, representing 80% of the adult population of the island. We developed novel software that uses SNP data to delineate ancestry for individual segments of the genome. Through this analysis, we determined that 39% of Kosraens have some European ancestry. However, the vast majority of admixed individuals (77%) have European alleles spanning less than 10% of their genomes. Data from uniparental markers show most of this admixture to be male, introduced in the late nineteenth century. Furthermore, pedigree analysis shows that the majority of European admixture on Kosrae is because of the contribution of one individual. This approach shows the benefit of combining information from autosomal and uniparental polymorphisms and provides new methodology for determining ancestry in a population.

%B Eur J Hum Genet %V 18 %P 309-16 %8 2010 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/19844264?dopt=Abstract %R 10.1038/ejhg.2009.180