Format

Send to

Choose Destination
Am J Hum Genet. 2018 May 3;102(5):731-743. doi: 10.1016/j.ajhg.2018.03.010. Epub 2018 Apr 26.

Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana.

Author information

1
Department of Biological Sciences, University of Botswana, Gaborone, Botswana.
2
Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda.
3
Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda; Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; USDA/ARS/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda.
7
Baylor College of Medicine Children's Foundation, Kampala, Uganda.
8
Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda; Department of Bio-molecular Resources, College of Veterinary Medicine, Makerere University, Kampala, Uganda.
9
Department of Medical Laboratory Sciences, University of Botswana, Gaborone, Botswana.
10
Botswana-Baylor Children's Clinical Centre of Excellence, Gaborone, Botswana.
11
Botswana-Baylor Children's Clinical Centre of Excellence, Gaborone, Botswana; Pediatric Retrovirology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
12
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; University of Tennessee Health Science Center, Memphis, TN 38105, USA.
13
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
14
Baylor College of Medicine Children's Foundation, Kampala, Uganda; Pediatric Retrovirology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
15
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
16
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; USDA/ARS/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hanchard@bcm.edu.

Abstract

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 × 10-16) 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.

KEYWORDS:

AIDS; Africa; HIV; genetic mapping; genomics; population genetics

PMID:
29706352
PMCID:
PMC5986695
DOI:
10.1016/j.ajhg.2018.03.010
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center