The African Genome Variation Project shapes medical genetics in Africa

Gurdasani, Deepti; Carstensen, Tommy; Tekola‐Ayele, Fasil; Pagani, Luca; Tachmazidou, Ioanna; Hatzikotoulas, Konstantinos; Karthikeyan, Savita; Iles, Louise; Pollard, Martin; Choudhury, Ananyo; Ritchie, Graham R. S.; Xue, Yali; Asimit, Jennifer; Nsubuga, Rebecca N.; Young, Elizabeth H.; Pomilla, Cristina; Kivinen, Katja; Rockett, Kirk; Kamali, Anatoli; Doumatey, Ayo P.; Asiki, Gershim; Seeley, Janet; Sisay-Joof, Fatoumatta; Jallow, Muminatou; Tollman, Stephen; Mekonnen, Ephrem; Ekong, Rosemary; Oljira, Tamiru; Bradman, Neil; Bojang, Kalifa; Ramsay, Michèle; Adeyemo, Adebowale; Bekele, Endashaw; Motala, Ayesha A.; Norris, Shane A.; Pirie, Fraser; Kaleebu, Pontiano; Kwiatkowski, Dominic P.; Tyler‐Smith, Chris; Rotimi, Charles N.; Zeggini, Eleftheria; Sandhu, Manjinder S.

doi:10.1038/nature13997

Cited by 485 publications

(592 citation statements)

References 48 publications

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“…Transethnic fine-mapping of deeply imputed datasets can then deliver further resolution of causal genes and variants. 86 We found moderate overlap of genes implicated by the GWAS, the two fine-mapping methods, and eQTL and mQTL analyses (Table 3). Altogether we have found 283 unique genes, 225 (79.5%) of which were found by only one method, while there were no genes identified by all methods (46 and 12 genes were found by two or three methods, respectively).…”

Section: Discussionmentioning

confidence: 88%

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Tachmazidou

Süveges

Min

et al. 2017

The American Journal of Human Genetics

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139

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Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common-and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

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Section: Discussionmentioning

confidence: 88%

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Tachmazidou

Süveges

Min

et al. 2017

The American Journal of Human Genetics

Self Cite

139

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“…4B). This reflects the current understanding of Africa as the most genetically diverse region in the world (5). Of the 150 million SNVs observed in the ECR, 82 million (54.7%) have not been reported in dbSNP of the National Center for Biotechnology Information (NCBI) or in the most recent phase 3 of the 1000 Genomes Project (3).…”

Section: Resultsmentioning

confidence: 99%

“…genomics | noncoding genome | human genetic diversity R ecent technological advances have allowed for the largescale sequencing of the whole human genome (1)(2)(3)(4)(5)(6)(7). Most studies generated population-based information on human diversity using low to intermediate coverage of the genome (4× to 20× sequencing depth).…”

mentioning

confidence: 99%

Deep sequencing of 10,000 human genomes

Telenti

Pierce

Biggs

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

311

195

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We report on the sequencing of 10,545 human genomes at 30×-40× coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome can be sequenced confidently. This high-confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present the distribution of over 150 million single-nucleotide variants in the coding and noncoding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries on average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct high-resolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.genomics | noncoding genome | human genetic diversity

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“…This analysis utilized data from the Zulu [64] (Omni 2.5 array and low coverage sequence data, re-called with the rest of the African samples) and 6 ¼Khomani San (550K and Omni Express and Omni Express Plus) and exome data). Exome data along with SNP array data (550k, Omni Express and Omni Express Plus) were merged with the HGDP set for the network analysis.…”

Section: Population Structure Analysesmentioning

confidence: 99%

Population Genetic Analysis of the DARC Locus (Duffy) Reveals Adaptation from Standing Variation Associated with Malaria Resistance in Humans

McManus

Taravella

Henn

et al. 2016

Preprint

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The human DARC (Duffy antigen receptor for chemokines) gene encodes a membranebound chemokine receptor crucial for the infection of red blood cells by Plasmodium vivax, a major causative agent of malaria. Of the three major allelic classes segregating in human populations, the FY*O allele has been shown to protect against P. vivax infection and is at near fixation in sub-Saharan Africa, while FY*B and FY*A are common in Europe and Asia, respectively. Due to the combination of strong geographic differentiation and association with malaria resistance, DARC is considered a canonical example of positive selection in humans. Despite this, details of the timing and mode of selection at DARC remain poorly understood. Here, we use sequencing data from over 1,000 individuals in twenty-one human populations, as well as ancient human genomes, to perform a fine-scale investigation of the evolutionary history of DARC. We estimate the time to most recent common ancestor (T MRCA ) of the most common FY*O haplotype to be 42 kya (95% CI: 34-49 kya). We infer the FY*O null mutation swept to fixation in Africa from standing variation with very low initial frequency (0.1%) and a selection coefficient of 0.043 (95% CI:0.011-0.18), which is among the strongest estimated in the human genome. We estimate the T MRCA of the FY*A mutation in non-Africans to be 57 kya (95% CI: 48-65 kya) and infer that, prior to the sweep of FY*O, all three alleles were segregating in Africa, as highly diverged populations from Asia and 6 ¼Khomani San hunter-gatherers share the same FY*A haplotypes. We test multiple models of admixture that may account for this observation and reject recent Asian or European admixture as the cause.

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The African Genome Variation Project shapes medical genetics in Africa

Cited by 485 publications

References 48 publications

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Deep sequencing of 10,000 human genomes

Population Genetic Analysis of the DARC Locus (Duffy) Reveals Adaptation from Standing Variation Associated with Malaria Resistance in Humans

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