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Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt".

ABSTRACT: Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ? 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations.

SUBMITTER: Gouveia MH

PROVIDER: S-EPMC6426263 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt".

Gouveia Mateus H MH Bergen Andrew W AW Borda Victor V Nunes Kelly K Leal Thiago P TP Ogwang Martin D MD Yeboah Edward D ED Mensah James E JE Kinyera Tobias T Otim Isaac I Nabalende Hadijah H Legason Ismail D ID Mpoloka Sununguko Wata SW Mokone Gaonyadiwe George GG Kerchan Patrick P Bhatia Kishor K Reynolds Steven J SJ Birtwum Richard B RB Adjei Andrew A AA Tettey Yao Y Tay Evelyn E Hoover Robert R Pfeiffer Ruth M RM Biggar Robert J RJ Goedert James J JJ Prokunina-Olsson Ludmila L Dean Michael M Yeager Meredith M Lima-Costa M Fernanda MF Hsing Ann W AW Tishkoff Sarah A SA Chanock Stephen J SJ Tarazona-Santos Eduardo E Mbulaiteye Sam M SM

PLoS genetics 20190308 3

Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories r ...[more]

PMID: 30849090

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Project description:Background: Malaria infection is reportedly linked to endemic Burkitt lymphoma (eBL) in malaria-endemic areas. This study aimed to pool the overall risk (or odds) of eBL among children with previous or concurrent malaria infection. Methods: We searched PubMed, Web of Science, Scopus, and reference lists of publications for potentially relevant studies on malaria infection and eBL. The quality of the included studies was assessed using the Joanna Briggs Institute for case-control studies. Random-effects meta-analysis was used to summarize whether the odds of eBL can be increased by (1) malaria infection or (2) elevated titer of IgGs to malaria antigen. The level of heterogeneity was evaluated using Cochran's Q statistic and I2. The individual study data, pooled odds, and confidence interval (CI) were illustrated using the forest plot. Publication bias was assessed using funnel plots and Egger's test. Results: Ten studies were included, reporting the number of malaria cases in eBL and non-eBL (5 studied malaria infection and the odds of eBL; five studied the burden of IgGs to malarial antigens and the odds of eBL). According to the meta-analysis results, the odds of eBL was not increased by malaria infection (p = 0.562, OR: 0.87, 95% CI: 0.54-1.39, I2: 93.5%, malaria in eBL: 604/1506 cases, malaria in non-eBL: 2117/4549 cases) and the elevated titer of IgGs to malaria antigen (p = 0.051, OR: 1.50, 95% CI: 1.00-2.25, I2: 89%, increased IgG titer in eBL: 1059/1736 cases, increased IgG titer in non-eBL: 847/1722 cases). In meta-regression analysis, sex was not a confounding factor for the effect size of malaria infection and eBL (p = 0.10) and that of increased IgGs and eBL (p = 0.80). Conclusions: Malaria infection and IgG titer elevation did not increase the risk for eBL among children. However, the included studies, which are only few, do not generally agree on this point. Therefore, the risk for eBL in children diagnosed with malaria should be investigated further by longitudinal studies to confirm our evidence-based approach.

Project description:BACKGROUND:Burkitt lymphoma (BL) is characterized by overexpression of the c-myc oncogene, which in the vast majority of cases is a consequence of an IGH/MYC translocation. While myc is the seminal event, BL is a complex amalgam of genetic and epigenetic changes causing dysregulation of both coding and non-coding transcripts. Emerging evidence suggest that abnormal modulation of mRNA transcription via miRNAs might be a significant factor in lymphomagenesis. However, the alterations in these miRNAs and their correlations to their putative mRNA targets have not been extensively studied relative to normal germinal center (GC) B cells. METHODS:Using more sensitive and specific transcriptome deep sequencing, we compared previously published small miRNA and long mRNA of a set of GC B cells and eBL tumors. MiRWalk2.0 was used to identify the validated target genes for the deregulated miRNAs, which would be important for understanding the regulatory networks associated with eBL development. RESULTS:We found 211 differentially expressed (DE) genes (79 upregulated and 132 downregulated) and 49 DE miRNAs (22 up-regulated and 27 down-regulated). Gene Set enrichment analysis identified the enrichment of a set of MYC regulated genes. Network propagation-based method and correlated miRNA-mRNA expression analysis identified dysregulated miRNAs, including miR-17~95 cluster members and their target genes, which have diverse oncogenic properties to be critical to eBL lymphomagenesis. Central to all these findings, we observed the downregulation of ATM and NLK genes, which represent important regulators in response to DNA damage in eBL tumor cells. These tumor suppressors were targeted by multiple upregulated miRNAs (miR-19b-3p, miR-26a-5p, miR-30b-5p, miR-92a-5p and miR-27b-3p) which could account for their aberrant expression in eBL. CONCLUSION:Combined loss of p53 induction and function due to miRNA-mediated regulation of ATM and NLK, together with the upregulation of TFAP4, may be a central role for human miRNAs in eBL oncogenesis. This facilitates survival of eBL tumor cells with the IGH/MYC chromosomal translocation and promotes MYC-induced cell cycle progression, initiating eBL lymphomagenesis. This characterization of miRNA-mRNA interactions in eBL relative to GC B cells provides new insights on miRNA-mediated transcript regulation in eBL, which are potentially useful for new improved therapeutic strategies.

Dataset Information

Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt".

Publications

Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt".

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