title: Identifying Darwinian selection acting on different human APOL1 variants among diverse African populations.
abstract: Disease susceptibility can arise as a consequence of adaptation to infectious disease. Recent findings have suggested that higher rates of chronic kidney disease (CKD) in individuals with recent African ancestry might be attributed to two risk alleles (G1 and G2) at the serum-resistance-associated (SRA)-interacting-domain-encoding region of APOL1. These two alleles appear to have arisen adaptively, possibly as a result of their protective effects against human African trypanosomiasis (HAT), or African sleeping sickness. In order to explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. Whereas allele frequencies of G2 were similar across all populations (3%-8%), the G1 allele was only common in the Yoruba (39%). Additionally, we identified a haplotype (termed G3) that contains a nonsynonymous change at the membrane-addressing-domain-encoding region of APOL1 and is present in all populations except for the Yoruba. Analyses of long-range patterns of linkage disequilibrium indicate evidence of recent selection acting on the G3 haplotype in Fulani from Cameroon. Our results indicate that the G1 and G2 variants in APOL1 are geographically restricted and that there might be other functional variants that could play a role in HAT resistance and CKD risk in African populations.
authors.affiliation: Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wen-Ya
authors.initials: WY
authors.lastname: Ko
authors.forename: Prianka
authors.initials: P
authors.lastname: Rajan
authors.forename: Felicia
authors.initials: F
authors.lastname: Gomez
authors.forename: Laura
authors.initials: L
authors.lastname: Scheinfeldt
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: Alain
authors.initials: A
authors.lastname: Froment
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Nyambo
authors.forename: Sabah A
authors.initials: SA
authors.lastname: Omar
authors.forename: Charles
authors.initials: C
authors.lastname: Wambebe
authors.forename: Alessia
authors.initials: A
authors.lastname: Ranciaro
authors.forename: Jibril B
authors.initials: JB
authors.lastname: Hirbo
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tishkoff
mesh_terms: D000220:Adaptation, Biological; D000349:Africa; D000483:Alleles; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D060467:Disease Resistance / Q000235:genetics; D019143:Evolution, Molecular; D005091:Exons; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population / Q000379:methods; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008075:Lipoproteins, HDL / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000208:ethnology / Q000235:genetics; D012307:Risk Factors; D012641:Selection, Genetic; D014353:Trypanosomiasis, African / Q000208:ethnology / Q000235:genetics
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL