title: Haptoglobin (HP) and Haptoglobin-related protein (HPR) copy number variation, natural selection, and trypanosomiasis.
abstract: Haptoglobin, coded by the HP gene, is a plasma protein that acts as a scavenger for free heme, and haptoglobin-related protein (coded by the HPR gene) forms part of the trypanolytic factor TLF-1, together with apolipoprotein L1 (ApoL1). We analyse the polymorphic small intragenic duplication of the HP gene, with alleles Hp1 and Hp2, in 52 populations, and find no evidence for natural selection either from extended haplotype analysis or from correlation with pathogen richness matrices. Using fiber-FISH, the paralog ratio test, and array-CGH data, we also confirm that the HPR gene is copy number variable, with duplication of the whole HPR gene at polymorphic frequencies in west and central Africa, up to an allele frequency of 15 %. The geographical distribution of the HPR duplication allele overlaps the region where the pathogen causing chronic human African trypanosomiasis, Trypanosoma brucei gambiense, is endemic. The HPR duplication has occurred on one SNP haplotype, but there is no strong evidence of extended homozygosity, a characteristic of recent natural selection. The HPR duplication shows a slight, non-significant undertransmission to human African trypanosomiasis-affected children of unaffected parents in the Democratic Republic of Congo. However, taken together with alleles of APOL1, there is an overall significant undertransmission of putative protective alleles to human African trypanosomiasis-affected children.
authors.affiliation: Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hardwick
authors.forename: Anne
authors.initials: A
authors.lastname: Ménard
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Milet
authors.forename: André
authors.initials: A
authors.lastname: Garcia
authors.forename: Claude
authors.initials: C
authors.lastname: Sese
authors.forename: Fengtang
authors.initials: F
authors.lastname: Yang
authors.forename: Beiyuan
authors.initials: B
authors.lastname: Fu
authors.forename: David
authors.initials: D
authors.lastname: Courtin
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hollox
mesh_terms: D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics*; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics; D055028:Comparative Genomic Hybridization; D003223:Congo; D056915:DNA Copy Number Variations; D020440:Gene Duplication; D005787:Gene Frequency; D056726:Genetic Association Studies; D005828:Genetics, Population; D006239:Haplotypes; D006242:Haptoglobins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008075:Lipoproteins, HDL / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D014347:Trypanosoma brucei gambiense / Q000302:isolation & purification; D014353:Trypanosomiasis, African / Q000453:epidemiology / Q000235:genetics*
chemical_list: C108666:APOL1 protein, human; D000951:Antigens, Neoplasm; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; C058632:HPR protein, human; D006242:Haptoglobins; D008075:Lipoproteins, HDL; C434063:TLF1 protein, human