title: Evolution of the primate trypanolytic factor APOL1.
abstract: ApolipoproteinL1 (APOL1) protects humans and some primates against several African trypanosomes. APOL1 genetic variants strongly associated with kidney disease in African Americans have additional trypanolytic activity against Trypanosoma brucei rhodesiense, the cause of acute African sleeping sickness. We combined genetic, physiological, and biochemical studies to explore coevolution between the APOL1 gene and trypanosomes. We analyzed the APOL1 sequence in modern and archaic humans and baboons along with geographic distribution in present day Africa to understand how the kidney risk variants evolved. Then, we tested Old World monkey, human, and engineered APOL1 variants for their ability to kill human infective trypanosomes in vivo to identify the molecular mechanism whereby human trypanolytic APOL1 variants evade T. brucei rhodesiense virulence factor serum resistance-associated protein (SRA). For one APOL1 kidney risk variant, a two-residue deletion of amino acids 388 and 389 causes a shift in a single lysine residue that mimics the Old World monkey sequence, which augments trypanolytic activity by preventing SRA binding. A second human APOL1 kidney risk allele, with an amino acid substitution that also restores sequence alignment with Old World monkeys, protected against T. brucei rhodesiense due in part to reduced SRA binding. Both APOL1 risk variants induced tissue injury in murine livers, the site of transgenic gene expression. Our study shows that both genetic variants of human APOL1 that protect against T. brucei rhodesiense have recapitulated molecular signatures found in Old World monkeys and raises the possibility that APOL1 variants have broader innate immune activity that extends beyond trypanosomes.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016;
authors.forename: Russell
authors.initials: R
authors.lastname: Thomson
authors.affiliation: Renal Division andBroad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA 02215;
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016;Department of Biological Sciences, Hunter College at City University of New York, New York, NY 10065;
authors.forename: Chelsea
authors.initials: C
authors.lastname: Canon
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016;Department of Biological Sciences, Hunter College at City University of New York, New York, NY 10065;
authors.forename: Daniella
authors.initials: D
authors.lastname: Kovacsics
authors.affiliation: Department Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom;
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Higgins
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom;
authors.forename: Mark
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Kidney Disease Section, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kopp
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Charles
authors.initials: C
authors.lastname: Rotimi
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Ayo
authors.initials: A
authors.lastname: Doumatey
authors.affiliation: Kenya Medical Research Institute, Kisumu, Kenya; andDivision of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55454.
authors.forename: George
authors.initials: G
authors.lastname: Ayodo
authors.affiliation: Renal Division and.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.affiliation: Renal Division andBroad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA 02215;
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
authors.affiliation: Renal Division andCenter for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; dfriedma@bidmc.harvard.edu raper@genectr.hunter.cuny.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Friedman
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016;Department of Biological Sciences, Hunter College at City University of New York, New York, NY 10065; dfriedma@bidmc.harvard.edu raper@genectr.hunter.cuny.edu.
authors.forename: Jayne
authors.initials: J
authors.lastname: Raper
mesh_terms: D000349:Africa; D000483:Alleles; D000818:Animals; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics* / Q000502:physiology; D005075:Biological Evolution; D060467:Disease Resistance / Q000235:genetics*; D005787:Gene Frequency; D005843:Geography; D006239:Haplotypes; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics* / Q000502:physiology; D008239:Lysine / Q000235:genetics; D048528:Mandrillus; D051379:Mice; D008822:Mice, Transgenic; D008962:Models, Theoretical; D010215:Papio / Q000235:genetics; D011110:Polymorphism, Genetic; D016833:Trypanosoma brucei rhodesiense; D014353:Trypanosomiasis, African / Q000235:genetics*
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; D008239:Lysine