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Evolution of the primate trypanolytic factor APOL1
- Source :
- Proceedings of the National Academy of Sciences. 111
- Publication Year :
- 2014
- Publisher :
- Proceedings of the National Academy of Sciences, 2014.
-
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.
- Subjects :
- Trypanosoma brucei rhodesiense
Apolipoprotein L1
Transgene
Mice, Transgenic
Sequence alignment
Old World monkey
Mice
Gene Frequency
Animals
Humans
Allele
Gene
Alleles
Disease Resistance
Genetics
Polymorphism, Genetic
Multidisciplinary
Innate immune system
Geography
biology
Lysine
Models, Theoretical
biology.organism_classification
Biological Evolution
Apolipoproteins
Trypanosomiasis, African
PNAS Plus
Haplotypes
Africa
biology.protein
Mandrillus
Lipoproteins, HDL
Papio
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 111
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....b8d7c6668985a06fd10bb6a5512e40c2