Major histocompatibility complex (MHC) encoded proteins and Killer cell immunoglobulin-like receptors (KIR) serve critical functions in innate immunity, adaptive immunity and reproduction. The combination of HLA class I and KIR genotype uniquely diversifies human immune systems and is strongly associated with infectious, allergic, autoimmune and inflammatory diseases as well as reproductive success. Because MHC and KIR genes evolve rapidly, Great Apes, the species most closely related to humans, are by far best model systems for immunogenetic and immunogenomic comparisons. But such studies have been limited to small numbers of captive animals that poorly represent the natural diversity and population structure. In a pioneering study of the Gombe population of wild chimpanzees, we uncovered deep evolutionary roots of a trans-species lineage of MHC-B alleles, that includes chimpanzee Patr-B*06 and human HLA-B*57 and protects against HIV/SIV disease progression. This demonstrates how studying wild ape populations reveals novel linkage and insight between structural variation and function. We propose to expand this analysis in two dimensions. First, we will deepen the analysis to encompass all MHC and KIR genes. Second, we will broaden the analysis to 43 populations that represent eight of the nine African Great Ape species and subspecies.
Aim 1 will develop new methods for rapid acquisition of sequence data and its automated analysis.
Aim 2 will produce a complete description of the African Great Ape KIR and MHC genes and their allelic diversity in natural populations. Analysis of these data will determine how the KIR receptors and their MHC class I ligands have co-evolved in African Great Apes and how this differs between species and subspecies.
Aim 3 will connect immunogenetic diversity with functional outcomes associated with the variable occurrence of SIV in the African Great Ape populations. Longitudinal data from two well-studied chimpanzee populations will be used to identify factors associated with disease, survival and reproductive success. In sum, we propose a comprehensive analysis of the immunogenetics and immunogenomics of natural populations of the species most closely related to humans. The results will give new perspectives on the human immune system and greatly expand our knowledge of its strengths and weaknesses.

Public Health Relevance

The major histocompatibility complex (MHC) and killer cell immunoglobulin-like (KIR) gene family are functionally interacting genomic regions associated with a broad range of disease susceptibilities and resistances as well as reproductive success. In this project we will investigate the KIR and MHC of the Great Apes, the closest relatives to humans, and the best model system for understanding the association of variation in these regions with disease and reproductive success. As part of this project we will compare Great Ape populations with and without SIV (the progenitor of HIV) to identify shared factors influencing resistance and susceptibility to this global epidemic.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
Program Officer
Bridges, Nancy D
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Stanford University
Schools of Medicine
United States
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Norman, Paul J; Norberg, Steven J; Guethlein, Lisbeth A et al. (2017) Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II. Genome Res 27:813-823
Wroblewski, Emily E; Guethlein, Lisbeth A; Norman, Paul J et al. (2017) Bonobos Maintain Immune System Diversity with Three Functional Types of MHC-B. J Immunol 198:3480-3493
Guethlein, Lisbeth A; Norman, Paul J; Heijmans, Corinne M C et al. (2017) Two Orangutan Species Have Evolved Different KIR Alleles and Haplotypes. J Immunol 198:3157-3169
Norman, Paul J; Hollenbach, Jill A; Nemat-Gorgani, Neda et al. (2016) Defining KIR and HLA Class I Genotypes at Highest Resolution via High-Throughput Sequencing. Am J Hum Genet 99:375-91
Abi-Rached, Laurent; Guethlein, Lisbeth A; Norman, Paul J et al. (2015) Chimpanzee susceptibility to hepatitis C virus infection correlates with presence of Pt-KIR3DS2 and Pt-KIR2DL9: paired activating and inhibitory natural killer cell receptors. Immunogenetics 67:625-8
Wroblewski, Emily E; Norman, Paul J; Guethlein, Lisbeth A et al. (2015) Signature Patterns of MHC Diversity in Three Gombe Communities of Wild Chimpanzees Reflect Fitness in Reproduction and Immune Defense against SIVcpz. PLoS Biol 13:e1002144
Guethlein, Lisbeth A; Norman, Paul J; Hilton, Hugo G et al. (2015) Co-evolution of MHC class I and variable NK cell receptors in placental mammals. Immunol Rev 267:259-82
Parham, Peter; Moffett, Ashley (2013) Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nat Rev Immunol 13:133-44
Hammond, John A; Guethlein, Lisbeth A; Norman, Paul J et al. (2012) Natural selection on marine carnivores elaborated a diverse family of classical MHC class I genes exhibiting haplotypic gene content variation and allelic polymorphism. Immunogenetics 64:915-33
Parham, P; Norman, P J; Abi-Rached, L et al. (2012) Review: Immunogenetics of human placentation. Placenta 33 Suppl:S71-80

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