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Co-evolution of human leukocyte antigen (HLA) class I ligands with killer-cell immunoglobulin-like receptors (KIR) in a genetically diverse population of sub-Saharan Africans.

Norman PJ, Hollenbach JA, Nemat-Gorgani N, Guethlein LA, Hilton HG, Pando MJ, Koram KA, Riley EM, Abi-Rached L, Parham P - PLoS Genet. (2013)

Bottom Line: Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression.Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution.These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa.

View Article: PubMed Central - PubMed

Affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT
Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1-14 functional ligand-receptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous associations of cerebral malaria with HLA-B*53:01 and KIR, Plasmodium falciparum is a candidate pathogen.

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Distinctive evolution of centromeric and telomeric regions of the Ga-Adangbe KIR locus.A. Shown are histograms of the mismatch distributions, determined using p-distance, for the nucleotide sequences of the centromeric (upper histogram) and telomeric (lower histogram) region of the 262 Ga-Adangbe KIR haplotypes. B. Values for Tajima's D performed on the KIR regions of panel A, and their 2-tail statistical significance following 10,000 coalescence simulations under the ancient-expansion demographic model (m2). The D value for the centromeric region was significantly higher than the simulations and the telomeric significantly lower. C. Network plots derived from comparison of the nucleotide sequences of the centromeric (left plot) and telomeric (right plot) regions of the Ga-Adangbe KIR haplotypes. These plots show the structural and possible evolutionary relationships between the haplotypes. Each circular node corresponds to a haplotype, for which the area is proportional to the haplotype's frequency in the Ga-Adangbe population. The distance between the centres of two nodes, as represented by the drawn straight lines, is proportional to the number of mutations and/or recombination events that distinguish the two haplotypes. Nodes corresponding to centromeric A or telomeric A motifs are colored red, nodes corresponding to centromeric B and telomeric B motifs are colored blue. Every node probability is >0.99.
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pgen-1003938-g003: Distinctive evolution of centromeric and telomeric regions of the Ga-Adangbe KIR locus.A. Shown are histograms of the mismatch distributions, determined using p-distance, for the nucleotide sequences of the centromeric (upper histogram) and telomeric (lower histogram) region of the 262 Ga-Adangbe KIR haplotypes. B. Values for Tajima's D performed on the KIR regions of panel A, and their 2-tail statistical significance following 10,000 coalescence simulations under the ancient-expansion demographic model (m2). The D value for the centromeric region was significantly higher than the simulations and the telomeric significantly lower. C. Network plots derived from comparison of the nucleotide sequences of the centromeric (left plot) and telomeric (right plot) regions of the Ga-Adangbe KIR haplotypes. These plots show the structural and possible evolutionary relationships between the haplotypes. Each circular node corresponds to a haplotype, for which the area is proportional to the haplotype's frequency in the Ga-Adangbe population. The distance between the centres of two nodes, as represented by the drawn straight lines, is proportional to the number of mutations and/or recombination events that distinguish the two haplotypes. Nodes corresponding to centromeric A or telomeric A motifs are colored red, nodes corresponding to centromeric B and telomeric B motifs are colored blue. Every node probability is >0.99.

Mentions: The centromeric region of the Ga-Adangbe KIR locus exhibits a bimodal mismatch distribution, a network indicating successive formation and expansion of haplotypes, and a significantly elevated value for Tajima's D (Figure 3A–C). All these features reflect the presence of a variety of divergent haplotypes that are at comparable frequencies and maintained by balancing selection. In contrast, the telomeric region of the KIR locus displays a unimodal mismatch distribution, a star-like haplotype network pattern (Figure 3C) and a Tajima's D value significantly below that expected for neutrality (Figure 3B), features reflecting the presence of numerous closely-related variants under directional selection. Such difference in the evolution of the centromeric and telomeric KIR regions is not a general feature of human populations, as exemplified by comparison of the Ga-Adangbe with Yucpa Amerindians and US Europeans (Figure S6).


Co-evolution of human leukocyte antigen (HLA) class I ligands with killer-cell immunoglobulin-like receptors (KIR) in a genetically diverse population of sub-Saharan Africans.

Norman PJ, Hollenbach JA, Nemat-Gorgani N, Guethlein LA, Hilton HG, Pando MJ, Koram KA, Riley EM, Abi-Rached L, Parham P - PLoS Genet. (2013)

Distinctive evolution of centromeric and telomeric regions of the Ga-Adangbe KIR locus.A. Shown are histograms of the mismatch distributions, determined using p-distance, for the nucleotide sequences of the centromeric (upper histogram) and telomeric (lower histogram) region of the 262 Ga-Adangbe KIR haplotypes. B. Values for Tajima's D performed on the KIR regions of panel A, and their 2-tail statistical significance following 10,000 coalescence simulations under the ancient-expansion demographic model (m2). The D value for the centromeric region was significantly higher than the simulations and the telomeric significantly lower. C. Network plots derived from comparison of the nucleotide sequences of the centromeric (left plot) and telomeric (right plot) regions of the Ga-Adangbe KIR haplotypes. These plots show the structural and possible evolutionary relationships between the haplotypes. Each circular node corresponds to a haplotype, for which the area is proportional to the haplotype's frequency in the Ga-Adangbe population. The distance between the centres of two nodes, as represented by the drawn straight lines, is proportional to the number of mutations and/or recombination events that distinguish the two haplotypes. Nodes corresponding to centromeric A or telomeric A motifs are colored red, nodes corresponding to centromeric B and telomeric B motifs are colored blue. Every node probability is >0.99.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814319&req=5

pgen-1003938-g003: Distinctive evolution of centromeric and telomeric regions of the Ga-Adangbe KIR locus.A. Shown are histograms of the mismatch distributions, determined using p-distance, for the nucleotide sequences of the centromeric (upper histogram) and telomeric (lower histogram) region of the 262 Ga-Adangbe KIR haplotypes. B. Values for Tajima's D performed on the KIR regions of panel A, and their 2-tail statistical significance following 10,000 coalescence simulations under the ancient-expansion demographic model (m2). The D value for the centromeric region was significantly higher than the simulations and the telomeric significantly lower. C. Network plots derived from comparison of the nucleotide sequences of the centromeric (left plot) and telomeric (right plot) regions of the Ga-Adangbe KIR haplotypes. These plots show the structural and possible evolutionary relationships between the haplotypes. Each circular node corresponds to a haplotype, for which the area is proportional to the haplotype's frequency in the Ga-Adangbe population. The distance between the centres of two nodes, as represented by the drawn straight lines, is proportional to the number of mutations and/or recombination events that distinguish the two haplotypes. Nodes corresponding to centromeric A or telomeric A motifs are colored red, nodes corresponding to centromeric B and telomeric B motifs are colored blue. Every node probability is >0.99.
Mentions: The centromeric region of the Ga-Adangbe KIR locus exhibits a bimodal mismatch distribution, a network indicating successive formation and expansion of haplotypes, and a significantly elevated value for Tajima's D (Figure 3A–C). All these features reflect the presence of a variety of divergent haplotypes that are at comparable frequencies and maintained by balancing selection. In contrast, the telomeric region of the KIR locus displays a unimodal mismatch distribution, a star-like haplotype network pattern (Figure 3C) and a Tajima's D value significantly below that expected for neutrality (Figure 3B), features reflecting the presence of numerous closely-related variants under directional selection. Such difference in the evolution of the centromeric and telomeric KIR regions is not a general feature of human populations, as exemplified by comparison of the Ga-Adangbe with Yucpa Amerindians and US Europeans (Figure S6).

Bottom Line: Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression.Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution.These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa.

View Article: PubMed Central - PubMed

Affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT
Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1-14 functional ligand-receptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous associations of cerebral malaria with HLA-B*53:01 and KIR, Plasmodium falciparum is a candidate pathogen.

Show MeSH
Related in: MedlinePlus