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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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Low diversity in the telomeric region of Ga-Adangbe KIR haplotypes.A. Shown are the 19 KIR gene-content haplotypes detected in the Ga-Adangbe study population (2N = 366) and their frequencies (right column). Presence of a gene is indicated with a black box. ‘Cen’ and ‘Tel’ in the left columns denote the component haplotype motifs in the centromeric and telomeric regions of the KIR locus. † indicates eight KIR haplotypes that have not been identified in other populations. The tB04 motif is unique to Africa and harbors the KIR3DL1/2v fusion gene, a recombinant of KIR3DL1 and KIR3DL2[57], [112]. B. Shown are the heterozygosity values (He = 1-SSF) of 72 populations who were genotyped for KIR gene-content only (reference [74] and Materials and Methods). The genotypes were split into centromeric (left) and telomeric regions (right: p<0.001 for SSA vs. each other population group by T-test). EA East Asia (11 populations: mean N = 106), EUR Europe (15∶161), ME Middle East (12∶121), OCE Oceania (9∶47), SA South Asia (8∶82), SAM South America (12∶66), SSA sub-Saharan Africa (5∶58).
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pgen-1003938-g001: Low diversity in the telomeric region of Ga-Adangbe KIR haplotypes.A. Shown are the 19 KIR gene-content haplotypes detected in the Ga-Adangbe study population (2N = 366) and their frequencies (right column). Presence of a gene is indicated with a black box. ‘Cen’ and ‘Tel’ in the left columns denote the component haplotype motifs in the centromeric and telomeric regions of the KIR locus. † indicates eight KIR haplotypes that have not been identified in other populations. The tB04 motif is unique to Africa and harbors the KIR3DL1/2v fusion gene, a recombinant of KIR3DL1 and KIR3DL2[57], [112]. B. Shown are the heterozygosity values (He = 1-SSF) of 72 populations who were genotyped for KIR gene-content only (reference [74] and Materials and Methods). The genotypes were split into centromeric (left) and telomeric regions (right: p<0.001 for SSA vs. each other population group by T-test). EA East Asia (11 populations: mean N = 106), EUR Europe (15∶161), ME Middle East (12∶121), OCE Oceania (9∶47), SA South Asia (8∶82), SAM South America (12∶66), SSA sub-Saharan Africa (5∶58).

Mentions: Initial low-resolution analysis of the Ga-Adangbe KIR locus identified 19 KIR gene-content haplotypes (Figure 1A) and 16 different KIR genotypes (Figure S3). The 53% frequency of the KIR A haplotype (h1) is comparable to the 47% combined frequency of the 18 KIR B haplotypes (h2–h19), consistent with balancing selection having been active on the two haplotype groups [49]. The number of KIR genes per B haplotype varies from four (h9) to twelve (h11), with only two genes, KIR3DL3 and KIR2DL2/3, being detected on every haplotype. By frequency, over 10% of the Ga-Adangbe KIR haplotypes (h5, 7–10, 12, 13) lack one of the three framework genes (KIR3DL3, KIR2DL4 and KIR3DL2) that define the structure of the KIR locus [37] and its organization into centromeric and telomeric regions; haplotypes h5 and h13 lack KIR2DL4, whereas haplotypes h7–10 and h15 lack KIR3DL2. In previous studies of non-African populations such haplotypes were either absent [49], [51] or rare [50], [52]. Haplotype h12 has a duplication of the KIR2DL4 and KIR3DL1/S1 genes, of the sort that has been described previously in Europeans [28], [55], [56] and South and East Asians [57].


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)

Low diversity in the telomeric region of Ga-Adangbe KIR haplotypes.A. Shown are the 19 KIR gene-content haplotypes detected in the Ga-Adangbe study population (2N = 366) and their frequencies (right column). Presence of a gene is indicated with a black box. ‘Cen’ and ‘Tel’ in the left columns denote the component haplotype motifs in the centromeric and telomeric regions of the KIR locus. † indicates eight KIR haplotypes that have not been identified in other populations. The tB04 motif is unique to Africa and harbors the KIR3DL1/2v fusion gene, a recombinant of KIR3DL1 and KIR3DL2[57], [112]. B. Shown are the heterozygosity values (He = 1-SSF) of 72 populations who were genotyped for KIR gene-content only (reference [74] and Materials and Methods). The genotypes were split into centromeric (left) and telomeric regions (right: p<0.001 for SSA vs. each other population group by T-test). EA East Asia (11 populations: mean N = 106), EUR Europe (15∶161), ME Middle East (12∶121), OCE Oceania (9∶47), SA South Asia (8∶82), SAM South America (12∶66), SSA sub-Saharan Africa (5∶58).
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1003938-g001: Low diversity in the telomeric region of Ga-Adangbe KIR haplotypes.A. Shown are the 19 KIR gene-content haplotypes detected in the Ga-Adangbe study population (2N = 366) and their frequencies (right column). Presence of a gene is indicated with a black box. ‘Cen’ and ‘Tel’ in the left columns denote the component haplotype motifs in the centromeric and telomeric regions of the KIR locus. † indicates eight KIR haplotypes that have not been identified in other populations. The tB04 motif is unique to Africa and harbors the KIR3DL1/2v fusion gene, a recombinant of KIR3DL1 and KIR3DL2[57], [112]. B. Shown are the heterozygosity values (He = 1-SSF) of 72 populations who were genotyped for KIR gene-content only (reference [74] and Materials and Methods). The genotypes were split into centromeric (left) and telomeric regions (right: p<0.001 for SSA vs. each other population group by T-test). EA East Asia (11 populations: mean N = 106), EUR Europe (15∶161), ME Middle East (12∶121), OCE Oceania (9∶47), SA South Asia (8∶82), SAM South America (12∶66), SSA sub-Saharan Africa (5∶58).
Mentions: Initial low-resolution analysis of the Ga-Adangbe KIR locus identified 19 KIR gene-content haplotypes (Figure 1A) and 16 different KIR genotypes (Figure S3). The 53% frequency of the KIR A haplotype (h1) is comparable to the 47% combined frequency of the 18 KIR B haplotypes (h2–h19), consistent with balancing selection having been active on the two haplotype groups [49]. The number of KIR genes per B haplotype varies from four (h9) to twelve (h11), with only two genes, KIR3DL3 and KIR2DL2/3, being detected on every haplotype. By frequency, over 10% of the Ga-Adangbe KIR haplotypes (h5, 7–10, 12, 13) lack one of the three framework genes (KIR3DL3, KIR2DL4 and KIR3DL2) that define the structure of the KIR locus [37] and its organization into centromeric and telomeric regions; haplotypes h5 and h13 lack KIR2DL4, whereas haplotypes h7–10 and h15 lack KIR3DL2. In previous studies of non-African populations such haplotypes were either absent [49], [51] or rare [50], [52]. Haplotype h12 has a duplication of the KIR2DL4 and KIR3DL1/S1 genes, of the sort that has been described previously in Europeans [28], [55], [56] and South and East Asians [57].

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