Dating the origin of the CCR5-Δ32 AIDS-resistance allele by the coalescence of … (original) (raw)
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Dating the Origin of the CCR5-Δ32 AIDS-Resistance Allele by the Coalescence of Haplotypes
The American Journal of Human Genetics, 1998
The CCR5-D32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-D32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-D32-containing ancestral haplotype to be ∼700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-D32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g., an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.
The roles of CCR5delta32 allele on HIV/AIDS epidemic in native Africans
Studying the replication pattern of Human immunodeficiency virus (HIV) is essential to understand modalities that could halt its survival in-vivo. The CC chemokine receptor 5 (CCR5) is exploited by HIV to gain entry into CD4+ cells. There are several polymorphisms in CCR5; the major coreceptor of HIV that has major influence on HIV transmission and progression to acquired immunodeficiency syndrome (AIDS). CCR5 genes that code for the CCR5 differ in humans, some individuals acquire mutant form this gene with 32 base pair deletion through mendelian inheritance pattern. Individuals who are homozygous for this gene are completely resistant to HIV infection while heterozygous individuals had extended life span while being infected for an average of 2 to 3 years. CCR5∆32 allele is young in evolutionary time, yet it has reached relatively high frequencies in Caucasians but very low among native Africans. These properties indicate that the mutation has been under intense pressure selection. Surprisingly, there has not been any categorical explanation for this genetic selection. The absence or rare occurrence of CCR5 32 allele among native Africans may be an explanation for high HIV transmission rate and burden in this race. There are very limited CCR5Δ32 studies from Africa thus, justifies the need for researchers to embark on more CCR5Δ32 projects in order to establish full range of mutant CCR5 genes that may exist in our societies.
HIV and the CCR5-Delta32 resistance allele
FEMS microbiology letters, 2004
The combination of molecular biology, epidemiology, virology, evolutionary and population genetics has enabled us to understand the delicate interplay between HIV and the CCR5-D32 HIV resistance allele. We here review and collect from the different approaches to show how they can be combined to elucidate the interaction between host and pathogen genetics in this system. We will present an overview of the normal role of CCR5, its involvement in HIV, the molecular biology of the CCR5-D32 allele and its probable origins. By focusing on this well-documented and important system we hope to demonstrate the power that such a ''holistic'' approach might offer in the study of infectious diseases.
Dating the Origin of the CCR 5D 32 AIDS-Resistance Allele by the Coalescence of Haplotypes
2007
J. Claiborne Stephens, David E. Reich, David B. Goldstein, Hyoung Doo Shin, Michael W. Smith, Mary Carrington, Cheryl Winkler, Gavin A. Huttley, Rando Allikmets, Lynn Schriml, Bernard Gerrard, Michael Malasky, Maria D. Ramos, Susanne Morlot, Maria Tzetis, Carole Oddoux, Francesco S. di Giovine, Georgios Nasioulas, David Chandler, Michael Aseev, Matthew Hanson, Luba Kalaydjieva, Damjan Glavac, Paolo Gasparini, E. Kanavakis, Mireille Claustres, Marios Kambouris, Harry Ostrer, Gordon Duff, Vladislav Baranov, Hiljar Sibul, Andres Metspalu, David Goldman, Nick Martin, David Duffy, Jorg Schmidtke, Xavier Estivill, Stephen J. O’Brien, and Michael Dean
Genetic Redundancy and Chemokines: CCR5 Δ32 HIV-Resistance Allele
Tropical Medicine and Surgery, 2015
Gene mutation is a change in nucleotide sequence of DNA which results in an impaired or loss of functions of the associated gene. Mutation can occur spontaneously or be induced by mutagenic agent. It is considered deleterious when it affects the phenotypic expression of the gene products. However, some mutations, such as CCR5 gene mutation turns out to be beneficial. HIV virus uses the gene product, CCR5, as a co-receptor along with CD4 receptor to enter the host’s cell. The product of CCR5 mutant gene does not interact with HIV surface antigen, hence blocks the primary entry of the virus and thus provides immunity to AIDS for homozygous carriers and greatly slows the progress of the disease in heterozygous carriers. How about the critical role of the gene, being the gene encoding a member of the beta chemokine receptors, which in turn play an important role in the immune response? This is probably compensated by genomic redundancy of chemokine-receptor functions. Genetic redundancy refers to the situation where the loss of a gene can be completely or partially compensated by one or more other genes. Taken together, CCR5 ∆32 protein product is of clinical significance in conferring resistance to HIV infection and is thought to reduce the surface expression of wild type CCR5. In this review we highlight the origin of CCR5 Δ32 HIV-Resistance Allele and discuss chemokine receptors’ functional redundancy as the phenomenon compensating for the normal function the allele in individuals carrying the mutation.
Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective haplotype
AIDS, 2000
Objectives: Several natural polymorphisms in the genes for the human CC-chemokine receptors CCR5 and CCR2 are associated with HIV-1 disease. The CCR2-64I genetic variant [a G to A substitution resulting in a valine (V) to isoleucine (I) change at position 64] is in strong linkage disequilibrium with a mutation within the CCR5 regulatory region (CCR5-59653T). Individuals with two CCR2-64I alleles are not resistant to sexual transmission of HIV-1, but progress signi®cantly more slowly to HIV-1 disease. It is therefore important to determine the global distributions of CCR2-64I and CCR5-59653T genetic variants and de®ne the degree of linkage between them. Design and methods: We have developed molecular beacon-based, real-time PCR allele discrimination assays for all three chemokine receptor mutations, and used these spectral genotyping assays to genotype 3923 individuals from a globally distributed set of 53 populations. Results: CCR2-64I and CCR5-59653T genetic variants are found in almost all populations studied: their allele frequencies are greatest ($35%) in Africa and Asia but decrease in Northern Europe. We con®rm that CCR2-64I is in strong linkage disequilibrium with CCR5-59653T (96.92% of individuals had the same genotype for both CCR2-64I and CCR5-59653T polymorphisms). Conclusions: The greater geographical distribution of the CCR2-64I/CCR5-59653T haplotype compared with that of CCR5-Ä32 suggests that it is a much older mutation whose origin predates the dispersal of modern humans.
Molecular medicine (Cambridge, Mass.), 1997
CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus-1 (HIV-1). Recently, an inactive CCR5 allele (designated here as CCR5-2) was identified that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. The reports conflict on the effect of heterozygous CCR5-2 on HIV-1 susceptibility, and race and risk levels have not yet been fully analyzed. Here we report our independent identification of CCR5-2 and test its effects on HIV-1 pathogenesis in individuals with contrasting clinical outcomes, defined race, and quantified risk. Mutant CCR5 alleles were sought by directed heteroduplex analysis of genomic DNA from random blood donors. Genotypic frequencies were then determined in (1) random blood donors from North America, Asia, and Africa; (2) HIV-1+ individuals; and (3) highly exposed-seronegative homosexuals with quantified risk. CCR5-2 was the only mutant allele fo...
Genetic Redundancy and Chemokines: CCR5 ÃÂ32 HIV-Resistance Allele
Tropical Medicine & Surgery, 2015
Gene mutation is a change in nucleotide sequence of DNA which results in an impaired or loss of functions of the associated gene. Mutation can occur spontaneously or be induced by mutagenic agent. It is considered deleterious when it affects the phenotypic expression of the gene products. However, some mutations, such as CCR5 gene mutation turns out to be beneficial. HIV virus uses the gene product, CCR5, as a co-receptor along with CD4 receptor to enter the host's cell. The product of CCR5 mutant gene does not interact with HIV surface antigen, hence blocks the primary entry of the virus and thus provides immunity to AIDS for homozygous carriers and greatly slows the progress of the disease in heterozygous carriers. How about the critical role of the gene, being the gene encoding a member of the beta chemokine receptors, which in turn play an important role in the immune response? This is probably compensated by genomic redundancy of chemokine-receptor functions. Genetic redundancy refers to the situation where the loss of a gene can be completely or partially compensated by one or more other genes. Taken together, CCR5 ∆32 protein product is of clinical significance in conferring resistance to HIV infection and is thought to reduce the surface expression of wild type CCR5. In this review we highlight the origin of CCR5 Δ32 HIV-Resistance Allele and discuss chemokine receptors' functional redundancy as the phenomenon compensating for the normal function the allele in individuals carrying the mutation.
Journal of Clinical Virology, 2002
Background: Both clinical and laboratory evidence in exposed seronegative (ESN) individuals to human HIV-1 has suggested the existence of mechanisms of natural resistance to the infection. A 32 base-pair deletion in the gene that codes for the CCR5, which is the main coreceptor for HIV-1, confers a high degree of resistance to HIV-1 infection. However, the genotype D32/D32 is present only in 2-4% of Caucasoid ESN individuals suggesting the existence of other mechanisms of protection. Mutations different from D32 have also been proposed as playing a role in resistance/susceptibility to this infection. Objecti6e: To screen for different mutations along the entire coding region of the ccr5 gene that can potentially explain the persistent seronegativity in a group of ESN individuals. Study design: Of a total of 86 individuals analyzed for D32 mutation by the PCR technique, 36 scored HIV seropositive (SP) and 50 were ESN. The entire group of ESN individuals was screened for other mutations in the ccr5 gene by single strand conformational polymorphism (SSCP) and DNA sequencing. Results: The frequency of the mutant allele D32 was 4% (4/100) for ESN individuals and 4.2% (3/72) for SP individuals. The homozygous mutant genotype (D32/D32) was found in only 2% (1/50) of ESN individuals, but in no SP individuals. The heterozygous genotype was found in 8.3% (3/36) of SP individuals and in 4% (2/50) of ESN individuals. The differences in the allelic and genotypic frequencies among the groups were not statistically significant. A comparison between the observed and the expected genotypic frequencies showed that they were significantly different for the ESN group, suggesting a protective, yet indirect effect of the mutant genotype. Conclusions: The screening of the entire coding region of the ccr5 gene in all ESN did not revealed no other mutations that could account for resistance to HIV-1 infection. Although the CCR5 molecule is the most important coreceptor for HIV-1, mutations in this gene do not account for most of the cases of natural resistance to this virus that have so far been reported.