Genetics majors only please Having a mutation of the CCR5 gene is an advantage i

Question

Genetics majors only please
Having a mutation of the CCR5 gene is an advantage in resistance to HIV infection, but a disadvantage against west nile. At least one copy of the defective allele exists in approx 4-16% people of N European descent, but rare in Japan.

A) describe the common mutation and its effects on the genes protein, and its role in HIV resistance
B) explain the differences in frequency of the mutant Allele in the different populations Genetics majors only please
Having a mutation of the CCR5 gene is an advantage in resistance to HIV infection, but a disadvantage against west nile. At least one copy of the defective allele exists in approx 4-16% people of N European descent, but rare in Japan.

A) describe the common mutation and its effects on the genes protein, and its role in HIV resistance
B) explain the differences in frequency of the mutant Allele in the different populations
Having a mutation of the CCR5 gene is an advantage in resistance to HIV infection, but a disadvantage against west nile. At least one copy of the defective allele exists in approx 4-16% people of N European descent, but rare in Japan.

A) describe the common mutation and its effects on the genes protein, and its role in HIV resistance
B) explain the differences in frequency of the mutant Allele in the different populations

Explanation / Answer

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. This is the process by which T cells are attracted to specific tissue and organ targets. Many forms of HIV, the virus that causes AIDS, initially use CCR5 to enter and infect host cells. Certain individuals carry a mutation known as CCR5-32 in the CCR5 gene, protecting them against these strains of HIV.

The experiments using CCR5 knockout demonstrated that lack of CCR5 is associated with an increased T-cell immune response in various infectious diseases. Studies on the clinical relevance of CCR532 mutation in humans indicated that absence of the CCR5 receptor may, under certain circumstances, have either a positive or a negative effect. Patients carrying a homozygous CCR532-genotype have a higher risk of death during infection with West Nile virus. On the other hand, it is presumed that the absence of CCR5 confers some protection against infection with smallpox (or the plague), which is reflected by the relatively high prevalence of this mutation in Central and Northern Europe.

In some studies different cohorts of HIV-positive and HIV-negative persons were analyzed with regard to polymorphisms in the CCR5 gene and the gene of the CCR5 ligand CCL3L1. CCR5 is an important co-receptor for HIV and earlier studies demonstrated that the CCR5D32 mutation blocks infection of CD4 lymphocytes. Some scientists identified another mechanism by which CCR5 in association with its ligands affect the course of HIV infection.

Thus, it was concluded that CCR5 and its ligands not only interfere with viral entry of HIV into the cell but also affect anti-viral responses via modulating cellular immunity. The CCR5 haplotype (HHG*2) comprising the 32-mutation (both homozygous or in combination with another specific haplotype (HHE)) is a predictor of a weak cell-mediated immune response and a rapid progression of HIV infection. However, the same CCR5 HHG*2 haplotype in combination with the CCR5 HHC haplotype was associated with a slower progression of infection and possibly with a stronger immune response.

The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the 32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells.  First, CCR5 32 has a relatively high frequency in several different Caucasian populations but is comparatively absent in Asian, Middle Eastern and American Indian populations, suggesting that a single mutation occurred after divergence of Caucasians from their African ancestor. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%).

Large-scale studies conducted among Caucasians indicate that individuals who are homozygous for this deletion mutation (32/32) are protected against HIV-1 infection despite multiple high-risk exposures, whereas CCR5/32 heterozygotes have a slower progression to acquired immunodeficiency syndrome (AIDS). The comparative frequency of CCR5/32 heterozygosity was 61 of 363 (16.8%) in Caucasians, 17 of 303 (5.6%) in Puerto Rican Hispanics, 9 of 490 (1.8%) in Pacific Islanders, 0 of 606 (0%) in Asians, and 0 of 150 (0%) in Africans.

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