While many mutations are neutral, or nearly so, and many others are harmful, some mutations are beneficial. In human populations, beneficial mutations are often discovered through their effects in protecting against infectious disease. The most widely known example is probably the sickle-cell allele in the gene encoding the β chain of hemoglobin, which when heterozygous protects against malaria (see Fig. 15.1). In this section, we consider another example: This one protects against AIDS, which is caused by the human immunodeficiency virus (HIV).

By means of its surface glycoprotein (a product of the env region in the annotated HIV genome shown in Fig. 13.7), HIV combines with a cell-surface receptor called CD4 to gain entry into immune cells called T cells. Interaction with CD4 alone, however, does not enable the virus to infect the T cell. The HIV surface glycoprotein must also interact with another receptor on the T cell, which is denoted CCR5, in the early stages of infection (Fig. 15.3). The normal function of CCR5 is to bind certain small secreted proteins that promote tissue inflammation in response to infection. But because CCR5 is also an HIV receptor, cells lacking CCR5 are more difficult to invade.

A beneficial effect of a particular mutation in the CCR5 gene was discovered in studies focusing on HIV patients whose infection had not progressed to full-blown AIDS after 10 years or more. The protective allele is denoted the Δ32 allele because the mutation is a 32-base-pair deletion in the coding sequence of the CCR5 gene (Fig. 15.4). Because 32 is not a multiple of 3, the reading frame for translation is shifted at the site of the deletion, and instead of the normal amino acid sequence Ser–Gln–Tyr–Gln–Phe …, the mutant sequence is Ile–Lys–Asp–Ser–His . . . . Not only is the amino acid sequence different from the nonmutant form, the ribosome encounters a stop codon a mere 26 amino acids farther along and translation terminates. The mutant protein is 215, not 352, amino acids long. The CCR5 protein produced by the Δ32 allele is completely inactive.

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The effect of the Δ32 allele is pronounced. In individuals with the homozygous Δ32/Δ32 genotype, HIV progression to AIDS is rarely observed. There is some protection even in individuals with heterozygous Δ32 genotypes, where progression to AIDS is delayed by an average of about 2 years after infection by HIV.

Much has been written about the evolutionary history of the Δ32 allele. It is found almost exclusively in European populations, where the frequency of heterozygous genotypes ranges from 10% to 25%. The narrow geographical distribution was originally interpreted to mean that the allele was selected over time because it provided protection against some other infectious agent that also interacted with the CCR5 protein.

Beneficial mutations not only provide protection against disease. Many beneficial mutations permit organisms to become better adapted to their environment. For example, certain birds, such as Rüppell’s vulture, commonly fly at altitudes of 20,000 feet and sometimes much higher. This feat is possible because of mutations in the structure of hemoglobin that allow hemoglobin to bind oxygen with high affinity, even at the low pressure of oxygen high in the atmosphere. These mutations were selected and passed on generation after generation, making the birds well adapted to flying at high altitudes.