Let’s examine how genotype influences phenotype with an example of a genetic polymorphism that we introduced in the previous chapter. Fig. 15.1 shows genetic variation in the gene for β-(beta-)globin, one of the subunits of hemoglobin that carries oxygen in red blood cells. Three forms of the β -globin gene are shown in the figure: A, S, and C. These three forms of the gene are relatively common in certain African populations. The different forms of any gene are called alleles, and they correspond to different DNA sequences (polymorphisms) in the genes. In this case, the most common allele is the A allele, which has a GAG codon in the position indicated. This codon translates to glutamic acid (Glu) in the resulting polypeptide.

The allele denoted “S” in Fig. 15.1 is associated with sickle-cell anemia (Chapter 14). In this allele, the GAG codon of the A allele is instead a GTG codon, with the result that the glutamic acid in the protein is replaced with valine (Val). The third allele in Fig. 15.1 is the C allele. It has a variation in the same codon as the S allele, but in this case the change is from GAG to AAG, with the result that glutamic acid is replaced by lysine (Lys). Although in each case only one amino acid of the β-globin protein is affected, this change can have a dramatic effect on the function of the protein, since the amino acid sequence determines how a protein folds, and protein folding in turn determines the protein’s function (Chapter 4).

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An individual who inherits an allele of the same type from each parent is said to be homozygous. For the hemoglobin A, S, and C alleles, there are three possible homozygous genotypes: AA, SS, and CC. The first letter or symbol in each pair indicates the allele inherited from one parent, and the second indicates the allele inherited from the other parent. By convention, alleles and genotypes are designated by italic letters.

By contrast, individuals who inherit different types of allele from their parents are heterozygous. For the hemoglobin A, S, and C alleles, there are three possible heterozygous genotypes: AS, AC, and SC. Note that while each individual can have only two alleles of a gene, many more alleles can exist in an entire population. In the hemoglobin example, a person can be homozygous, with two identical alleles, or heterozygous, with two different alleles, but there are three different alleles available in the population can mix and match in an individual. How those alleles are inherited is explored in Chapter 16.

What are the effects of these mutations? Are they beneficial, harmful, or neutral? The short answer is, it depends. Let’s consider the S allele. When it is inherited from both parents, the individual is homozygous SS, which results in the phenotype of sickle-cell anemia. In the absence of proper medical care, patients with sickle-cell anemia usually die before adulthood. However, when the S allele is inherited from one parent and the A allele is inherited from the other parent, the individual is heterozygous (AS) and the phenotype is only a mild form of sickle-cell disease. Furthermore, in Africa, where malaria is widespread, being a heterozygote is actually beneficial because it affords partial protection against malaria.

Whether the effects of an allele, in this case the S allele, are beneficial or harmful illustrates two important principles about the connection between genotype and phenotype. First, the answer often depends on whether the mutation is homozygous or heterozygous. In areas with malaria, the S allele is harmful as a homozygous genotype but beneficial as a heterozygous genotype. Second, the effect of a particular genotype may depend on the environment. The S allele, as a heterozygous genotype, is beneficial only in malarial-prone regions, where it offers protection from the disease that outweighs its other effects. In areas without malaria, it is harmful.

What about the C allele? Individuals who inherit an A allele from one parent and a C allele from the other parent (genotype AC) have the phenotype of partial protection against malaria, and those who inherit a C allele from both parents (genotype CC) are not only more protected from malaria but also have at worst a mild anemia that usually needs no medical treatment. As with the S allele, the phenotype of the C allele depends on whether the individual is heterozygous or homozygous for the allele.

Quick Check 1 A mutation arises in a bacterium that confers antibiotic resistance. Is this mutation harmful, beneficial, or neutral?