Many genetic mutations are expressed as nonfunctional enzymes, structural proteins, or membrane proteins. Human genetic diseases may be inherited in dominant, codominant, or recessive patterns, and they may be sex-
learning outcomes
You should be able to:
Describe an abnormal protein in humans that results from a genetic mutation and causes a disease.
Show how the following mutations can lead to phenotypic change: point mutations, large deletions, and chromosomal abnormality.
Justify the claim that most diseases arise from complex interactions between genetic and environmental factors.
Alkaptonuria is an inborn error of metabolism, caused by defects in an enzyme in the pathway that breaks down tyrosine (see Key Concept 14.1). Humans who are homozygous for one of these mutations make nonfunctional enzyme and accumulate the enzyme’s substrate, homogentisic acid, which causes their disease symptoms. In 1996, researchers in Spain cloned and sequenced the gene for the enzyme, and characterized several mutant alleles. Here is the wild-
... TTG ATA CCC ATT GCC ...
... Leu Ile Pro Ile Ala ...
Here is the sequence for one of the mutant alleles:
... TTG ATA TCC ATT GCC ...
What is the amino acid sequence produced by the mutant allele? What type of mutation is this: silent, nonsense, missense, or frame-
Why is this mutation likely to affect the function of the enzyme? (Hint: see Key Concept 3.2, especially Table 3.2.)
The amino acid sequence produced by the mutant allele is Leu-
The mutation replaces proline with serine. Proline is a nonpolar amino acid that is usually part of bends or loops in a protein; serine is a polar amino acid with a smaller side chain. The mutation is likely to affect enzyme activity because it is likely to affect protein structure.
Not all women with a mutation in the BRCA1 gene get early-
Simply having a particular genetic mutation is not sufficient to lead to cancer. There are other genetic and environmental factors that may be involved in developing breast cancer. For example, a person can have a mutation in a different gene for DNA repair, such that it takes over the functions that are lost by the BRCA mutation.
Why do some members of a family show symptoms of fragile-
The symptoms occur only if there are a large number of repeats of the CGC sequence in the promoter region of the FMR1 gene, so that they disrupt expression of the gene. Family members may carry the mutation but not show symptoms because the mutation contains a low number of repeats rather than a high number.
In the previous section we described the ways in which mutations can lead to human disease. We will turn now to the ways that biologists detect mutations in DNA.