10.5: Mutations

Mutations are changes in the bases in DNA. The effect—or lack of an effect—depends on where and which bases are changed. An obvious impact of a mutation is its potential to change the instructions to make a protein. UUA codes for the amino acid leucine (see Table 10-1). If this changes to UUG, there’s no effect (it’s a “silent mutation”)—UUG also codes for leucine. But if the UUA is changed to UAA, the protein can’t be made—UAA means stop. Most mutations have relatively mild effects. In contrast, a mutation that results in the inability to make an enzyme needed to make ATP wouldn’t allow survival as an embryo. Also, many mutations occur in areas of DNA that aren’t part of our genes.

Mutations that occur in the genes of “germ cells” (cells holding the genetic material passed onto offspring, e.g., ova and sperm) are responsible for genetic diversity among species, and are a major factor in adaptation and evolution. They are also responsible for genetically based diseases.

Sickle Cell Anemia

Sickle cell anemia is caused by a single mutation (a change in a single base)† in the gene for hemoglobin (the oxygen-carrying protein in red blood cells). As a result, the amino acid valine (code GUU, GUC, GUA, or GUG) replaces glutamate (GAA or GAG) as the 6th amino acid in hemoglobin’s chain of 146 amino acids. Valine (the wrong amino acid) is chemically different from glutamate. As a result, sickle cell hemoglobin has a “sticky” spot (valine at position #6) on its surface.

The sticky spot is exposed only when hemoglobin isn’t carrying oxygen (oxygen changes hemoglobin’s shape). Whenever oxygen falls in the blood, the hemoglobins stick together, forming long strands. This distorts the shape of red blood cells into a sickle, causing them to get trapped in small blood vessels. This causes severe pain by restricting the blood supply in the area, just as the narrowing of a coronary artery causes the pain of angina (Chap. 8).

Interfering with blood flow not only damages organs, but also causes oxygen in blood to fall even more, causing more sickling. Also, sickled red blood cells are very fragile and break easily, resulting in fewer red blood cells (anemia).

Sickle cell anemia is a severe disease involving many organs. Steady improvements in treatment have extended survival to well beyond age 40. The gene for sickle cell anemia is found almost exclusively in Blacks, and the gene is recessive, meaning that a person must get it from both parents to get the disease. The disease occurs in about 0.3% of blacks in this country. About 10% of Blacks inherit the gene (sickle cell trait) from only one parent; they don’t have the disease, but their red blood cells can sickle under certain circumstances of oxygen deprivation, e.g., strenuous exercise at high altitudes.

The prevalence of sickle cell trait in Africa suggests a selective advantage. Malaria is prevalent in Africa and is caused by a parasite that multiplies in red blood cells. Sickle cell trait protects against the most lethal form of malaria. The likely explanation for the prevalence of this mutation is that those who have it tend to survive malaria, enabling them to pass the mutation on to their descendants. This mutation was a mixed bag. It caused severe anemia, yet it gave people a better chance of surviving the most lethal form of malaria.*

In 2010, another “mixed bag” mutation was discovered that increases the risk of kidney disease and protects against sleeping sickness (trypanosomiasis) caused by tsetse flies infected with a particular parasite. These flies and parasite are found in sub-Saharan Africa. African-Americans have higher rates of kidney disease; about 30% of African-Americans carry this mutation.

Some mutations are much more one-sided. Mutations in certain genes cause cancer.†† At the other extreme, there’s a mutation that causes extremely high HDL-cholesterol (Chap. 8). This seems to increase longevity without any drawbacks. But genetic mutations that, say, extend life expectancy from age 75 to 95 don’t tend to become widespread. In contrast, the mutation for sickle cell anemia helps children survive malaria, allowing them to make it to the childbearing years and pass on the mutation. It’s been joked that “longevity genes” might be propagated by only letting men over age 90 father children!

^{†Variation in a single base (nucleotide) at a precise point in our DNA is called a SNP (single nucleotide polymorphism), pronounced “snip.” More than 99% of our DNA sequences are identical. About 90% of the variations that make us unique individuals are our SNPs. Unlike a single-SNP disease like sickle cell anemia, many diseases involve many SNPs. We maintain a SNP database (www.ncbi.nlm.nih.gov/snp). SNPs not only predict our reactions to drugs, etc., but can describe us, e.g., “This DNA appears to be from a tall blond male of Danish heritage.”
*Thalassemia is also caused by a mutation that both protects against malaria and causes anemia. Worldwide, it’s one of the most common inherited diseases, especially in those from Mediterranean areas, Africa, and Southeast Asia.
††These genes regulate normal growth of a cell. Harold Varmus and J. Michael Bishop shared a Nobel Prize in 1989 for discovering these genes and their connection to cancer.}

Spontaneous Mutations

The public tends to think of mutations as something caused by environmental insults. While these can certainly cause mutations, mutations also occur as copying errors. Each time a cell divides, the two strands of DNA separate, and copies of the original DNA are duplicated in the two new cells (Figure 10.2).

A “spontaneous” mutation occurs if, for example, the wrong base is inserted in the process of making a matching strand—a copying error. In humans, copying errors are unusual because when our DNA is duplicated, the two strands are carefully checked to make sure that the bases are paired correctly. For a copying error to occur, it has to slip by the cell’s diligent proofreader. But copying errors do slip by, and are more likely the more times something is copied, i.e., the more times a cell divides.

Spontaneous mutations are especially unusual in sperm and ova—DNA we pass on. As such, the number of mutations is used as an evolutionary clock. Molecular paleontologists compare DNA from animals to estimate when they branched apart from a common ancestor. They estimate how many mutations would have had to occur to account for the DNA differences between the animals and their common ancestor (e.g., 1000 mutations), estimate the rate of spontaneous mutations (e.g., 1 per 100 years), then estimate how long ago the animals branched apart [(1000 mutations)/(1 mutation/ 100 yrs) = 100,000 years].

Spontaneous mutations are common in microbes, allowing them to adapt easily. Suppose that disease-causing bacteria are flourishing in an environment that’s then changed by introducing an antibiotic. If the antibiotic quickly kills all the bacteria, the treatment is a success. If the antibiotic doesn’t quite do its job (e.g., dose is too low or isn’t taken long enough), the bacteria have an opportunity to adapt/mutate.

If even a single bacterium becomes resistant to the antibiotic because of a spontaneous mutation, that bacterium will flourish in the new environment and become a new, antibiotic-resistant strain. Such bacteria can then transfer this antibiotic resistance to other bacteria.

Transmission of a disease-causing mutated gene has been avoided by parents using in-vitro pre-implantation genetic diagnosis (PGD), or abortion following prenatal diagnosis. Some conditions tend to perpetuate mutations that would normally be kept in check by nature or social forces.

When hemophilia was untreatable, only women passed on the mutation. They themselves didn’t get hemophilia.* When a male inherited the mutation, he got hemophilia but didn’t pass on the mutation because he often died before he could reproduce or didn’t marry because of his disease.

With an outside source of clotting factors, hemophiliacs can now live quite normal lives, including having children.† Men, in addition to women, now transmit the gene. If a man with hemophilia marries a woman who carries the gene (the odds are remote, but go up with inbreeding), all their children have a 50:50 chance of having hemophilia. A woman with hemophilia carries the gene on both of her X-chromosomes. All her sons—regardless of the father—will have hemophilia, and all her daughters will be carriers.

The hope is that gene therapy or editing will be able to cure not only genetic diseases, but genetic susceptibilities as well. Breast cancer is thought to involve several mutations. Women with a genetic susceptibility to breast cancer may have inherited at least one of those mutations (breast-cancer genes), giving them a head start. As yet, breast-cancer genes can’t be corrected, but testing for them can be useful.

In 1992, the Wall Street Journal told of a woman with a strong family history of breast cancer. She so feared getting it that she scheduled surgery to remove her breasts. Her extended family happened to be part of a research project looking for breast-cancer genes, and the scientists were able to tell her that she didn’t inherit the breast cancer gene in her family.** She canceled her surgery.

^{*Genes for blood-clotting factors are on the X-chromosome. A male only has the X-chromosome from his mother (if he had gotten an X- instead of a Y-chromosome from his father, he would have been a she). If his X-chromosome carries the defective gene, he’s born with hemophilia. Females have two X-chromosomes—one from each parent. If one of her X-chromosomes has the defective gene, she doesn’t get hemophilia because the gene is normal in the other X-chromosome—she has a back-up set of X-linked genes—but her children have a 50:50 chance of inheriting the defective one.
†When a HIV+ man with or without hemophilia wants to have a child, he wants to impregnate his wife without infecting her. “Safe sex” presents a problem. Today, antiretroviral drugs are used to lower the risk of passing on the infection.
**The scientists included Mary-Claire King, who helped identify the children of the missing in Argentina, and Francis Collins, who helped find the cystic fibrosis gene, headed the Human Genome Project and the National Institutes of Health.}