Written Assignment 2

Sometimes, something occurs to alter the sequence of bases in an organism’s DNA. Such an

alteration is called a mutation, and it can lead to changes in the structure and function of the

proteins produced. Mutations can have a range of effects. Sometimes mutations result in

serious, even deadly, problems. Sometimes mutations have little or no detrimental effect. And

occasionally—but very rarely—they may even turn out to be beneficial to the organism.

As an example of how mutations can affect organisms, consider breast cancer in humans.

When two human genes called BRCA1 and BRCA2 are functioning properly, they reduce

breast cancer risk by helping to repair DNA damage, which prevents accumulation of changes

that lead to cancer. If the DNA sequence of either of these genes is altered through mutation

and the gene’s normal function is lost, the person carrying the gene has a significantly

increased risk of developing breast cancer. (Because a variety of factors, including

environmental variables, are involved, it’s impossible to know whether these individuals will

develop breast cancer.) Currently, more than 200 different mutations in the DNA sequences of

these genes have been detected, each of which results in an increased risk of developing

breast cancer.

Given the havoc mutations can cause for an organism, it might be surprising that most

mutations are neutral, having neither a positive nor a negative effect on an organism. This

happens when a mutation occurs in a noncoding region of DNA, or when a change in DNA

within a gene doesn’t alter the function of the protein produced. Researchers estimate that the

rate of mutations in cells involved in reproduction is approximately 10–8 per base pair per

generation.

Mutations are essential to evolution. Those mutations that don’t kill an organism, or reduce its

ability to survive and reproduce, can be beneficial. Every genetic feature in every organism

was, initially, the result of a mutation. Most mutations you inherit from your parents will have no

effect. And all of us are carrying mutations that we will never know about! 34

The type of cell in which a mutation occurs is important. Mutations in non-sex cells (such as skin or lung cells) can have bad health consequences for the person carrying them. Many forms of cancer, such as lung cancer and skin cancer, result from such mutations. But, non- sex-cell mutations are not passed on to your children. Mutations in the sex cells (gametes), conversely, do not have any adverse health effects on those carrying them, but these mutations can be passed on to offspring. Individuals inheriting mutations from a parent can be at increased risk for diseases such as breast cancer or cardiovascular disease. Inherited mutations can also have an effect before birth, sometimes causing miscarriages or birth defects. The changes to DNA caused by mutations are generally of two types: point mutations and chromosomal aberrations, which we explore in depth on the next slide.

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Point mutations are mutations in which one nucleotide base pair in the DNA is replaced with another or in which a base pair is inserted or deleted. Insertions and deletions can be much more harmful than substitutions because they can alter the reading-frame for the rest of the gene. Remember that the amino acid sequence of a protein is determined by reading the bases on an mRNA molecule three at a time and attaching the specific amino acid that is specified by that sequence. If a single base is added or removed, the three-base groupings get thrown off and the sequence of amino acids stipulated will be all wrong. It’s almost like putting your hands on a computer keyboard, but offset by one key to the left or right, and then typing what should be a normal sentence. It comes out as gibberish.

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Chromosomal aberrations are changes to the overall organization of the genes on a chromosome. Chromosomal aberrations are like the manipulation of large chunks of text within a paper. They can involve the complete deletion of an entire section of DNA, the moving of a gene from one part of a chromosome to another, or the duplication of a gene with the new copy inserted elsewhere on the chromosome. In any case, a gene’s expression— the production of the protein the gene’s sequence codes for—can be altered when it is moved, as can the expression of the genes around it.

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There are three chief causes of mutation, and although one of them is beyond our control, the other two can be significantly reduced. 1. Spontaneous mutations. Some mutations arise by accident as DNA is duplicating itself— at the rate of more than a thousand bases a minute in humans—when cells are dividing. DNA repair enzymes correct most errors, but not all. 2. Radiation-induced mutations. Ionizing radiation, such as X rays, has enough energy to disrupt atomic structure—even break apart chromosomes—by removing tightly bound electrons. Because ionizing rays cannot pass through lead, the lead apron you wear during a dental X ray protects your body from them. However, even non-ionizing, lower-energy radiation (which does not remove electrons) can damage DNA. Ultraviolet (UV) rays from the sun, for example, can be absorbed by bases in DNA, causing them to rearrange bonds. This can prevent them from pairing correctly with the complementary DNA strand and can transform a cell into a cancer cell. This is why long-term sun exposure can contribute to the development of skin cancer. Another source of dangerous ionizing radiation is found in nuclear power plants, where radioactive atoms are used in energy-generating reactions. The high energy of the radioactivity can pass through the body and disrupt its DNA, causing point mutations and chromosomal aberrations. With safety precautions, however, nuclear power plant workers can minimize their exposure to harmful radiation. 3. Chemical-induced mutations. Chemicals, such as those found in cigarette smoke and engine exhaust, can also react with the atoms in DNA molecules and induce mutations. In Section 6.11, we examine how even tiny changes in the sequence of bases in DNA can lead to errors in protein production and profound health problems.

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It might come as a surprise that, according to many studies, sunscreen does not protect people from skin cancer. Even more surprising, many studies have shown that sunscreen use is even associated with an increased risk of the most dangerous of all skin cancers, melanoma. When skin cells are exposed to a type of ultraviolet radiation called UVB radiation, the cells and their contents—including RNA and DNA molecules—can be damaged. This signals nearby cells to produce chemicals that cause inflammation—which you know as sunburn—as part of the process by which the damaged cells are cleared away. Sunscreens contain chemicals that absorb or reflect some of the UV radiation. In doing so, they protect against many of the harmful effects of the sun, including sunburn. Nearly everyone assumed that the same wavelengths of sunlight that caused sunburn were also responsible for causing skin cancers. So it followed that sunscreen would provide protection from skin cancer as well as sunburn. There has been an increase in the incidence of melanoma since the 1960s and 1970s, when sunscreens first became widely available. And eight studies published between 1979 and 1995 found a positive association between sunscreen use and melanoma. How can this be true? Sunscreen users may have a false sense of security, and may not limit sun exposure or wear protective clothing. Further complicating matters, as recently as 2010, only one-third of sunscreens offered protection from all the wavelengths of UV radiation in sunlight. In other words, the sunscreen protected against “burns,” but did not block harmful radiation. Before throwing away your sunscreen, let’s do some scientific thinking to be sure that it is of no benefit.

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All of the studies suggesting a positive relationship between sunscreen use and melanoma risk were “case-controlled” studies. This is a study design in which individuals with a particular outcome (such as developing melanoma) are identified and then compared with a group of individuals that do not have that outcome (do not have melanoma). The groups are analyzed to see whether they differ in some significant way—such as sunscreen use. Such a study design has some limitations. It can identify factors influencing the outcome of interest, but the validity of any associations depends on how similar the two groups actually are. In this case, for example, an assumption was made that the healthy subjects and the subjects with melanoma experienced similar sun exposure. An alternative—and usually more powerful—study design is a randomized controlled study. In 2011, researchers reported on just such a study in Queensland, Australia, which had randomly assigned 1,621 adults to one of two groups: regular sunscreen use and discretionary sunscreen use. For 5 years, those in the sunscreen group received unlimited sunscreen and were asked to apply it every morning (and to reapply it after sweating, bathing, or long sun exposure). The discretionary sunscreen users were allowed to use sunscreen at their usual frequency (which included no use at all for some people). At the end of the 5-year treatment period, and continuing for 10 additional years, the researchers noted the incidence of melanomas. They also obtained, from questionnaires filled out by study participants, information about time spent outdoors and sunscreen usage.

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The results were dramatic. Among the 812 subjects in the sunscreen-use group, 11 new melanomas were identified. Among the 809 subjects in the discretionary-use group, twice as many new melanomas were identified. Invasive melanomas, the most severe type, occurred almost four times more frequently among people in the discretionary group. Based on the questionnaires, there were no differences between the groups for any known risk factors, or for the amount of time they had spent in the sun during the trial. Cancer experts describe this first randomized, controlled study as a potential game changer. They also view the results as a clear indication that melanoma-prevention strategies should incorporate efforts at increasing regular use of sunscreen.

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Although the details differ from case to case, the overall picture is the same when it comes to many, if not most inherited diseases. The pathway from mutation to illness includes just four short steps (Figure 6-22): 1) A mutated gene codes for a non-functioning protein, commonly an enzyme. 2) The non-functioning enzyme can’t catalyze the reaction as it normally would, bringing it to a halt. 3) The molecule with which the enzyme would have reacted accumulates, like a blocked assembly line. 4) The accumulating chemical causes sickness and/or death. The fact that many genetic diseases involve illnesses brought about by faulty enzymes suggests strategies for treatment. These include administering medications containing the normal-functioning version of the enzyme. For instance, lactose-intolerant individuals can consume the enzyme lactase, which gives them the ability to digest lactose. Alternatively, lactose-intolerant individuals can reduce their consumption of lactose-containing foods to keep the chemical from accumulating, reducing the problems that come from lactose overabundance.

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