Human Genetic Variation
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Understanding Human Genetic Variation (continued)

The classic example from the high school biology curriculum is the mutation for sickle hemoglobin, which in the heterozygous state provides a selective advantage in areas where malaria is endemic.

More recent examples include mutations in the CCR5 gene that appear to provide protection against AIDS. The CCR5 gene encodes a protein on the surface of human immune cells. HIV, the virus that causes AIDS, infects immune cells by binding to this protein and another protein on the surface of those cells. Mutations in the CCR5 gene that alter its level of expression or the structure of the resulting protein can decrease HIV infection. Early research on one genetic variant indicates that it may have risen to high frequency in Northern Europe about 700 years ago, at about the time of the European epidemic of bubonic plague. This finding has led some scientists to hypothesize that the CCR5 mutation may have provided protection against infection by Yersinia pestis, the bacterium that causes plague. The fact that HIV and Y. pestis both infect macrophages supports the argument for selective advantage of this genetic variant.

The sickle cell and AIDS/plague stories remind us that the biological significance of genetic variation depends on the environment in which genes are expressed. It also reminds us that differential selection and evolution would not proceed in the absence of genetic variation within a species.

Some genetic variation, of course, is associated with disease, as classic single-gene disorders such as sickle cell disease, cystic fibrosis, and Duchenne muscular dystrophy remind us. Increasingly, research is also uncovering genetic variations associated with the more common diseases that are among the major causes of sickness and death in developed countries—diseases such as heart dis-ease, cancer, diabetes, and psychiatric disorders such as schizophrenia and bipolar disease (manic-depression). Whereas disorders such as cystic fibrosis or Huntington disease result from the effects of mutation in a single gene and are evident in virtually all environments, the more common diseases result from the interaction of multiple genes and environmental variables. Such diseases therefore are termed polygenic and multifactorial . In fact, the vast majority of human traits, diseases or otherwise, are multifactorial.

The genetic distinctions between relatively rare single-gene disorders and the more common multifactorial diseases are significant. Genetic variations that underlie single-gene disorders generally are relatively recent, and they often have a major, detrimental impact, disrupting homeostasis in significant ways. Such disorders also generally exact their toll early in life, often before the end of childhood. In contrast, the genetic variations that underlie common, multifactorial diseases generally are of older origin and have a smaller, more gradual effect on homeostasis. They also generally have their onset in adulthood. The last two characteristics make the ability to detect genetic variations that predispose/increase risk of common diseases especially valuable because people have time to modify their behavior in ways that can reduce the likelihood that the disease will develop, even against a background of genetic predisposition.

How Is Our Understanding of Human Genetic Variation Affecting Medicine?

Figure 5
Figure 5 - Virtually all human diseases, except perhaps trauma, have a genetic component. D

As noted earlier, one of the benefits of understanding human genetic variation is its practical value for understanding and promoting health and for understanding and combating disease. We probably cannot overestimate the importance of this benefit. First, virtually every human disease has a genetic component. In some diseases, such as Huntington disease, Tay-Sachs disease, and cystic fibrosis, this component is very large. In other diseases, such as cancer, diabetes, and heart disease, the genetic component is more modest. In fact, we do not typically think of these diseases as "genetic diseases," because we inherit not the certainty of developing a disease, but only a predisposition to developing it.

In still other diseases, the genetic component is very small. The crucial point, however, is that it is there. Even infectious diseases, diseases that we have traditionally placed in a completely different category from genetic disorders, have a real, albeit small, genetic component. For example, as the CCR5 example described earlier illustrates, even AIDS is influenced by a person's genotype. In fact, some people appear to have genetic resistance to HIV infection as a result of carrying a variant of the CCR5 gene.

Second, each of us is at some genetic risk and therefore can benefit, at least theoretically, from the progress scientists are making in understanding and learning how to respond to these risks. Scientists estimate that each of us carries between 5 and 50 mutations that carry some risk for disease or disability. Some of us may not experience negative consequences from the mutations we carry, either because we do not live long enough for it to happen or because we may not be exposed to the relevant environmental triggers. The reality, however, is that the potential for negative consequences from our genes exists for each of us.

How is modern genetics helping us address the challenge of human disease? As Figure 6 shows, modern genetic analysis of a human disease begins with mapping and cloning the associated gene or genes. Some of the earliest disease genes to be mapped and cloned were the genes associated with Duchenne muscular dystrophy, retinoblastoma, and cystic fibrosis. More recently, scientists have announced the cloning of genes for breast cancer, diabetes, and Parkinson disease.

Figure 6
Figure 6 - Mapping and cloning a gene can lead to strategies that reduce the risk of disease (preventive medicine); guidelines for prescribing drugs based on a person's genotype (pharmacogenomics); procedures that alter the affected gene (gene therapy); or drugs targeted at the biological mechanism that produces the disease symptoms (drug therapy). The Human Genome Project has accelerated the development of these strategies. D

As Figure 6 also shows, mapping and cloning a disease-related gene opens the way for the development of a variety of new health care strategies. At one end of the spectrum are genetic tests intended to identify people at increased risk for the disease and recognize genotypic differences that have implications for effective treatment. At the other end are new drug and gene therapies that specifically target the biochemical mechanisms that underlie the disease symptoms or even replace, manipulate, or supplement nonfunctional genes with functional ones. Indeed, as Figure 6 suggests, we are entering the era of molecular medicine.

Genetic testing is not a new health care strategy. Newborn screening for diseases like PKU has been going on for 30 years in many states. Nevertheless, the remarkable progress scientists are making in mapping and cloning human disease genes brings with it the prospect for the development of more genetic tests in the future. The availability of such tests can have a significant impact on the way the public perceives a particular disease and can also change the pattern of care that people in affected families might seek and receive. For example, the identification of the BRCA1 and BRCA2 genes and the demonstration that particular variants of these genes are associated with an increased risk of breast and ovarian cancer have paved the way for the development of guidelines and protocols for testing individuals with a family history of these diseases. BRCA1, located on the long arm of chromosome 17, was the first to be isolated, and variants of this gene account for about 50 percent of all inherited breast cancer, or about 5 percent of all breast cancer. Variants of BRCA2, located on the long arm of chromosome 13, appear to account for about 30 to 40 percent of all inherited breast cancer.

Variants of these genes also increase slightly the risk for men of developing breast, prostate, or possibly other cancers.

Scientists estimate that hundreds of thousands of women in the United States have 1 of hundreds of significant mutations already detected in the BRCA1 gene. For a woman with a family history of breast cancer, the knowledge that she carries one of the variants of BRCA1 or BRCA2 associated with increased risk can be important information. If she does carry one of these variants, she and her physician can consider several changes in her health care, such as increasing the frequency of physical examinations; introducing mammography at an earlier age; and even having a prophylactic mastectomy. In the future, drugs may also be available that decrease the risk of developing breast cancer.

The ability to test for the presence in individuals of particular gene variants is also changing the way drugs are prescribed and developed. A rapidly growing field known as pharmacogenomics focuses on crucial genetic differences that cause drugs to work well in some people and less well, or with dangerous adverse reactions, in others. For example, researchers investigating Alzheimer disease have found that the way patients respond to drug treatment can depend on which of three genetic variants of the ApoE (Apolipoprotein E) gene a person carries. Likewise, some of the variability in children's responses to therapeutic doses of albuterol, a drug used to treat asthma, was recently linked to genotypic differences in the beta-2-adrenergic receptor. Because beta-2-adrenergic receptor agonists (of which albuterol is one) are the most widely used agents in the treatment of asthma, these results may have profound implications for understanding the genetic factors that determine an individual's response to asthma therapy.

Experts predict that increasingly in the future, physicians will use genetic tests to match drugs to an individual patient's body chemistry, so that the safest and most effective drugs and dosages can be prescribed. After identifying the genotypes that determine individual responses to particular drugs, pharmaceutical companies also likely will set out to develop new, highly specific drugs and revive older ones whose effects seemed in the past too unpredictable to be of clinical value.

Knowledge of the molecular structure of disease related genes is also changing the way researchers approach developing new drugs. A striking example followed the discovery in 1989 of the gene associated with cystic fibrosis (CF). Researchers began to study the function of the normal and defective proteins involved in order to understand the biochemical consequences of the gene's variant forms and to develop new treatment strategies based on that knowledge. The normal protein, called CFTR for cystic fibrosis transmembrane conductance regulator, is embedded in the membranes of several cell types in the body, where it serves as a channel, transporting chloride ions out of the cells. In CF patients, depending on the particular mutation the individual carries, the CFTR protein may be reduced or missing from the cell membrane, or may be present but not function properly. In some mutations, synthesis of CFTR protein is interrupted, and the cells produce no CFTR molecules at all.

Although all of the mutations associated with CF impair chloride transport, the consequences for patients with different mutations vary. For example, patients with mutations causing absent or markedly reduced CFTR protein may have more severe disease than patients with mutations in which CFTR is present but has altered function. The different mutations also suggest different treatment strategies. For example, the most common CF-related mutation (called delta F508) leads to the production of protein molecules (called delta F508 CFTR) that are misprocessed and are degraded prematurely before they reach the cell membrane. This finding suggests that drug treatments that would enhance transport of the defective delta F508 protein to the cell membrane or prevent its degradation could yield important benefits for patients with delta F508.

Finally, the identification, cloning, and sequencing of a disease-related gene can open the door to the development of strategies for treating the disease using the instructions encoded in the gene itself. Collectively referred to as gene therapy, these strategies typically involve adding a copy of the normal variant of a disease-related gene to a patient's cells. The most familiar examples of this type of gene therapy are cases in which researchers use a vector to introduce the normal variant of a disease-related gene into a patient's cells and then return those cells to the patient's body to provide the function that was missing. This strategy was first used in the early 1990s to introduce the normal allele of the adenosine deaminase (ADA) gene into the body of a little girl who had been born with ADA deficiency. In this disease, an abnormal variant of the ADA gene fails to make adenosine deaminase, a protein that is required for the correct functioning of T-lymphocytes.

Although researchers are continuing to refine this general approach to gene therapy, they are also developing new approaches. For example, scientists hope that one very new strategy, called chimeraplasty, may one day be used to actually correct genetic defects that involve only a single base change. Chimeraplasty uses specially synthesized molecules that base pair with a patient's DNA and stimulate the cell's normal DNA-repair mechanisms to remove the incorrect base and substitute the correct one. At this point, chimeraplasty is still in early development and the first clinical trials are about to get under way.

Yet another approach to gene therapy involves providing new or altered functions to a cell through the introduction of new genetic information. For example, recent experiments have demonstrated that it is possible, under carefully controlled experimental conditions, to introduce genetic information into cancer cells that will alter their metabolism so that they commit suicide when exposed to a normally innocuous environmental trigger. Researchers are also using similar experiments to investigate the feasibility of introducing genetic changes into cells that will make them immune to infection by HIV. Although this research is currently being done only in nonhuman primates, it may eventually benefit patients infected with HIV.

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