Understanding Human Genetic Variation – NCBI Bookshelf

Genetics is the scientific study of inherited variation. Human genetics, then, is the scientific study of inherited human variation.

Why study human genetics? One reason is simply an interest in better understanding ourselves. As a branch of genetics, human genetics concerns itself with what most of us consider to be the most interesting species on earth: Homo sapiens. But our interest in human genetics does not stop at the boundaries of the species, for what we learn about human genetic variation and its sources and transmission inevitably contributes to our understanding of genetics in general, just as the study of variation in other species informs our understanding of our own.

A second reason for studying human genetics is its practical value for human welfare. In this sense, human genetics is more an applied science than a fundamental science. One benefit of studying human genetic variation is the discovery and description of the genetic contribution to many human diseases. This is an increasingly powerful motivation in light of our growing understanding of the contribution that genes make to the development of diseases such as cancer, heart disease, and diabetes. In fact, society has been willing in the past and continues to be willing to pay significant amounts of money for research in this area, primarily because of its perception that such study has enormous potential to improve human health. This perception, and its realization in the discoveries of the past 20 years, have led to a marked increase in the number of people and organizations involved in human genetics.

This second reason for studying human genetics is related to the first. The desire to develop medical practices that can alleviate the suffering associated with human disease has provided strong support to basic research. Many basic biological phenomena have been discovered and described during the course of investigations into particular disease conditions. A classic example is the knowledge about human sex chromosomes that was gained through the study of patients with sex chromosome abnormalities. A more current example is our rapidly increasing understanding of the mechanisms that regulate cell growth and reproduction, understanding that we have gained primarily through a study of genes that, when mutated, increase the risk of cancer.

Likewise, the results of basic research inform and stimulate research into human disease. For example, the development of recombinant DNA techniques () rapidly transformed the study of human genetics, ultimately allowing scientists to study the detailed structure and functions of individual human genes, as well as to manipulate these genes in a variety of previously unimaginable ways.

Recombinant techniques have transformed the study of human genetics.

A third reason for studying human genetics is that it gives us a powerful tool for understanding and describing human evolution. At one time, data from physical anthropology (including information about skin color, body build, and facial traits) were the only source of information available to scholars interested in tracing human evolutionary history. Today, however, researchers have a wealth of genetic data, including molecular data, to call upon in their work.

Two research approaches were historically important in helping investigators understand the biological basis of heredity. The first of these approaches, transmission genetics, involved crossing organisms and studying the offsprings' traits to develop hypotheses about the mechanisms of inheritance. This work demonstrated that in some organisms at least, heredity seems to follow a few definite and rather simple rules.

The second approach involved using cytologic techniques to study the machinery and processes of cellular reproduction. This approach laid a solid foundation for the more conceptual understanding of inheritance that developed as a result of transmission genetics. By the early 1900s, cytologists had demonstrated that heredity is the consequence of the genetic continuity of cells by cell division, had identified the gametes as the vehicles that transmit genetic information from one generation to another, and had collected strong evidence for the central role of the nucleus and the chromosomes in heredity.

As important as they were, the techniques of transmission genetics and cytology were not enough to help scientists understand human genetic variation at the level of detail that is now possible. The central advantage that today's molecular techniques offer is that they allow researchers to study DNA directly. Before the development of these techniques, scientists studying human genetic variation were forced to make inferences about molecular differences from the phenotypes produced by mutant genes. Furthermore, because the genes associated with most single-gene disorders are relatively rare, they could be studied in only a small number of families. Many of the traits associated with these genes also are recessive and so could not be detected in people with heterozygous genotypes. Unlike researchers working with other species, human geneticists are restricted by ethical considerations from performing experimental, "at-will" crosses on human subjects. In addition, human generations are on the order of 20 to 40 years, much too slow to be useful in classic breeding experiments. All of these limitations made identifying and studying genes in humans both tedious and slow.

In the last 50 years, however, beginning with the discovery of the structure of DNA and accelerating significantly with the development of recombinant DNA techniques in the mid-1970s, a growing battery of molecular techniques has made direct study of human DNA a reality. Key among these techniques are restriction analysis and molecular recombination, which allow researchers to cut and rejoin DNA molecules in highly specific and predictable ways; amplification techniques, such as the polymerase chain reaction (PCR), which make it possible to make unlimited copies of any fragment of DNA; hybridization techniques, such as fluorescence in situ hybridization, which allow scientists to compare DNA samples from different sources and to locate specific base sequences within samples; and the automated sequencing techniques that today are allowing workers to sequence the human genome at an unprecedented rate.

On the immediate horizon are even more powerful techniques, techniques that scientists expect will have a formidable impact on the future of both research and clinical genetics. One such technique, DNA chip technology (also called DNA microarray technology), is a revolutionary new tool designed to identify mutations in genes or survey expression of tens of thousands of genes in one experiment.

In one application of this technology, the chip is designed to detect mutations in a particular gene. The DNA microchip consists of a small glass plate encased in plastic. It is manufactured using a process similar to the process used to make computer microchips. On its surface, it contains synthetic single-stranded DNA sequences identical to that of the normal gene and all possible mutations of that gene. To determine whether an individual possesses a mutation in the gene, a scientist first obtains a sample of DNA from the person's blood, as well as a sample of DNA that does not contain a mutation in that gene. After denaturing, or separating, the DNA samples into single strands and cutting them into smaller, more manageable fragments, the scientist labels the fragments with fluorescent dyes: the person's DNA with red dye and the normal DNA with green dye. Both sets of labeled DNA are allowed to hybridize, or bind, to the synthetic DNA on the chip. If the person does not have a mutation in the gene, both DNA samples will hybridize equivalently to the chip and the chip will appear uniformly yellow. However, if the person does possess a mutation, the mutant sequence on the chip will hybridize to the patient's sample, but not to the normal DNA, causing it (the chip) to appear red in that area. The scientist can then examine this area more closely to confirm that a mutation is present.

DNA microarray technology is also allowing scientists to investigate the activity in different cell types of thousands of genes at the same time, an advance that will help researchers determine the complex functional relationships that exist between individual genes. This type of analysis involves placing small snippets of DNA from hundreds or thousands of genes on a single microscope slide, then allowing fluorescently labeled mRNA molecules from a particular cell type to hybridize to them. By measuring the fluorescence of each spot on the slide, scientists can determine how active various genes are in that cell type. Strong fluorescence indicates that many mRNA molecules hybridized to the gene and, therefore, that the gene is very active in that cell type. Conversely, no fluorescence indicates that none of the cell's mRNA molecules hybridized to the gene and that the gene is inactive in that cell type.

Although these technologies are still relatively new and are being used primarily for research, scientists expect that one day they will have significant clinical applications. For example, DNA chip technology has the potential to significantly reduce the time and expense involved in genetic testing. This technology or others like it may one day help make it possible to define an individual's risk of developing many types of hereditary cancer as well as other common disorders, such as heart disease and diabetes. Likewise, scientists may one day be able to classify human cancers based on the patterns of gene activity in the tumor cells and then be able to design treatment strategies that are targeted directly to each specific type of cancer.

Homo sapiens is a relatively young species and has not had as much time to accumulate genetic variation as have the vast majority of species on earth, most of which predate humans by enormous expanses of time. Nonetheless, there is considerable genetic variation in our species. The human genome comprises about 3 109 base pairs of DNA, and the extent of human genetic variation is such that no two humans, save identical twins, ever have been or will be genetically identical. Between any two humans, the amount of genetic variationbiochemical individualityis about .1 percent. This means that about one base pair out of every 1,000 will be different between any two individuals. Any two (diploid) people have about 6 106 base pairs that are different, an important reason for the development of automated procedures to analyze genetic variation.

The most common polymorphisms (or genetic differences) in the human genome are single base-pair differences. Scientists call these differences SNPs, for single-nucleotide polymorphisms. When two different haploid genomes are compared, SNPs occur, on average, about every 1,000 bases. Other types of polymorphismsfor example, differences in copy number, insertions, deletions, duplications, and rearrangementsalso occur, but much less frequently.

Notwithstanding the genetic differences between individuals, all humans have a great deal of their genetic information in common. These similarities help define us as a species. Furthermore, genetic variation around the world is distributed in a rather continuous manner; there are no sharp, discontinuous boundaries between human population groups. In fact, research results consistently demonstrate that about 85 percent of all human genetic variation exists within human populations, whereas about only 15 percent of variation exists between populations (). That is, research reveals that Homo sapiens is one continuously variable, interbreeding species. Ongoing investigation of human genetic variation has even led biologists and physical anthropologists to rethink traditional notions of human racial groups. The amount of genetic variation between these traditional classifications actually falls below the level that taxonomists use to designate subspecies, the taxonomic category for other species that corresponds to the designation of race in Homo sapiens. This finding has caused some biologists to call the validity of race as a biological construct into serious question.

Most variation occurs within populations.

Analysis of human genetic variation also confirms that humans share much of their genetic information with the rest of the natural worldan indication of the relatedness of all life by descent with modification from common ancestors. The highly conserved nature of many genetic regions across considerable evolutionary distance is especially obvious in genes related to development. For example, mutations in the patched gene produce developmental abnormalities in Drosophila, and mutations in the patched homolog in humans produce analogous structural deformities in the developing human embryo.

Geneticists have used the reality of evolutionary conservation to detect genetic variations associated with some cancers. For example, mutations in the genes responsible for repair of DNA mismatches that arise during DNA replication are associated with one form of colon cancer. These mismatched repair genes are conserved in evolutionary history all the way back to the bacterium Escherichia coli, where the genes are designated Mutl and Muts. Geneticists suspected that this form of colon cancer was associated with a failure of mismatch repair, and they used the known sequences from the E. coli genes to probe the human genome for homologous sequences. This work led ultimately to the identification of a gene that is associated with increased risk for colon cancer.

Almost all human genetic variation is relatively insignificant biologically; that is, it has no adaptive significance. Some variation (for example, a neutral mutation) alters the amino acid sequence of the resulting protein but produces no detectable change in its function. Other variation (for example, a silent mutation) does not even change the amino acid sequence. Furthermore, only a small percentage of the DNA sequences in the human genome are coding sequences (sequences that are ultimately translated into protein) or regulatory sequences (sequences that can influence the level, timing, and tissue specificity of gene expression). Differences that occur elsewhere in the DNAin the vast majority of the DNA that has no known functionhave no impact.

Some genetic variation, however, can be positive, providing an advantage in changing environments. 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 also is uncovering genetic variations associated with the more common diseases that are among the major causes of sickness and death in developed countriesdiseases such as heart disease, 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.

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, as shows, 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.

Virtually all human diseases, except perhaps trauma, have a genetic component.

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 than 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 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.

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 (more...)

As 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 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 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 also is 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 CFTR.

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 also are 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 underway.

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.

As indicates, the Human Genome Project (HGP) has significantly accelerated the pace of both the discovery of human genes and the development of new health care strategies based on a knowledge of a gene's structure and function. The new knowledge and technologies emerging from HGP-related research also are reducing the cost of finding human genes. For example, the search for the gene associated with cystic fibrosis, which ended in 1989, before the inception of the HGP, required more than eight years and $50 million. In contrast, finding a gene associated with a Mendelian disorder now can be accomplished in less than a year at a cost of approximately $100,000.

The last few years of research into human genetic variation also have seen a gradual transition from a primary focus on genes associated with single-gene disorders, which are relatively rare in the human population, to an increasing focus on genes associated with multifactorial diseases. Because these diseases are not rare, we can expect that this work will affect many more people. Understanding the genetic and environmental bases for these multifactorial diseases also will lead to increased testing and the development of new interventions that likely will have an enormous effect on the practice of medicine in the next century.

What are the implications of using our growing knowledge of human genetic variation to improve personal and public health? As noted earlier, the rapid pace of the discovery of genetic factors in disease has improved our ability to predict the risk of disease in asymptomatic individuals. We have learned how to prevent the manifestations of some of these diseases, and we are developing the capacity to treat others.

Yet, much remains unknown about the benefits and risks of building an understanding of human genetic variation at the molecular level. While this information would have the potential to dramatically improve human health, the architects of the HGP realized that it also would raise a number of complex ethical, legal, and social issues. Thus, in 1990 they established the Ethical, Legal, and Social Implications (ELSI) program to anticipate and address the ethical, legal, and social issues that arise from human genetic research. This program, perhaps more than any other, has focused public attention, as well as the attention of educators, on the increasing importance of preparing citizens to understand and contribute to the ongoing public dialogue related to advances in genetics.

Ethics is the study of right and wrong, good and bad. It has to do with the actions and character of individuals, families, communities, institutions, and societies. During the last two and one-half millennia, Western philosophy has developed a variety of powerful methods and a reliable set of concepts and technical terms for studying and talking about the ethical life. Generally speaking, we apply the terms "right" and "good" to those actions and qualities that foster the interests of individuals, families, communities, institutions, and society. Here, an "interest" refers to a participant's share or participation in a situation. The terms "wrong" or "bad" apply to those actions and qualities that impair interests.

Ethical considerations are complex, multifaceted, and raise many questions. Often, there are competing, well-reasoned answers to questions about what is right and wrong, and good and bad, about an individual's or group's conduct or actions. Typically, these answers all involve appeals to values. A value is something that has significance or worth in a given situation. One of the exciting events to witness in any discussion in ethics is the varying ways in which the individuals involved assign values to things, persons, and states of affairs. Examples of values that students may appeal to in a discussion about ethics include autonomy, freedom, privacy, sanctity of life, religion, protecting another from harm, promoting another's good, justice, fairness, relationships, scientific knowledge, and technological progress.

Acknowledging the complex, multifaceted nature of ethical discussions is not to suggest that "anything goes." Experts generally agree on the following features of ethics. First, ethics is a process of rational inquiry. It involves posing clearly formulated questions and seeking well-reasoned answers to those questions. For example, we can ask questions about an individual's right to privacy regarding personal genetic information; we also can ask questions about the appropriateness of particular uses of gene therapy. Well-reasoned answers to such questions constitute arguments. Ethical analysis and argument, then, result from successful ethical inquiry.

Second, ethics requires a solid foundation of information and rigorous interpretation of that information. For example, one must have a solid understanding of biology to evaluate the recent decision by the Icelandic government to create a database that will contain extensive genetic and medical information about the country's citizens. A knowledge of science also is needed to discuss the ethics of genetic screening or of germ-line gene therapy. Ethics is not strictly a theoretical discipline but is concerned in vital ways with practical matters.

Third, discussions of ethical issues often lead to the identification of very different answers to questions about what is right and wrong and good and bad. This is especially true in a society such as our own, which is characterized by a diversity of perspectives and values. Consider, for example, the question of whether adolescents should be tested for late-onset genetic conditions. Genetic testing centers routinely withhold genetic tests for Huntington disease (HD) from asymptomatic patients under the age of 18. The rationale is that the condition expresses itself later in life and, at present, treatment is unavailable. Therefore, there is no immediate, physical health benefit for a minor from a specific diagnosis based on genetic testing. In addition, there is concern about the psychological effects of knowing that later in life one will get a debilitating, life-threatening condition. Teenagers can wait until they are adults to decide what and when they would like to know. In response, some argue that many adolescents and young children do have sufficient autonomy in consent and decision making and may wish to know their future. Others argue that parents should have the right to have their children tested, because parents make many other medical decisions on behalf of their children. This example illustrates how the tools of ethics can bring clarity and rigor to discussions involving values.

One of the goals of this module is to help students see how understanding science can help individuals and society make reasoned decisions about issues related to genetics and health. Activity 5, Making Decisions in the Face of Uncertainty, presents students with a case of a woman who is concerned that she may carry an altered gene that predisposes her to breast and ovarian cancer. The woman is faced with numerous decisions, which students also consider. Thus, the focus of Activity 5 is prudential decision making, which involves the ability to avoid unnecessary risk when it is uncertain whether an event actually will occur. By completing the activity, students understand that uncertainty is often a feature of questions related to genetics and health, because our knowledge of genetics is incomplete and constantly changing. In addition, students see that making decisions about an uncertain future is complex. In simple terms, students have to ask themselves, "How bad is the outcome and how likely is it to occur?" When the issues are weighed, different outcomes are possible, depending on one's estimate of the incidence of the occurrence and how much burden one attaches to the risk.

Clearly, science as well as ethics play important roles in helping individuals make choices about individual and public health. Science provides evidence that can help us understand and treat human disease, illness, deformity, and dysfunction. And ethics provides a framework for identifying and clarifying values and the choices that flow from these values. But the relationships between scientific information and human choices, and between choices and behaviors, are not straightforward. In other words, human choice allows individuals to choose against sound knowledge, and choice does not require action.

Nevertheless, it is increasingly difficult to deny the claims of science. We are continually presented with great amounts of relevant scientific and medical knowledge that is publicly accessible. As a consequence, we can think about the relationships between knowledge, choice, behavior, and human welfare in the following ways:

One of the goals of this module is to encourage students to think in terms of these relationships, now and as they grow older.

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The following glossary was modified from the glossary on the National Human Genome Research Institute's Web site, available at http://www.nhgri.nih.gov.

One of the variant forms of a gene at a particular locus, or location, on a chromosome. Different alleles produce variation in inherited characteristics such as hair color or blood type. In an individual, one form of the allele (the dominant one) may be expressed more than another form (the recessive one).

One of 20 different kinds of small molecules that link together in long chains to form proteins. Amino acids are referred to as the "building blocks" of proteins.

Gene on one of the autosomes that, if present, will almost always produce a specific trait or disease. The chance of passing the gene (and therefore the disease) to children is 50-50 in each pregnancy.

Chromosome other than a sex chromosome. Humans have 22 pairs of autosomes.

Two bases that form a "rung of the DNA ladder." The bases are the "letters" that spell out the genetic code. In DNA, the code letters are A, T, G, and C, which stand for the chemicals adenine, thymine, guanine, and cytosine, respectively. In base pairing, adenine always pairs with thymine, and guanine always pairs with cytosine.

Defect present at birth, whether caused by mutant genes or by prenatal events that are not genetic.

First breast cancer genes to be identified. Mutated forms of these genes are believed to be responsible for about one-half the cases of inherited breast cancer, especially those that occur in younger women, and also to increase a woman's risk for ovarian cancer. Both are tumor suppressor genes.

Diseases in which abnormal cells divide and grow unchecked. Cancer can spread from its original site to other parts of the body and can be fatal if not treated adequately.

Gene, located in a chromosome region suspected of being involved in a disease, whose protein product suggests that it could be the disease gene in question.

Mutation that confers immunity to infection by HIV. The mutation alters the structure of a receptor on the surface of macrophages such that HIV cannot enter the cell.

Collection of DNA sequences generated from mRNA sequences. This type of library contains only protein-coding DNA (genes) and does not include any noncoding DNA.

Basic unit of any living organism. It is a small, watery, compartment filled with chemicals and a complete copy of the organism's genome.

One of the thread like "packages" of genes and other DNA in the nucleus of a cell. Different kinds of organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes, 46 in all: 44 autosomes and two sex chromosomes. Each parent contributes one chromosome to each pair, so children get one-half of their chromosomes from their mothers and one-half from their fathers.

Process of making copies of a specific piece of DNA, usually a gene. When geneticists speak of cloning, they do not mean the process of making genetically identical copies of an entire organism.

Three bases in a DNA or RNA sequence that specify a single amino acid.

Hereditary disease whose symptoms usually appear shortly after birth. They include faulty digestion, breathing difficulties and respiratory infections due to mucus accumulation, and excessive loss of salt in sweat. In the past, cystic fibrosis was almost always fatal in childhood, but treatment is now so improved that patients commonly live to their 20s and beyond.

Visual appearance of a chromo some when stained and examined under a microscope. Particularly important are visually distinct regions, called light and dark bands, that give each of the chromosomes a unique appearance. This feature allows a person's chromosomes to be studied in a clinical test known as a karyotype, which allows scientists to look for chromosomal alterations.

Particular kind of mutation: loss of a piece of DNA from a chromosome. Deletion of a gene or part of a gene can lead to a disease or abnormality.

Chemical inside the nucleus of a cell that carries the genetic instructions for making living organisms.

Number of chromosomes in most cells except the gametes. In humans, the diploid number is 46.

Technology that identifies mutations in genes. It uses small glass plates that contain synthetic single-stranded DNA sequences identical to those of a normal gene.

Process by which the DNA double helix unwinds and makes an exact copy of itself.

Determining the exact order of the base pairs in a segment of DNA.

Gene that almost always results in a specific physical characteristic (for example, a disease) even though the patient's genome possesses only one copy. With a dominant gene, the chance of passing on the gene (and therefore the disease) to children is 50-50 in each pregnancy.

Structural arrangement of DNA, which looks something like an immensely long ladder twisted into a helix, or coil. The sides of the "ladder" are formed by a backbone of sugar and phosphate molecules, and the "rungs" consist of nucleotide bases joined weakly in the middle by hydrogen bonds.

Particular kind of mutation: production of one or more copies of any piece of DNA, including a gene or even an entire chromosome.

Process in which molecules (such as proteins, DNA, or RNA fragments) can be separated according to size and electrical charge by applying an electric current to them. The current forces the molecules through pores in a thin layer of gel, a firm, jellylike substance. The gel can be made so that its pores are just the right dimensions for separating molecules within a specific range of sizes and shapes. Smaller fragments usually travel further than large ones. The process is sometimes called gel electrophoresis.

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Understanding Human Genetic Variation - NCBI Bookshelf