We could wish that … life-histories were found in every family, showing the health and diseases of its different members. We might thus in time find evidences of pathological connections and morbid liabilities not now suspected.
—William Gull, 1896
It has long been known that heredity affects health. Genetics, the study of single genes and their effects on the body and mind, explains how and why certain traits such as hair color and blood types run in families. Genomics, a discipline that is only about two decades old, is the study of more than single genes; it considers the functions and interactions of all the genes in the genome. In terms of health and disease, genomics has a broader and more promising range than genetics. The science of genomics relies on knowledge of and access to the entire genome and applies to common conditions, such as breast and colorectal cancer, Parkinson's disease, and Alzheimer's disease. It also has a role in infectious diseases once believed to be entirely environmentally caused such as human immunodeficiency virus (HIV, which is the virus that causes acquired immune deficiency syndrome [AIDS]) infection and tuberculosis. Like most diseases, these frequently occurring disorders are due to the interactions of multiple genes and environmental factors. Genetic variations in these disorders may have a protective or a causative role in the expression of diseases.
It is commonly accepted that diseases fall into one of three broad categories: those few that are primarily genetic in origin; those that are largely attributable to environmental causes; and those—the majority of conditions—in which genetics and environmental factors make comparable, though not necessarily equal, contributions. As understanding in genomics advances and scientists identify genes involved in more diseases, the distinctions between these three classes of disorders is diminishing. This chapter considers some of the disorders believed to be predominantly genetic in origin and some that are the result of genes acted on by environmental factors.
There are two types of genes: dominant and recessive. When a dominant gene is passed on to offspring, the feature or trait it determines will appear regardless of the characteristics of the corresponding gene on the chromosome inherited from the other parent. If the gene is recessive, the feature it determines will not show up in the offspring unless both the parents' chromosomes contain the recessive gene for that characteristic. Similarly, among diseases and conditions primarily attributable to a gene or genes, there are autosomal dominant disorders and autosomal recessive disorders.
Another way to characterize genetic disorders is by their pattern of inheritance, as single gene, multifactorial, chromosomal, or mitochondrial. Single-gene disorders (also called Mendelian or monogenic) are caused by mutations in the deoxyribonucleic acid (DNA) sequence of one gene. Since genes code for proteins, when a gene is mutated so that its protein product can no longer carry out its normal function, it may produce a disorder. There are more than 6,000 known single-gene disorders, which occur in about one in every 200 births. Examples are cystic fibrosis, sickle-cell anemia, Huntington's disease, and hereditary hemochromatosis (a disorder in which the body absorbs too much iron from food; rather than the excess iron being excreted, it is stored throughout the body, and iron deposits damage the pancreas, liver, skin, and other tissues). Figure 5.1 shows the cystic fibrosis gene and its location on chromosome 7; Figure 5.2 shows the sickle-cell anemia gene found on chromosome 11; and Figure 5.3 shows the hereditary hemochromatosis gene located on chromosome 6. Single-gene disorders are the result of either autosomal dominant, autosomal recessive, or X-linked inheritance.
Multifactorial or polygenic disorders result from a complex combination of environmental factors and mutations in multiple genes. For example, different
The cystic fibrosis gene
SOURCE: "CFTR: The Gene Associated with Cystic Fibrosis," in Gene Gateway—Exploring Genes and Genetic Disorders, U.S. Department of Energy, Office of Biological and Environmental Research, http://www.ornl.gov/TechResources/Human_Genome/posters/chromosome/cftr.html%20(accessed February 7, 2005)
genes that influence breast cancer susceptibility have been found on seven different chromosomes, rendering it more difficult to analyze than single-gene or chromosomal disorders. Some of the most common chronic diseases are multifactorial in origin. Examples include heart disease, Alzheimer's disease, arthritis, diabetes, and cancer.
Chromosomal disorders are produced by abnormalities in chromosome structure, missing or extra copies of chromosomes, or errors such as translocations (movement of a chromosome section from one chromosome to another). Down's syndrome or trisomy 21 is a chromosomal disorder that results when an individual has an extra copy, or a total of three copies, of chromosome 21. Mitochondrial disorders result from mutations in the nonchromosomal DNA of mitochondria, which are organelles involved in cellular respiration. Compared with the three other patterns of inheritance, mitochondrial disorders occur infrequently.
There are significant differences between the nineteenth-century germ theory of disease and the twenty-first-century genomic theory of disease. By
The sickle cell anemia gene
SOURCE: "HBB: The Gene Associated with Sickle Cell Anemia," in Gene Gateway—Exploring Genes and Genetic Disorders, U.S. Department of Energy, Office of Biological and Environmental Research, http://www.ornl.gov/TechResources/Human_Genome/posters/chromosome/hbb.html%20(accessed February 7, 2005)
the middle of the twentieth century it became possible to improve the quality of life and to save the lives of people with some genetic diseases. Effective treatment included changes in diet to prevent or manage conditions such as phenylketonuria (PKU) and glucose galactose malabsorption (GGM). PKU is an inherited error of metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase. (See Figure 5.4.) It may result in mental retardation, organ damage, and unusual posture. Dietary changes are also used to treat GGM, a rare metabolic disorder caused by lack of the enzyme that converts galactose into glucose. For people with severe cases of GGM, it is vital to avoid lactose (milk sugar), sucrose (table sugar), glucose, and galactose. Other therapeutic measures may involve surgery to correct deformities and avoidance of environmental triggers, as in some types of asthma.
At the dawn of the twenty-first century, the possibility of preventing and changing genetic legacies appears within reach of modern medical science. Genomic medicine predicts the risk of disease in the individual, whether highly probable, as in the case of some of the well-established single-gene disorders, or in terms of an increased susceptibility likely to be influenced by environmental factors.
The hemochromatosis gene
SOURCE: "The Hemochromatosis Gene," in Gene Gateway—Exploring Genes and Genetic Disorders, U.S. Department of Energy, Office of Biological and Environmental Research, http://www.ornl.gov/TechResources/Human_Genome/posters/chromosome/hfe.html(accessed February 7, 2005)
The enzyme phenylalanine hydroxylase converts the amino
acid phenylalanine to tyrosine
SOURCE: "The Enzyme Phenylalanine Hydroxylase Converts the Amino Acid Phenylalanine to Tyrosine," in "Phenylketonuria (PKU)," Science: The Human Gene Maps 7, National Institutes of Health, National Center for Biotechnology Information, 2004, http://www.ncbi.nlm.nih.gov/SCIENCE96/gene.cgi?PAH (accessed February 8, 2005)
The promise of genomic medicine is to make preventive medicine more powerful and treatment more specific to the individual, enabling investigation and treatment that are custom-tailored to an individual's genetic susceptibilities, or to the characteristics of the specific disease or disorder.