The patterns governing how genetic information is transmitted from generation to generation are collectively known as the principles of inheritance.
Genes are composed of DNA (deoxyribonucleic acid), whose building blocks, the nucleotides, code for the multitude of proteins in the human body, including enzymes and structural proteins. In 2001, estimates place the number of human protein-coding genes between 25,000 and 35,000. A single-gene disorder is one caused by an alteration (mutation) in a specific gene that normally plays an important role in the human body. The protein product of a mutated gene is either abnormal in function, reduced in amount, or missing entirely.
Genes are passed down from parent to child in predictable patterns, discussed below. Knowledge of these patterns allows health care providers to explain to patients why a certain genetic disease is present in members of the family, and to predict the possibility that another family member will also be affected. As of 2001 more than 10,000 traits or diseases had been identified as following a single-gene pattern of inheritance. These are catalogued in the Online Mendelian Inheritance in Man (OMIM) at <<a href="http://www.ncbi.nlm.nih.gov/omim/">http://www.ncbi.nlm.nih.gov/omim/>. In the following discussion, the MIM numbers associated with each disease example are the OMIM catalogue numbers.
In order to understand single-gene inheritance, it is necessary to be familiar with several terms and concepts. With some exceptions, discussed later, genes are present in pairs. Each member of the pair is termed an allele. An individual is said to be homozygous (a homozygote) at a certain gene locus if the two alleles of a pair are the same(i.e., if both alleles are either normal or carry the same mutation). In contrast, if the two alleles are different, the person is heterozygous (a heterozygote). For example, a person is heterozygous if he or she has one normal and one mutant allele; or if he or she has two abnormal alleles, each of which has a different mutation. The word "genotype" refers to an individual's allelic makeup at a gene. "Phenotype" refers to the observable result of having a certain genotype. Hair color is an example of a phenotype. Phenotype can be affected by other genes or by environmental influences.
Genetic traits caused by single genes are often referred to as Mendelian traits, in tribute to the Austrian monk Gregor Mendel, who in 1865 reported the results of his painstaking work on the transmission of traits such as color and shape in the garden pea. His three laws of heredity are:
- Unit inheritance. Prior to Mendel, many believed that traits were blended as they were passed from generation to generation. Although genes would not be "discovered"until the next century, Mendel clearly spelled out that inheritance is a matter of passing on discrete traits.
- Segregation. The two alleles of a gene are never transmitted together from one parent to an offspring. This means that, in humans, an individual egg or sperm is formed with only one allele of each gene.
- Independent assortment. Alleles of different genes pass randomly to offspring. This law was later found to have important exceptions: If two genes are very close to each other on a chromosome, they tend to be passed down together.
Mendel's laws went unnoticed until 35 years later, when they were simultaneously and independently discovered by Hugo De Vries in the Netherlands, Erich von Tschermak in Austria, and Carl Correns in Germany. These rediscoveries marked the real beginning of genetics as a science. Over the years many other scientists and physicians have contributed to our current understanding of inheritance in humans.
AUTOSOMAL INHERITANCE. The transmission of single-gene traits from generation to generation follows one of several basic patterns, depending on the location of the particular gene. A gene on one of the 22 pairs of auto-someshat is, the non-sex-determining chromosomess called an autosomal gene. Similarly, a trait or disease associated with that gene is an autosomal trait. Autosomal conditions are the most common and are equally likely to occur in males or females. Autosomal traits are further classified as either dominant or recessive.
Autosomal-dominant inheritance. Dominant conditions are those that are expressed in heterozygotes. For example, in a dominant disorder, if the two alleles of the gene are labeled A for the mutant (disease-producing) copy and B for the normal copy, an individual who is AB at that gene locus will have the disease, as will the individual who is AA. However, because a mutant allele is much less common than its normal counterpart, it is very unlikely that an affected individual would be AA.
The inheritance pattern of dominant traits is distinctive. If one parent has a particular dominant trait (e.g., an AB genotype), he or she has a 50% chance of passing the mutant allele (A) to each offspring, and, similarly, a 50% chance of passing the normal allele. Since most mutant alleles are very rare, there is usually little chance that the other parent would have the same mutant allele. Therefore, the total risk of having a child with the same disorder is 50% with each pregnancy. However, depending on the particular trait or disease, there are often circumstances in which the actual risk is less than 50%. For example, whether or not a person with the mutant gene
exhibits the trait may depend on a phenomenon called penetrance. If an autosomal-dominant disorder is fully penetrant, every individual with a mutant copy of the gene will have the disease. An allele is said to have reduced penetrance if only some individuals with the allele ever develop signs of the disorder. Similarly, expressivity refers to the degree to which someone who has inherited the mutant gene will be affected. For example, one person with a particular mutant allele might be severely affected, while another will have only mild features of the disease. The degree to which penetrance and expressivity play a role in autosomal-dominant disorders varies with the particular gene. In addition, some mutant alleles cause disease only later in life; these are the socalled adult-onset single-gene disorders.
Of the 10,000 genetic traits and diseases currently known, more than half are autosomal-dominant. When considered individually, the majority are rare, with the most common being present in only 1 in 500 to 1,000 individuals. However, taken together, they have an important impact on health. One of the most common is familial hypercholesterolemia (MIM 143890), a cause of early-onset heart disease. Mutations in the gene for this condition disrupt the normal metabolism of fats in the body and lead to a significant buildup of cholesterol deposits in the arteries. Huntington disease (MIM143100), a progressive neurological disorder affecting approximately 1 in 20,000 individuals, is an example of an autosomal-dominant disorder that does not usually appear until well into adulthood. Individuals with a mutant copy of this gene typically begin to show symptoms between ages 30 and 50, with death occurring approximately 15 years later. Neurofibromatosis (von Recklinghausen disease, MIM 162200), a commonly encountered autosomal-dominant condition (1 in 3,000 individuals), is a good example of a disease exhibiting variable expressivity. Signs and symptoms can vary from extremely mild ones such as pigmentary changes of the skin (cafe-au-lait spots) to more severe complications (including learning disabilities and multiple disfiguring tumors).
Autosomal-recessive inheritance. The genes for autosomal-recessive traits are also located on the autosomes, but the mutant, disease-causing alleles are recessive to the normal alleles; thus, if one normal allele is present, it is usually sufficient to prevent any expression of the disease. If the normal allele is designated A and the mutant allele is designated a, individuals who are AA or Aa will be phenotypically normal. Only those with an aa genotype will exhibit signs of the disease. Aa individuals are termed carriers, because they carry one mutant copy without showing symptoms themselves. Except for extremely rare cases of new mutations, both parents of an individual (aa) with an autosomal recessive disorder are carriers (Aa). Each time they make a germ cell (egg or sperm), that germ cell can receive only one allele. Thus, each parent always has a 50% (1 in 2) chance of passing on the mutant allele. If both parents pass the mutant allele to their germ cells, at fertilization the resulting embryo will have two mutant alleles (aa) and no normal allele. Thus, the chance that two parents who are both carriers of a mutant allele at the same gene locus will have a child with the disease is 25% (50% x 50%), or 1 in 4 with each pregnancy. Similarly, the probability of their having a child who is a carrier (Aa) is 50%, and the chance of having a child (AA) who did not inherit the disease allele from either parent is 25%.
Because an individual who carries one copy of a gene for an autosomal-recessive disorder is usually symptom-free, he or she can unknowingly transmit the disease allele to offspring. However, because of the rarity of most autosomal-recessive disorders, it is unlikely that both members of a couple will be carriers for the same disease gene and have a risk for producing children with the disorder. An exception to this is when parents are consanguineous (blood relatives), because they are both at risk of being carriers for the same disease allele present in their family. Consanguinity is a hallmark of autosomal-recessive traits, and couples who are related may be at an increased risk over nonconsanguineous couples for an autosomal-recessive disorder in their offspring if a disease allele is carried in their family.
X-LINKED INHERITANCE. In addition to the 22 pairs of autosomes, humans have two sex chromosomes, X and Y, which determine an individual's sex (gender). Females have two X chromosomes (XX) and males have an X and a Y (XY). Because the smaller Y chromosome has only a very few genes as compared to the larger X, X-linked inheritance is often referred to as sex-linked inheritance. The pattern of inheritance of X-linked traits is very different from that of autosomal conditions. A distinguishing feature is the lack of male-to-male transmission, because a father transmits only his Y chromosome, not his X, to his sons. There are examples of both X-linked recessive and X-linked dominant diseases, although the former are far more common.
X-linked recessive inheritance. Another hallmark of X-linked recessive traits is that they are almost exclu sively seen in males, while females are the carriers. This is explained by the fact that males only have one X chromosome and females have two Xs. The rarity of an particular mutant allele (Xm) in the general population means that a female's other allele at that gene locus is likely to be normal (Xn). Because the mutant allele is recessive, females with one mutant allele and one normal allele (Xm Xn) are rarely affected. However, on average, one half, or 50%, of the sons of a carrier female will have the particular disease as a result of inheriting the mother's X chromosome with the mutant allele (XmY). Similarly, half of a carrier female's daughters will be carriers. Since a male with an X-linked recessive trait has only one X chromosome and he transmits that X to all of his daughters, all of his daughters will be carriers.
X-linked dominant inheritance. An X-linked disease is considered dominant if is expressed in heterozygotes (Xm Xn). All of the daughters of an affected male, but none of his sons, will have the disease. All offspring, female or male, of an affected female will be affected. However, because of a phenomenon called X-inactivation, some females may have a milder disease. In all females, one X in each cell is normally inactivated, and most genes on that X are nonfunctioning in that cell. The process is usually random, meaning that in females with one mutant and one normal allele, approximately half of the cells will have an active normal allele, which is often enough to ensure a milder course of the disease. In some severe X-linked disorders, most affected individuals are females, and it is rare to see a male with the disease. This is explained by the fact that males do not have another X with a normal allele. Rett syndrome (MIM 312750), a severe mental-retardation syndrome, is an X-linked dominant disorder seen only in females. It is proposed that male fetuses with the abnormal Rett syndrome gene do not survive to birth.
MITOCHONDRIAL INHERITANCE. The abovedescribed patterns of inheritance are applicable to genes present on the chromosomes in the nucleus of the cell. However, cells have additional genes in their mitochondria, the energy-producing organelles in the cytoplasm, the non-nuclear portion of the cell. Leber hereditary optic atrophy (MIM 535000), a severe type of midlife vision loss, is one of the rare disorders traced to mutations in mitochondrial DNA. Because mitochondria are almost exclusively passed from parent to child in the egg and not in the sperm, a hallmark of mitochondrial inheritance is transmission from an affected woman to all of her children. Although mitochondrial diseases are single-gene disorders, they are not considered Mendelian.
In humans, the 35,000 or so nuclear genes are located on 46 chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes. Unlike single-gene diseases that are due to mutations in the DNA, chromosomal disorders are the result of too little or too much normal DNA. These disorders are usually divided into two types, numerical and structural.
NUMERICAL CHROMOSOME ABNORMALITIES. Numerical disorders are the result of either a missing or an extra whole chromosome. Although classified as genetic disorders, they are not transmitted through families. Rather, they are usually the result of an error in the specialized cell divisions (meiosis) that produce eggs and sperm. Down syndrome, a condition involving mental retardation and characteristic physical features, with an incidence of approximately 1 in 800 live births, is perhaps the most familiar example of a chromosome disorder. In 95% of individuals with Down syndrome, the condition is due to an extra, free-standing chromosome 21 (trisomy 21). More than 90% of trisomy 21 is due to an extra chromosome being packaged into the egg. In less than 10% of individuals, the sperm is the source of the extra 21. The only known risk factor for trisomy 21 is the age of the mother. Women have an increasingly greater risk for having a child with trisomy 21 as they get older. The reason for this is not known. Other examples of clinically important conditions that result from either a missing or an extra chromosome are Turner syndrome, Klinefelter syndrome, trisomy 13, and trisomy 18.
STRUCTURAL CHROMOSOME ABNORMALITIES. Structural chromosome abnormalities are caused by chromosome breakage and rearrangement. Among the more common types are inversions, translocations, deletions, and duplications. If the rearrangement preserves all of the genetic material, it is called balanced. Individuals who carry balanced rearrangements are not affected themselves, but their altered chromosomes are at risk for further breakage and rearrangement during egg and sperm formation. This can result in offspring with extra or missing portions of chromosomes. In approximately 5% of individuals with Down syndrome, the extra chromosome 21 is not free-standing, as in trisomy 21, but is attached to another chromosome as the result of a unbalanced translocation. Often one parent will carry the balanced form of the translocation and be at risk for having other children with Down syndrome. Unbalanced structural chromosome abnormalities are found in about 1 in 17,000 live births. In the majority of cases, the resulting imbalance in the amount of genetic material results in serious physical and developmental abnormalities.
Instead of one single gene being of paramount importance in producing disease, a multifactorial disorder results from the interaction of a number of genes plus influences in the environment. Despite the fact that multifactorial disorders are among the most common causes of disease in humans, the specific genes and environmental factors are still poorly understood. In contrast to single-gene disorders, multifactorial diseases do not exhibit a clear-cut pattern of inheritance within families. After one affected individual in the family, the risk of a second affected with the disorder may be somewhat increased, but that increase is more in the range of 20% percent than the 250% seen in single-gene disorders.
In addition to the well-known patterns of inheritance described above, some important clinical disorders exhibit variations on these patterns. Several of these nontraditional types of inheritance are introduced briefly here. The reader is referred to other sources listed in the references for more detailed treatments.
- Triplet-repeat disorders. These are caused by genes that change in size and function from parent to child. Fragile X syndrome (MIM 309550), primarily affecting males, is caused by a gene on the X chromosome that can expand when passed from parent to child. The expansion disrupts gene function and results in mental retardation, characteristic facial features, and enlarged testes. There are a number of other triplet-repeat disorders, including the autosomal-dominant Huntington disease.
- Imprinting disorders. Most genes are expressed the same in an individual whether that gene was contributed by the mother or the father. However, there are exceptions in which the allele from one parent is normally imprinted and inactive. If the allele from the other parent is missing, for example, due to a deletion of a portion of the chromosome containing the gene, the individual is left with no functioning gene. Two very different conditions involving mental retardation, Prader-Willi syndrome (MIM 176270) and Angelman syndrome (MIM 105830), have been found to involve the phenomenon of imprinting.
- Uniparental disomy. This is the presence of both members of a chromosome pair from one parent and no copy from the other parent. The reader is referred to other sources for a more detailed treatment of this rare phenomenon. Uniparental disomy in combination with imprinting can also result in clinically important disorders, including some cases of Prader-Willi and Angelman syndromes.
Allele member of a pair of genes.
Chromosomestructures in the nucleus of a cell consisting of a thread of DNA containing the genetic information (genes). Humans have 46 chromosomes in 23 pairs.
Enzyme protein catalyst that promotes chemical reactions within the body.
Hemoglobinhe iron-containing protein of the red blood cells. Its function is to carry oxygen from the lungs to the tissues.
Role in human health
Although genetics plays a role in the majority of human diseases, the contribution of genes may be primary or secondary in the pathophysiology of diseases. A British Columbian survey of more than one million individuals estimated that by age 25, at least 53 of 1,000 will have a disease with a significant genetic component.
Common diseases and disorders
Most genetic disorders fall into one of three main types; single gene, chromosomal, and multifactorial. Each type has its important hallmarks, and a basic knowledge of the distinguishing factors of each is important for those who work in a clinical setting.
Cystic fibrosis (CF, MIM 602421) is a typical autosomal-recessive disease. CF is often said to be the most common serious autosomal-recessive condition in the Caucasian population, with a frequency of about 1 in 2,000 children. Its clinical features include chronic respiratory disease, pancreatic insufficiency, and a decreased life expectancy. At present there is no cure, but because a great deal is being learned about the function of the CF gene, CF is a disease for which treatment at the gene level (also known as gene replacement or gene therapy) is being considered. Carrier parents who have had one child with CF have a 25% risk, with each subsequent pregnancy, of having another affected child. It is customary to offer these couples the option of prenatal diagnosis in future pregnancies to determine if the fetus is affected.
Sickle-cell anemia (MIM 603903), another autosomal-recessive disorder, is due to a specific mutation in one of the genes that codes for hemoglobin. The resulting abnormalities in the hemoglobin-rich red blood cells lead to multiple clinical symptoms in affected (aa) individuals, including increased risks for infections, blood clots, strokes, and painful swelling of the joints. Sickle cell is more common in those who can trace their ancestry to the African continent. About 1 in 500 African Americans is born with this disease. Approximately 8% are carriers (Aa) but remain symptom-free.
Perhaps the best-known example of an X-linked recessive disease is hemophilia A (MIM 306700). Seen almost exclusively in males, this is a failure of the blood to clot normally because of a mutation in the gene for one of the clotting factors, factor VIII. Affected males require life-long treatment with blood transfusions and factor VIII concentrates. In recent years research has been directed toward being able to offer gene therapy for males with this disorder. Duchenne muscular dystrophy (DMD, MIM 310200) is another X-linked recessive condition affecting the muscle fibers; it results in death usually by age 20. Since most males with DMD do not survive to reproduce, their abnormal genes are not passed on. Nevertheless, the frequency of DMD does not decline over time, because approximately one third of all cases are due to new mutations and not to the transmission of the gene from a carrier mother.
Multifactoral inherited disorders
Spina bifida, or open-spine defect, is a multifactorial birth defect, as are many cases of cleft lip/palate. Recent studies have suggested that a deficiency of folic acid, one of the B vitamins, may play a role in causing spina bifida, and women who are planning a pregnancy are urged to take supplemental folic acid. Not withstanding the important part that multifactorial inheritance plays in the etiology of birth defects, perhaps its greatest role is in the common diseases that are adultonset. For example, most coronary heart disease is thought to be multifactorial, with genes plus dietary habits playing a part in determining an individual's risk for atherosclerosis, a narrowing of the arteries of heart caused by lipid (fat) deposits. A variety of cancers are also thought to be due to a combination of genetic and environmental factors. An enormous challenge awaits the next generation of geneticists as they attempt to unravel the complex interactions of genes and environment in these clinically important multifactorial disorders.
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Rimoin, D. L., J. M. Connor, and R. E. Pyeritz, editors. Emery and Rimoin's Principles and Practice of Medical Genetics, Third Edition. New York: Churchill Livingstone, 1997.
Baird, P. A., T. W. Anderson, H. B. Newcombe, and R. B. Lowry. "Genetic Disorders in Children and Young Adults: A Population Study." American Journal of Human Genetics 42: 677-693.
Wolfsberg, T. G., J. McEntyre, and G. D. Schuler. "Guide to the Draft Human Genome." Nature (February 15, 2001), 409: 824-825.
Medicine and the New Genetics: Human Genome Project Information. <<a href="http://www.ornl.gov/hgmis/medicine">http://www.ornl.gov/hgmis/medicine>.
OMIM (Online Mendelian Inheritance in Man). <<a href="http://www3.ncbi.nlm.nih.gov/htbin-post/Omim">http://www3.ncbi.nlm.nih.gov/htbin-post/Omim>.
Sallie Boineau Freeman, Ph.D.
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