Inheritance patterns are the predictable patterns seen in the transmission of genes from one generation to the next, and their expression in the organism that possesses them. (A gene is said to be expressed when it is read by cellular mechanisms that result in the production of a protein.) While people have long noted that offspring resemble parents, the formal description of inheritance patterns began with Gregor Mendel, whose discoveries laid the foundation for the modern understanding of genetic inheritance.
Phenotype and Genotype
An organism's observable characteristics, such as height, hair texture, skin color, or ear shape, are known as the phenotype of that organism. The phenotype is determined partly by the environment and partly by the set of genes that the organism inherited from its parents. Adult height, for instance, is due partly to nutrition (an environmental influence), and partly to a set of genes governing things such as rates of bone growth, sensitivity to specific hormones, and the like. Phenotype includes not only large-scale characteristics such as height, but every expressed trait, including the types and amounts of all the proteins produced in each cell in the body.
The set of genes an organism inherits is known as its genotype . Genes are carried on chromosomes in the cell nucleus. Animals and most other multicellular organisms possess two sets of chromosomes in each cell, one set inherited from the mother, and one from the father. Such an organism is said to be diploid . In humans, the maternal and paternal sets each include 23 chromosomes, so humans have 46 chromosomes in each cell. Analysis shows that the maternal and paternal chromosome sets are virtually identical, and they can be matched up to form 23 pairs. One pair, however, may not be a pair at all. These are the sex chromosomes, so called because they determine the sex of the organism. In humans, the female carries two identical sex chromosomes, called X chromosomes, while the male carries two dissimilar chromosomes, one X and one Y. The other 22 pairs of chromosomes are called autosomes .
Members of each chromosome pair (except for X and Y) carry the same set of genes, so that a diploid cell carries two copies of (almost) every gene, one on the maternally derived chromosome, and one on the paternally derived chromosome. These two copies may be precisely identical, meaning the two genes have precisely the same sequence of nucleotides, or their sequences may be slightly different. These sequence differences may have no effect at all on the phenotype, or they may lead to different forms of the same trait, such as brown versus blue eye color, or smooth versus wrinkled pea texture. The two different forms of the gene are called alleles , and so we speak of the brown eye color allele or the wrinkled pea texture allele.
While a single organism can possess no more than two different alleles for a single gene, many different alleles for a particular gene can exist in a population. For instance, there are three alleles for the ABO blood group gene, namely A, B, and O.
When both alleles for a particular trait are identical, the organism is said to be homozygous for that trait. When the alleles differ, the organism is heterozygous . The presence of two different alleles raises the question of whether one or the other, or both, will determine the phenotype of the organism. For his experiments on peas, Mendel chose traits for which one allele of each pair had a decisive effect, completely determining the phenotype even in the presence of the other allele. He called the determining allele "dominant" and the other allele "recessive." Only when the organism is homozygous for the recessive allele does the phenotype show the recessive trait. For instance, the albino skin pigmentation allele is recessive to other pigmentation alternatives.
While some sets of alleles do show a complete dominance-recessiveness relationship, most allele sets do not. Instead, each allele contributes to the phenotype. Such a relationship is called codominance. In humans, the A and B blood group alleles are codominant, and a person inheriting both will have blood type AB. Incomplete dominance is another variant in this system. In this case, the phenotype of the heterozygote is intermediate between the two extremes. Skin color in humans often shows this pattern.
Molecular Meaning of Dominance and Recessiveness
The terms "dominant" and "recessive" imply some competitive interaction between alleles over which one will control the phenotype. This is not the case, however. Alleles do not interact in the nucleus. Instead, both alleles are expressed (in most cases), and the phenotype reflects the result. How, then, can one allele determine the phenotype to the exclusion of another?
Genes code for proteins, and their effect on the phenotype is through the proteins they create. By analyzing the quantity and characteristics of protein produced from each allele, it has been shown that, in many cases, recessive alleles code for defective proteins, or for very low levels of protein. If the other allele codes for normal functional protein, and if the organism can make do with half the normal level of protein (or can increase production from the normal allele), the defective allele will have no effect on the phenotype, and will therefore act in a recessive manner. This type of allelic change is called a loss-of-function mutation. This is the case with the albino allele. This allele codes for a nonfunctional enzyme in the pathway that produces the pigment melanin. Even with only one functioning allele, the organism can still make enough melanin to obtain normal skin pigmentation. Thus, the functional allele will appear to be dominant .
Alleles coding for defective protein can act in a dominant manner in other situations, however. If the resulting protein is not properly regulated by other cell components, it may perform actions that harm the cell. This is called a toxic-gain-of-function mutation. Huntington's disease is thought to be due to a toxic-gain-of function mutation, although it is not yet clear what the exact toxic mechanism is.
A defective protein can also have a dominant effect if its absence cannot be compensated for by the other functioning allele (this is called a dominant negative effect). This may occur when half the normal protein level is insufficient for normal function (a condition called haploin-sufficiency), or when the protein forms part of a multiprotein complex, which is therefore defective in its entirety. Examples include a variety of human collagen-structure disorders. Collagen is the most abundant and important structural protein in the body, and is critical for bone formation and growth. Defects in one of the subunits cause a variety of dominant disorders termed "osteogenesis imperfecta."
Autosomal Dominant Inheritance
Autosomal dominant inheritance is due to a dominant allele carried on one of the autosomes. Autosomal dominant alleles need only be inherited from one parent, either the mother or the father, in order to be expressed in the phenotype. Because of this, any child has a 50 percent chance of inheriting the allele and expressing the trait if one parent has it.
Many normal human traits are due to autosomal dominant alleles, including the presence of dimples, a cleft chin, and a widow's-peak hairline. Note that dominant does not necessarily mean common. Dominant alleles can be rare in a population, and do not spread simply because they are dominant. This phenomenon is explained by the theory known as Hardy-Weinberg equilibrium.
There are hundreds of medical conditions due to autosomal dominant alleles, most of them very rare. They include neurodegenerative disorders such as Huntington's disease, a variety of deafness syndromes, and metabolic disorders such as familial hypercholesterolemia (affecting blood cholesterol levels) and variegate porphyria (affecting the oxygen-carrying porphyrin molecule). Table 1 lists some other examples.
Because inheritance of a harmful dominant allele can be lethal, these alleles tend to be quite rare in the population, and new mutations account for many cases of these conditions. Exceptions include late-onset disorders such as Huntington's disease, in which parents may pass on the gene to off-spring before developing the symptoms of the disease. Other exceptions arise from incomplete penetrance, in which the allele is present, but (for reasons usually unknown) it is not expressed. Genomic imprinting (see below) may explain some cases of incomplete penetrance. Variable expressivity is also possible, in which different individuals express the trait with different levels of severity.
|Condition||Chromosome Location and Inheritance Pattern||Protein Affected||Symptoms and Comments|
|Gaucher Disease||1, recessive||glycohydrolase glucocerebrosidase, a lipid metabolism enzyme||Common among European Jews. Lipid accumulation in liver, spleen, and bone marrow. Treat with enzyme replacement|
|Achondroplasia||4, dominant||fibroblast growth factor receptor 3||Causes dwarfism. Most cases are new mutations, not inherited|
|Huntington's Disease||4, dominant||huntingtin, function unknown||Expansion of a three-nucleotide portion of the gene causes late-onset neurodegeneration and death|
|Juvenile Onset Diabetes||6, 11, 7, others||IDDM1, IDDM2, GCK, other genes||Multiple susceptibility alleles are known for this form of diabetes, a disorder of blood sugar regulation. Treated with dietary control and insulin injection|
|Hemochromatosis||6, recessive||HFE protein, involved in iron absorption from the gut||Defect leads to excess iron accumulation, liver damage. Menstruation reduces iron in women. Bloodletting used as a treatment|
|Cystic Fibrosis||7, recessive||cystic fibrosis transmembrane regulator, in ion channel||Sticky secretions in the lungs impairs breathing, and in the pancreas impairs digestion. Enzyme supplements help digestive problems|
|Friedreich's Ataxia||9, recessive||frataxin, mitochondrial protein of unknown function||Loss of function of this protein in mitochondria causes progressive loss of coordination and heart disease|
|Albinism||11, recessive||tyorsinase||Lack of pigment in skin, hair, eyes; loss of visual acuity|
|Best Disease||11, dominat||VMD2 gene, protein function unknown||Gradual loss of visual acuity|
|Sickle Cell Disease||11, recessive||hemoglobin beta subunit, oxygen transport protein in blood cells||Change in hemoglobin shape alters cell shape, decreases oxygen-carrying ability, leads to joint pain, anemia, and infections. Carriers are resistant to malaria. About 8% of US black population are carriers|
|Phenylketonuria||12, recessive||phenylalanine hydroxylase, an amino acid metabolism enzyme||Inability to breakdown the amino acid phenylalanine causes mental retardation. Dietary avoidance can minimize effects. Postnatal screening is widely done|
|Marfan Syndrome||15, dominant||fibrillin, a structural protein of connective tissue||Scoliosis, nearsightedness, heart defects, and other symptoms|
|Tay-Sachs Disease||15, recessive||beta-hexosaminidase A, a lipid metabolism enzyme||Accumulation of the lipid GM2 ganglioside in neurons leads to death in childhood|
|Breast Cancer||17, 13||BRCA1, BRCA2 genes||Susceptibility alleles for breast cancer are thought to involve reduced ability to repair damaged DNA|
|Myotonic Dystrophy||19, dominant||dystrophia myotonica protein kinase, a regulatory protein in muscle||Muscle weakness, wasting, impaired intelligence, cataracts|
|familial hypercholesterolemia||19, incomplete dominance||low-density lipoprotein (LDL) receptor adenosine deaminase, nucleotide metabolism enzyme||Accumulation of cholesterol-carrying LDL in the bloodstream leads to heart disease and heart attack|
|Severe Combined Immune Deficiency ("Bubble Boy" Disease)||20, recessive||respiratory complex proteins||Immature white blood cells die from accumulation of metabolic products, leading to complete loss of the immune response. Gene therapy has been a limited success|
|Leber's Hereditary Optic Neuropathy||mitochondria, maternal inheritance||transfer RNA||degeneration of the central portion of the optic nerve, loss of central vision|
|Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke (MELAS)||mitochondria, maternal inheritance||lignoceroyl-CoA ligase, in peroxisomes||recurring, stroke-like episodes in which sudden headaches are followed by vomiting and seizures; musle weakness|
|Adrenoleukodystrophy||X||dystrophin, muscle structural protein||Defect causes build-up of long-chain fatty acids. Degeneration of the adrenal gland, loss of myelin insulation in nerves. Featured in the film "Lorenzo's Oil"|
|Duchenne Muscular Dystrophy||X||Factor VIII, part of the blood clotting cascade||Lack of dystrophin leads to muscle breakdown, weakness, and impaired breathing|
|Hemophilia A||X||Uncontrolled bleeding, can be treated with injections or replacement protein|
|Rett Syndrome||X||methyl CpG-binding protein 2, regulates DNA transcription||Most boys die before birth. Girls develop mental retardation, mutism and movment disorder|
Autosomal Recessive Inheritance
Autosomal recessive inheritance is due to recessive alleles carried on autosomes. An individual possessing only one recessive allele is known as a carrier. An individual must inherit two recessive alleles, one from each parent, in order to express the recessive trait. When two carrier parents have off-spring, each offspring has a 25 percent chance of inheriting two alleles and expressing the trait. The two recessive alleles need not be precisely identical, as long as each is nonfunctional. An individual possessing two different alleles with the same effect is known as a compound heterozygote. Compound heterozygotes account for some cases of the neurologic disorder known as Friedreich's ataxia.
Medical conditions due to autosomal recessive traits also number in the many hundreds. These include cystic fibrosis (affecting ion transport in the lungs and pancreas), Tay-Sachs disease (affecting lipid metabolism and storage, especially in the brain), and hemochromatosis (affecting iron metabolism and storage in a variety of organs).
The number of people with such conditions is actually much higher than that for autosomal dominant conditions. This is because inheritance of one harmful recessive allele does not produce symptoms, and so the individual can reproduce and pass the allele on to children easily. Thus, most harmful recessive alleles are not deleted from a population's gene pool as rapidly as most dominant ones, and the likelihood of inheriting two copies is consequently higher. Most humans harbor a small handful of known harmful alleles; it is only when they mate with another who has the same set that there is a chance of bearing children that express the disorder. Customs that warn against marrying close relations have the effect of minimizing the likelihood of offspring with homozygous recessive conditions.
The two sex chromosomes differ in the genes they carry. The Y chromosome is very small, and appears to carry very few genes other than the SRY gene that determines male sex. Many genes are carried on the X chromosome, however, and these are as essential for males as they are for females. Genes carried on the X chromosome are said to be X-linked.
X-linked dominant alleles affect both males and females, although males may be more severely affected since they inherit only a single X chromosome and thus lack a compensating normal allele. An example of a disorder caused by an X-linked dominant allele is congenital generalized hypertrichosis, which causes dense hair growth on the face and other regions in both sexes. X-linked dominant alleles can be inherited by both males and females, but fathers cannot pass them on to sons.
X-linked recessive alleles affect males more often and more severely than females. A male inherits his single X chromosome from his mother. Because a male has only one X chromosome, he expresses every allele on it, including harmful recessive ones. Examples of conditions due to recessive X-linked alleles include Duchenne muscular dystrophy, one form of hemophilia, and red-green colorblindness. These conditions are much more common in males than in females. Female carriers have a 50 percent chance of giving birth to a male child affected by the recessive allele. The genetic status of the father with respect to X-linked conditions is not relevant in this case, because he donates a Y chromosome to his male children.
Since females have two X chromosomes, they are less likely than males to express harmful recessive X-linked traits. Female children have only a 25 percent chance of inheriting two recessive alleles from a carrier mother and an affected father.
The reason females are less often affected by recessive alleles is not as simple as it is for autosomes. Since females have twice the number of X chromosomes as males, the question arises as to whether they make twice the amount of each X-encoded protein as males do. In fact they do not, and are prevented from doing so by the random inactivation of one X chromosome in each cell. Therefore, about half of the heterozygote female's cells will express the normal allele, and half will express the harmful recessive allele. This is in contrast to the situation for autosomes, in which each cell expresses both alleles.
Inactivation begins early in development, with some cells shutting down one X and others shutting down the other, followed by faithful inheritance of the inactivated chromosome by each daughter cell following cell division. As a result, many tissues in the adult female are a mosaic of cells with different X chromosomes inactivated. The consequence of this is seen in a woman who is heterozygous for a harmful allele. If the affected tissue is primarily composed of cells expressing only the harmful one, she is likely to express the trait. However, most adult tissues will be a more even mixture, and for many disorders this will prevent her from developing symptoms of the disease.
The trait may also show variable expressivity, with the severity dependent on the proportion of the tissue affected. Duchenne muscular dystrophy in females is an example. Many women with one disease allele will show no symptoms. Others will develop only slightly elevated blood levels of certain enzymes indicating mild muscle damage, while others will develop heart problems and muscle weakness. Such women are referred to as "manifesting carriers."
Mitochondria are the cell's power plants. They possess their own chromosome, which carries thirty-seven genes. Mitochondria are inherited only from the mother. Mitochondrially inherited disorders include a number of rare muscle diseases (mitochondrial myopathies), as well as some deafness syndromes, optic nerve degeneration, and other neurological disorders.
Penetrance, Expressivity, and Anticipation
The presence of a dominant allele, or two recessive alleles, is not always a guarantee that the trait will be displayed in the phenotype, a phenomenon called incomplete penetrance. Variable expressivity also occurs, with some individuals more affected than others of the same genotype. In most cases the reasons for these differences are unknown, but they are assumed to be due at least in part to other differences between individuals. For instance, if there are differences between individuals in the other genes with which the product of incompletely penetrant or variably expressed allele interacts, this may account for some of these differences in expression.
One phenomenon also associated with changes in both timing and severity of expression is anticipation. Anticipation refers to the successive decrease in the age of symptom onset over several generations, so that a condition might first manifest at age 60 in a grandfather, at age 40 in a father, and at age 20 in a son. This increasingly earlier onset is often accompanied by increasingly severe symptoms as well. Some cases of anticipation are known to be due to changes in the allele itself over time. Spinocerebellar ataxia, for example, is an autosomal dominant disease that causes balance disorders. The normal allele has a section of its DNA that includes approximately 20 repeats of a nucleotide triplet, CAG. The disease allele has 40 or more CAG repeats. This number can increase between generations, leading to earlier onset and more severe disease over several generations. Other so-called triplet repeat diseases show the same pattern of anticipation.
Some cases of incomplete penetrance appear to be due to imprinting. In this phenomenon, expression of an allele is governed by whether it is derived from the mother or the father. Imprinted alleles are located on autosomes, but are "stamped" with the sex of the parent that contributed it. The chemical basis of the imprint is the addition of methyl (-CH3) groups to the allele's nucleotides, and the effect is thought to be to silence the allele so it is not expressed. For some genes the maternal allele is silenced, while for others the paternal allele is silenced. When a child inherits the two alleles, they retain these stamps, regardless of the sex of the child. However, when the child makes its own sperm or eggs, the child's own imprinting machinery stamps the alleles so that they correspond to the child's own sex. Therefore, a particular allele can be turned on or turned off as it is passed down through successive generations, from male to female and back again.
Imagine a dominant disease allele that is active when inherited from the mother, but is silenced when inherited from the father. Both the sons and daughters of the mother will develop symptoms of the disease. The daughter's children will also develop symptoms, while the son's children will not, despite having the same genotype. This is an example of incomplete penetrance. Prader-Willi syndrome and Angelman syndrome are examples of disorders arising from imprinted genes.
Polygenic, Multifactorial, and Complex Traits
Proteins, which are the products of genes, interact with one another in complex ways to determine the phenotype. Almost every trait we observe, such as height, normal metabolic level, or intelligence, is really the product of many genes. Many traits, however, also reflect the influence of the environment. Such traits are called complex traits, to distinguish them from simple traits that are governed by single genes. While any single gene contributing to a complex trait can be described in terms of dominance or recessiveness, autosomal or sex-linked, or other categories, the gene products interact to make a much more subtle phenotypic picture.
A polygenic trait is a complex trait controlled by the alleles of two or more genes, without the influence of the environment. A multifactorial trait is a complex trait controlled by both genes and the environment. Intelligence is multifactorial, with strong influences from both genes (such as those controlling nerve-cell growth and connectivity) and the environment (such as early childhood nutrition and education).
As the number of influences grows, so too does the number of possible phenotypes. Because of this, complex traits show not just a few phenotypes, but a continuum (as can be seen in the wide range of possible human heights). The distribution in a population will usually be described by a bell-shaped curve, with most people displaying the mid-range phenotype.
Pleiotropy and Epistasis
Most single genes affect more than one observable trait, a phenomenon know as pleiotropy . For example, the alleles for melanin pigment affect skin color, eye color, and hair color. The ion channel gene affected in cystic fibrosis acts in the lungs, the pancreas, and other passageways, and defects cause symptoms in both these organs, as well as elsewhere in the body.
Proteins are also involved in highly ordered metabolic pathways, and a defect "upstream" can mask or prevent expression of other alleles "down-stream." This condition is known as epistasis ("standing upon"), and the upstream gene is said to be epistatic to the downstream one. For instance, on blood cells, the well-known ABO markers are actually branched sugars attached to proteins embedded in the surface of the cell. In order for the cell to attach these sugars, it must first express a gene (called fucosyltransferase) that attaches one sugar group (fucose) that is common to all blood types. Absence of functional fucosyltransferase prevents the expression of the ABO alleles.
see also Color Vision; Crossing Over; Disease, Genetics of; Epistasis; Fertilization; Growth Disorders; Hardy-Weinberg Equilibrium; Hemophilia; Imprinting; Meiosis; Mendelian Genetics; Mitochondrial Diseases; Mosaicism; Muscular Dystrophy; Pedigree; Pleiotropy; Tay-Sachs Disease; Triplet Repeat Disease.
Hartwell, Leland H., et al. Genetics: From Genes to Genomes. New York: McGraw-Hill, 2000.
Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/omim>.