Genes are segments of deoxyribonucleic acid (DNA) that contain the code for a specific protein that functions in one or more types of cells in the body.
Chromosomes are made of a very long strand of DNA and contain many genes (hundreds to thousands). Except for certain cells (for example, sperm and egg cells), every normal human cell contains 23 pairs of chromosomes. There are 22 pairs of nonsex (autosomal) chromosomes and one pair of sex chromosomes, for a total of 46 chromosomes. Normally, each pair consists of one chromosome from the mother and one from the father.
The sex chromosomes determine whether a fetus becomes male or female. A male has one X and one Y sex chromosome. The X comes from his mother and the Y comes from his father. A female has two X chromosomes. One X comes from her mother and the other X comes from her father.
The traits (any gene-determined characteristic, such as eye color) produced by a gene can be characterized as
Dominant traits are expressed when even one copy of the gene for that trait is present.
Recessive traits carried on autosomal chromosomes can be expressed only when two copies of the gene for that trait are present, one on each of the pair of chromosomes. People with one copy of an abnormal gene for a recessive trait (and who thus do not have the disorder) are called carriers.
With codominant traits, both copies of a gene are expressed to some extent. An example of a codominant trait is blood type. If a person has one gene coding for blood type A and one gene coding for blood type B, the person has both A and B blood types expressed (blood type AB).
An X-linked (sex-linked) gene is one that is carried on an X chromosome. X-linking also determines expression. Among males, almost all genes on the X chromosome, whether the trait is dominant or recessive, are expressed because there is no paired gene to offset their expression.
Penetrance and expressivity
Penetrance refers to how often a trait is expressed in people with the gene for that trait. Penetrance may be complete or incomplete. A gene with incomplete penetrance is not always expressed even when the trait it produces is dominant or when the trait is recessive and present on both chromosomes. If half the people with a gene show its trait, its penetrance is said to be 50%.
Expressivity refers to how much a trait affects a single person, that is, whether the person is greatly, moderately, or mildly affected.
How Genes Affect People: Penetrance and Expressivity
People who have the same gene may be affected differently. Two terms explain these differences: penetrance and expressivity.
Penetrance refers to whether the gene is expressed or not. That is, it refers to how many people with the gene have the trait associated with the gene. Penetrance is complete (100%) if everyone with the gene has the trait. Penetrance is incomplete if only some people with the gene have the trait. For example, 50% penetrance means that only half the people with the gene have the trait.
Expressivity refers to how much the trait affects (or, is expressed in) a person. A trait may be very pronounced, barely noticeable, or in between. Various factors, including genetic makeup, exposure to harmful substances, other environmental influences, and age, can affect expressivity.
Both penetrance and expressivity can vary. People with the gene may or may not have the trait, and, in people with the trait, how the trait is expressed varies.
Many genetic disorders, particularly those involving traits controlled by multiple genes or those that are highly susceptible to environmental influences, do not have an obvious pattern of inheritance. However, some single-gene disorders display characteristic patterns, particularly when penetrance is high and expressivity is full. In such cases, patterns can be identified based on whether the trait is dominant or recessive, and whether the gene is X-linked or carried on the mitochondrial genome.
Examples of Genetic Disorders
Non–X-Linked (Autosomal) Inheritance
Non-X-linked genes are genes carried on one or both of the 22 pairs of nonsex (autosomal) chromosomes.
The following principles generally apply to dominant disorders determined by a dominant non–X-linked gene:
- When one parent has the disorder and the other does not, each child has a 50% chance of inheriting the disorder.
- People who do not have the disorder usually do not carry the gene and thus do not pass the trait on to their offspring.
- Males and females are equally likely to be affected.
- Most people with the disorder have at least one parent with the disorder, although the disorder may not be obvious and may even have been undiagnosed in the affected parent. However, sometimes the disorder arises as a new genetic mutation.
The following principles generally apply to recessive disorders determined by a recessive non–X-linked gene:
- Virtually everyone with the disorder has parents who both carry a copy of the abnormal gene, even though usually neither parent has the disorder (because two copies of the abnormal gene are necessary for the gene to be expressed).
- Single mutations are less likely to result in the disorder than in dominantly inherited disorders (because expression in recessive disorders requires that both of a pair of genes be abnormal).
- When one parent has the disorder and the other parent carries one abnormal gene but does not have the disorder, half of their children are likely to have the disorder. Their other children will be carriers with one abnormal gene.
- When one parent has the disorder and the other parent does not carry the abnormal gene, none of their children will have the disorder, but all of their children will inherit and carry the abnormal gene that they may pass on to their offspring.
- A person who does not have the disorder and whose parents do not have it but whose siblings do have it has a 66% chance of being a carrier of the abnormal gene.
- Males and females are equally likely to be affected.
Non–X-Linked (Autosomal) Recessive Disorders
Some disorders represent a non–X-linked recessive trait. To have the disorder, a person usually must receive two abnormal genes, one from each parent. If both parents carry one abnormal gene and one normal gene, neither parent has the disorder but each has a 50% chance of passing the abnormal gene to the children. Therefore, each child has
Therefore, among the children, the chance of not developing the disorder (that is, being normal or a carrier) is 75%.
X-linked genes are genes carried on X chromosomes.
Dominant x-linked disorders
The following principles generally apply to dominant disorders determined by a dominant X-linked gene:
- Affected males transmit the disorder to all of their daughters but to none of their sons. (The sons of the affected male do not receive his X chromosome, they get only his Y chromosome, which does not carry the abnormal gene.)
- Affected females with only one abnormal gene transmit the disorder to, on average, half their children, regardless of sex.
- Affected females with two abnormal genes transmit the disorder to all of their children.
- Many X-linked dominant disorders are lethal among affected males. Among females, even though the gene is dominant, having a second normal gene on the other X chromosome offsets the effect of the dominant gene to some extent, decreasing the severity of the resulting disorder.
- More females have the disorder than males. The difference between the sexes is even larger if the disorder is lethal in males.
Dominant X-linked severe diseases are rare. Examples are familial rickets (familial hypophosphatemic rickets) and hereditary nephritis (Alport syndrome). Females with hereditary rickets have fewer bone symptoms than do affected males. Females with hereditary nephritis usually have no symptoms and little abnormality of kidney function, whereas affected males develop kidney failure in early adult life.
Recessive x-linked disorders
The following principles generally apply to recessive disorders determined by a recessive X-linked gene:
- Nearly everyone affected is male.
- All daughters of an affected male are carriers of the abnormal gene.
- An affected male does not transmit the disorder to his sons.
- Females who carry the gene do not have the disorder (unless they have the abnormal gene on both X chromosomes or there is inactivation of the other normal chromosome). However, they transmit the gene to half their sons, who usually have the disorder. Their daughters, like their mother, usually do not have the disorder, but half are carriers.
An example of a common X-linked recessive trait is red–green color blindness, which affects about 10% of males but is unusual among females. In males, the gene for color blindness comes from a mother who usually has normal vision but is a carrier of the color-blindness gene. It never comes from the father, who instead supplies the Y chromosome. Daughters of color-blind fathers are rarely color-blind but are always carriers of the color-blindness gene. An example of a serious disease caused by an X-linked recessive gene is hemophilia, a disorder that causes excessive bleeding.
X-Linked Recessive Disorders
If a gene is X-linked, it is present on the X chromosome. Recessive X-linked disorders usually develop only in males. This male-only development occurs because males have only one X chromosome, so there is no paired gene to offset the effect of the abnormal gene. Females have two X chromosomes, so they usually receive a normal or offsetting gene on the second X chromosome. The normal or offsetting gene normally prevents females from developing the disorder (unless the offsetting gene is inactivated or lost).
If the father has the abnormal X-linked gene (and thus the disorder) and the mother has two normal genes, all of their daughters receive one abnormal gene and one normal gene, making them carriers. None of their sons receive the abnormal gene because they receive the father’s Y chromosome.
If the mother is a carrier and the father has the normal gene, any son has a 50% chance of receiving the abnormal gene from the mother (and developing the disorder). Any daughter has a 50% chance of receiving one abnormal gene and one normal gene (becoming a carrier) or a 50% chance of receiving two normal genes.
A trait that appears in only one sex is called sex-limited. Sex-limited inheritance differs from X-linked inheritance. Sex-linked inheritance refers to traits carried on the X chromosome. Sex-limited inheritance, perhaps more correctly called sex-influenced inheritance, is when penetrance and expressivity of a trait differ between males and females. The differences of penetrance and expressivity occur because males and females have different sex hormones and because of other factors. For example, premature baldness (known as male-pattern baldness) is a non–X-linked dominant trait, but such baldness is rarely expressed in females and then usually only after menopause.
Abnormal Mitochondrial Genes
Mitochondria are tiny structures inside every cell that provide the cell with energy. There are many mitochondria within each cell. Mitochondria carry their own chromosome, which contains some of the genes that control how the mitochondrion works.
Several rare diseases are caused by abnormal genes carried by the chromosome inside a mitochondrion. An example is Leber hereditary optic neuropathy, which causes a variable but often devastating loss of vision in both eyes that typically begins during adolescence. Another example is a disorder characterized by type 2 diabetes and deafness.
Because the father generally does not pass mitochondrial DNA to the child, diseases caused by abnormal mitochondrial genes are almost always transmitted by the mother. Thus, all children of an affected mother are at risk of inheriting the abnormality, but typically no children of an affected father are at risk. However, not all mitochondrial disorders are caused by abnormal mitochondrial genes (some are caused by genes in the cell nucleus that affect the mitochondria). Thus, the father’s DNA may contribute to some mitochondrial disorders.
Unlike the DNA in the nucleus of cells, the amount of abnormal mitochondrial DNA occasionally varies from cell to cell throughout the body. Thus, an abnormal mitochondrial gene in one body cell does not necessarily mean there is disease in another cell. Even when two people seem to have the same mitochondrial gene abnormality, the expression of disease may be very different in the two people. This variation makes diagnosis difficult and makes genetic testing and genetic counseling difficult when attempting to make predictions for people with known or suspected mitochondrial gene abnormalities.