Inheritance refers to the transmission of genetic information across generations. There are two types of inheritance patterns in humans: Mendelian nuclear inheritance and non-Mendelian mitochondrial inheritance. The 23 pairs of human chromosomes located in the nucleus of the cells make up the human nuclear genome. This genome contains an estimated 30 to 40 thousand genes that we inherit in combination from our parents. These genes are called Mendelian-inherited nuclear genes, after Gregor Mendel, the Austrian monk who first established the laws of inheritance in the late 1800s. There is also DNA, called mitochondrial DNA, or the mitochondrial human genome, in the cytoplasm that we inherit almost exclusively from our mothers. These mitochondrial genes are called non-Mendelian-inherited mitochondrial genes.
Mendelian type inheritance is the more familiar form of genetic inheritance. During reproduction, genetic material is passed from the mother and the father to the offspring. These genes are inherited according to the laws of segregation established by Gregor Mendel, and are called Mendelian-inherited nuclear genes.
A chromosomally normal human carries 23 pairs of chromosomes in the nucleus of each cell: 22 pairs of autosomes and one pair of sex chromosomes. An individual inherits one of each paired chromosome from each parent. Each of these chromosomes is made up of thousands of genes. Genes are the chemical sequences which together control all characteristics and functions of the body. A particular characteristic controlled by a single gene is called a trait.
Almost all genes are located on each of the two copies of the paired chromosomes. The two copies of these genes, taken together, are called an allele. If the two copies of this gene are identical to each other, this person is said to have a homozygous allele for that gene. If the two copies of this gene are not the same, this person is said to have a heterozygous allele for that gene.
The only genes that are not located on two copies of paired chromosomes occur when there is not a matching pair of chromosomes, such as those genes on the single X chromosome in an XY male. When only one chromosome carries a gene, this gene is called a hemizygous allele. A hemizygous allele is made up of only the one copy that is present.
There are three modes of Mendelian inheritance: dominant, semi-dominant, and recessive. Additionally, a trait may be sex-linked, or non-sex-linked (autosomal). A sex-linked trait is conferred from parents to their child on the X or Y chromosome. An autosomal trait is transmitted from parents to their child on one of the other 22 pairs of chromosomes (the autosomes).
Recent advances in molecular genetics have tended to blur the line between dominant and semi-dominant inheritance. It is now believed that semi-dominant inheritance is almost always observed in traits once felt to be strictly dominant traits. These research findings are in direct opposition to current clinical practice. Genetic counselors and other health care professionals prefer not to confuse their patients by referring to semi-dominant inheritance of a particular trait. Therefore, in a research setting, one is unlikely to discuss true dominance of a trait, while in a clinical setting, one is unlikely to encounter the usage of semi-dominance.
Autosomal Mendelian inheritance
AUTOSOMAL DOMINANT In autosomal dominant inheritance, only one copy of the gene that causes a specific trait must be present in order for the person to display (express) the trait. The gene is said to dominate the expression of the trait because its effects outweigh that of
By definition, parents who pass on an autosomal dominant mutation to their offspring express the characteristics of that mutation. These parents are not called carriers because they are already fully affected with the trait. In the case of one heterozygous affected parent, the probability that a child will inherit this trait is 50%. In the case of two heterozygous affected parents, the probability that a child will inherit this trait is 75%. In the case of one homozygous affected parent, regardless of whether or not the other parent is affected, the probability that a child will inherit this trait is 100%.
AUTOSOMAL SEMI-DOMINANT If a particular trait is an autosomal semi-dominant trait, homozygous and heterozygous individuals will both experience characteristics of the trait. The gene for this trait still dominates the expression of the trait, but the effect of the corresponding gene on the other chromosome is noticeable. In diseases caused by a genetic mutation, the homozygous individual will experience more severe characteristics of that disease than the heterozygous individual because of the extra copy of the mutated gene that the homozygous individual possesses. Heterozygous individuals are carriers of the trait. Because these heterozygous individuals will exhibit some symptoms of the trait, they are also called symptomatic carriers.
In the case of one carrier parent and one non-carrier parent, the probability that a child of these parents will be a carrier of the trait is 50%, but their child cannot be homozygous for the trait. In the case of a homozygous affected parent and a non-carrier parent, the probability of a child being homozygous for the trait is also zero. The probability that this child will be a carrier of the trait is, however, 100%. In the case of two carrier parents, the probability that a child will be homozygous for the trait is 25%. The probability that this child will be a symptomatic carrier is 50%. In the case of one carrier parent and one affected parent, the probability that a child will be affected is 50%. The probability that this child will be a symptomatic carrier is also 50%. In the case of two affected parents, the probability that a child will be affected is 100%.
AUTOSOMAL RECESSIVE If a particular trait is an autosomal recessive trait, two copies of the mutated gene that causes this trait must be present in order for the person to possess the trait. The effect of the recessive gene is less than that of the corresponding gene on the other half of the chromosome pair. Therefore, only homozygous individuals will be affected with the trait. Heterozygous individuals will not exhibit characteristics of the trait. These heterozygous individuals are called carriers because they carry the trait and can pass it on to their children. Because these heterozygous individuals do not show characteristics of the trait that they carry, they are also called asymptomatic carriers.
A child cannot exhibit the symptoms of a recessive trait unless her or his parents are either both carriers of the trait or one is a carrier of the trait and the other is affected with the trait. In the case of one carrier parent and one non-carrier parent, the probability of a child being affected with the trait is zero. However, the probability that a child of these parents will be a carrier of the trait is 50%. In the case of an affected parent and a noncarrier parent, the probability of a child being affected with the trait is also zero. The probability that this child will be a carrier of the trait is, however, 100%. In the case of two carrier parents, the probability that a child will be affected with the trait is 25%. The probability that this child will be an asymptomatic carrier is 50%. In the case of one carrier parent and one affected parent, the probability that a child will be affected is 50%. The probability that this child will be an asymptomatic carrier is also 50%. In the case of two affected parents, the probability that a child will be affected is 100%. The probability that an autosomal recessive trait will be passed to the child of consanguineous parents is much higher than it is in non-consanguineous parents.
Sex-linked Mendelian inheritance
Sex-linked traits are carried on the X and Y, or sex, chromosomes. Sex-linked traits may be linked to either the X or the Y chromosome and may also be either dominant, semi-dominant, or recessive. Many more X-linked traits have been identified than Y-linked traits.
The sex chromosomes control the biological sex of an individual. Individuals with XY chromosomes are male, and individuals with XX chromosomes are female. The chromosome inherited from the mother is always the X chromosome, while the chromosome carried by the father's sperm may be either an X or Y chromosome.
X-LINKED DOMINANT Chromosomally normal females possess two X chromosomes; therefore, they can be homozygous or heterozygous in a trait that is caused by a gene mutation on the X chromosome. In the case of X-linked dominant traits, only one copy of the mutant gene must be present for the trait to be fully expressed. A female child affected with an X-linked trait may inherit this trait from either her mother or her father. In cases of
A chromosomally normal male child must receive his only X chromosome from his mother. He gets his Y chromosome from his father. Therefore, in cases of X-linked dominant traits, a male child has a 50% chance that he will receive the mutant gene from his heterozygous affected mother. If his mother is homozygous, this male child has a 100% likelihood of being affected with the trait. Therefore, while X-linked dominant traits are passed on equally from mothers to daughters and from mothers to sons, females may also inherit X-linked dominant traits from their fathers.
In some instances of dominant X-linked inheritance, the lack of the presence of a copy of the normal gene causes embryonic, fetal, or neonatal death. Therefore, in these cases, only very few affected males are born alive, and those that are generally die within a few hours of birth. This inheritance pattern is also known as male-lethal X-linked dominant inheritance. Since there are no affected males to contribute to the inheritance patterns of these traits, inheritance from father to daughter is not possible. Likewise, homozygous females are not possible. Only heterozygous females survive. In this form of inheritance, all affected males will inherit this trait from their heterozygous mothers. These males will either
X-LINKED RECESSIVE In cases of X-linked recessive traits, female children can only be affected if their mothers are carriers and their fathers are affected with the trait. The inheritance patterns in females of X-linked recessive traits are identical to the inheritance patterns of autosomal recessive traits. However, because the odds of a carrier mother producing offspring with an affected father are extremely low, X-linked recessive traits are characterized by the general absence of affected females. Because males are hemizygous in all X-linked traits, they have a 50% probability of inheriting an X-linked recessive trait from their carrier mothers. In the rare instances of affected mothers, males have a 100% chance of inheritance. Fathers cannot pass any X-linked trait to their XY sons. When affected fathers produce female children, 100% of these girls will be carriers of this trait. Almost all cases of females affected by an X-linked recessive trait are the result of consanguineous parents.
X-LINKED SEMI-DOMINANT A few examples of X-linked semi-dominant traits exist. In these cases, the carrier females are generally affected with a milder form of the trait than the affected males. Occasionally, some females show mosaicism of their X chromosomes that causes an activation of one of the X chromosomes in preference to the other. In these cases, heterozygous females show characteristics of the trait caused by the mutant gene that are identical, or nearly identical, to those characteristics seen in hemizygous affected males. Examples of this type of X-inactivation are a form of
A human being is conceived by the joining of the egg from the mother and the sperm from the father. Relative to the egg, the sperm is extremely small. It contains almost no cellular material outside the nucleus (cytoplasm) and very few mitochondria. In the cytoplasm of the egg, cellular components called mitochrondria are present. These mitochondria carry mitochondrial DNA, which is circular and contains 16,569 base pairs. Each mitochondrion contains between two and ten copies of this mitochondrial DNA. This separate genome codes for two ribosomal RNAs, 22 transfer RNAs, and 13 proteins that are used as enzymes in oxidative phosphorylation (cellular metabolism). Almost all the mitochondria in a person are derived from maternal mitochondria. Therefore, traits that result from mutations in mitochondrial DNA are exclusively inherited from the mother. These traits are not characterized by dominant, recessive, or semi-dominant patterns.
Most often, mitochondrial DNA is mosaic for a particular trait. That is to say, the trait exists on some, but not all, of the mitochondrial DNA in each cell. There can be as few as two or as many as ten copies of this mitochondrial DNA in a single cell. When cell division occurs, these mitochondrial DNA are randomly distributed into the newly formed mitochondria of the daughter cells. In most cases this mosaicism is such that only certain cells of the body contain the mutant DNA forms while other cells of the body are normal.
Human pedigree analysis
A pedigree analysis is the inspection of a family tree to look for the inheritance pattern of a trait associated with a mutant gene or a chromosomal aberration. Because the size of human families is usually quite small, it is often impossible to determine the inheritance pattern of a particular trait by performing a pedigree analysis on a single family. Other complications arise when analyzing human pedigrees. Among these are: anticipation; de novo mutations, improper identification of members of the pedigree; mosaicism; penetrance; variable expression; and recessive conditions appearing dominant, or pseudo-dominant.
Anticipation is the tendency of a trait to become more severely expressed in succeeding generations. This is called anticipation because the more severely affected child is discovered first, then other members of the pedigree are often "anticipated" as having to be affected with milder forms of that trait. While this anticipation was originally thought to be an error in backward identification of a trait in preceding generations caused by the identification of that trait in succeeding generations, it is now recognized as a true genetic characteristic. As an example, fragile X syndrome has been demonstrated to affect each succeeding generation more severely than the preceding generation within the same family.
De novo mutations, or mutations that were not inherited from either parent, can cloud the pedigree analysis within a family. The individual who is affected did not inherit these de novo mutations but he or she may pass them on to his or her children. In these cases, if the pedigree analysis does not span a significant number of generations after the de novo affected person, the true genetic inheritance pattern of this new trait may not be able to be identified. In such cases of a lack of succeeding generations, the cause can often be mislabeled as not of hereditary origin (sporadic).
Improper identification of members of the pedigree has to be avoided when performing a pedigree analysis. This occurs most often when the father of a particular child is misidentified.
Mosaicism often causes traits to appear to have a dominant inheritance pattern in some families while that same trait appears to be recessive in other families.
Penetrance is the term used to describe the probability that a person possessing a genetic mutation will express that mutation. A true dominant trait will have a penetrance of 100%. However, many traits that are termed dominant do not have complete penetrance. Therefore, some individuals with an otherwise dominant seeming trait may be asymptomatic for that trait. Penetrance is often also problematic in age-related traits. In these traits, a dominant inheritance pattern may be missed because members of the pedigree died of causes unrelated to the dominant trait prior to developing symptoms of the trait.
Variable expression is extremely common in dominant traits. In these cases, identical mutant alleles cause different characteristics of expression in different people. This may be a variance of symptoms from one affected family to another affected family or it may be a variance of symptoms from one individual to another within a single family.
Recessive traits may appear to be dominant, or pseudo-dominant, within a pedigree. If a particular trait has a high frequency in the population, it is likely that two or more people may have independently introduced this trait into a single pedigree. This is in contrast to the typical founder effect, in which a single "founder" individual introduces the trait into the pedigree. A "founder" may be a person who is affected with a de novo mutation that enters the pedigree with them. Or, it may be a person who comes from a relatively separate gene pool, such as a European explorer entering the formerly isolated gene pool of a remote tribe or race of people.
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Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or (202) 966-5557. Fax: (888) 394-3937 info@geneticalliance. <http://www.geneticalliance.org>.
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Paul A. Johnson