Table of Contents- Lesson 1) ( Next) (Glossary)

MENDELIAN PATTERNS OF INHERITANCE

In this day and age, the principles of inheritance set by Gregor Mendel might seem matter of fact. However, in the 1850's, his findings were largely ignored because they did not conform to the conventional wisdom of the time: the belief that parental traits undergo blending in an offspring.

Through a series of experiments involving peas, Mendel showed that there are independent units of heredity (we now call genes) that are transmitted unchanged from generation to generation. Mendel studied seven traits in the pea that are defined by single genes (monogenic), including height (tall plant vs. short plant), seed shape (round vs. wrinkled) and seed color (yellow vs. green). When he crossed tall pea plants (homozygous TT) with short pea plants (homozygous tt), Mendel observed that the offspring were all tall (heterozygous Tt). The trait of shortness appeared to have been lost. When the first generation of tall pea plants (heterozygous Tt) were crossed with each other, the short pea plant resurfaced. This is illustrated in a Punnett square.


Fig. 1.13. Punnett square

The proportion of short plants produced by this cross was 1/4 (tt), and the proportion of tall plants was 3/4 (TT, Tt), as predicted by the Punnett square. This second cross showed that some character traits are dominant (tall) and some are recessive (short).

Mendelian genetic disorders are disorders caused by a single gene mutation that leads to an abnormality that is usually confined to an organ system (e.g., skeletal as in achondroplasia, CNS as in Huntington disease). However, there can be widespread effects if an enzyme or protein is needed by several tissues or organs (e.g., the mucopolysaccharidoses).

For a dominant trait to be expressed, one dominant gene will suffice. A gene mutation behaves in a dominant manner if it acquires a new or different function that is disadvantageous (or advantageous) to the cell. In effect, the mutation results in a "gain of function."

For a recessive trait to be observed, however, two recessive genes must be present. A gene mutation behaves in a recessive manner if it produces a nonfunctional protein. If a cell contains at least one gene that codes for normal protein production, the presence of the recessive gene will be masked. When a cell has two recessive genes and is not able to produce a functional protein, then the recessive trait will be expressed. In effect, the mutation results in "loss of function."

The Punnett square also illustrates the concept of genotype and phenotype. Genotype refers to the nature of the genes (or alleles) at a particular locus on a pair of chromosomes. Phenotype refers to the physical or biochemical characteristics of an organism. Thus, the tall phenotype is brought about by the genotypes TT and Tt; whereas the short phenotype is only brought about by the genotype tt. The convention is to use a capital letter for a dominant trait and a small case letter for a recessive trait.

The units of heredity, or genes, are DNA sequences that code for the synthesis of proteins. The DNA sequences are made of the nucleotide bases adenine, guanine, cytosine, and thymine. A gene is composed of several exons (coding sequences) and introns (intervening sequences). Genes are submicroscopic segments of DNA and cannot be detected by chromosome analysis. Like chromosomes, genes are inherited in pairs, one from each parent.

A gene may be altered by an event that causes a change in the nucleotide bases, a mutation. The different forms of a gene are called alleles (e.g., the gene for eye color has blue, brown, hazel, etc. alleles). If the pair of alleles is alike, the individual is said to be homozygous. If the pair of alleles is different, the individual is said to be heterozygous.

There are approximately 100,000 genes on the 23 pairs of chromosomes. It is estimated that every individual has several altered genes. In most cases these altered genes are recessive and the normal dominant allele results in expression of the normal trait.

There are thousands of different single gene disorders. If a condition is due to an alteration in a gene on an autosomal chromosome (1 through 22), it is inherited in an autosomal dominant or autosomal recessive fashion. If the altered gene is located on the X chromosome, it is inherited in an X-linked fashion.

AUTOSOMAL RECESSIVE INHERITANCE

The concept of one gene-one enzyme was introduced by Beadle and Tatum. This resulted in the identification of numerous inborn errors of metabolism, most of which are recessive traits.

Fig. 1.14. Metabolic pathway

In creating product E from precursor A, intermediate metabolites B, C, and D are formed. These are all dependent upon the presence of enzymes at each step, #1, #2, #3, and #4. Should there be a block in enzyme #3, then the consequences are: absence of product E, accumulation of intermediate metabolites C, B, A, and formation or accumulation of abnormal metabolites F and G.

A classic example of an autosomal recessive inborn error of metabolism is phenylketonuria (PKU). PKU is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) produced in the liver. Phenylalanine, an essential amino acid that comes from dietary sources, is transformed by PAH to tyrosine, which is essential for the formation of melanin, epinephrine, and thyroxin. The deficiency of PAH results in accumulation of phenylalanine and metabolites such as phenylpyruvic acid in the blood and cerebrospinal fluid. Patients are relatively healthy and survive into adult life. However, without treatment there is significant brain damage with severe to profound mental retardation.

To prevent retardation, the diagnosis of PKU should be made within the first two weeks of life (by newborn screening), and treatment instituted within the first month (by dietary restriction of phenylalanine). This treatment should be continued for life, especially in female patients with PKU. If untreated, the high phenylalanine levels in a pregnant woman with PKU can lead to brain damage and severe mental retardation in the developing fetus (in spite of the fact that the fetus does not have a PAH enzyme abnormality).

On occasion there are PKU patients who do not respond to dietary control and continue to have elevated blood phenylalanine levels with associated seizures and progressive mental retardation. This variant of PKU is the result of another gene mutation. In these patients, the PAH gene is normal. The problem is caused by a mutation in a gene involved in the synthesis of tetrahydrobiopterin, a co-factor of phenylalanine hydroxylase. This is an example of locus heterogeneity. In this example, PKU can be caused by abnormalities in two different genes at two different sites or loci on the chromosomes.

Genetic heterogeneity can also occur within a single gene at one locus, allele heterogeneity. Allele heterogeneity is seen in patients with cystic fibrosis (CF). The CF gene (CFTR-cystic fibrosis transmembrane conductance regulator) is a large gene that spans 250,000 bases (250 kb or kilobases). This gene has 27 exons and a similar number of introns. The most common CF gene mutation is F508; however, over 100 other mutations have been described.

Mutations can occur anywhere along the length of the gene, affecting introns, exons or the immediate flanking regions. These mutations can affect the amount of protein or enzyme that is produced or the protein or enzyme function. Mutations within a gene can result in the following:

Individuals with one normal gene and one mutated gene are often unaffected, suggesting that the enzyme product of one normal gene is sufficient to supply the needs of an individual. This is why biochemical assays often show 50% enzymatic function among carriers when compared with non-carriers. The vast majority of enzyme abnormalities are autosomal recessive, requiring two abnormal genes for clinical expression. There are, however, a few exceptions. Acute intermittent porphyria, for instance, behaves as an autosomal dominant single gene disorder. Heterozygous carriers, with one abnormal gene, produce half of the normal amount of the enzyme uroporphyrinogen synthetase which is not sufficient to prevent clinical consequences.

In autosomal recessive traits, the affected child receives two copies of the abnormal gene, one from each parent, and is, therefore, homozygous affected. The parents are presumed to be heterozygous carriers. Following the Punnett square previously described, there is a 1/4 chance for an affected offspring and a 3/4 chance for a normal offspring. Of the normal offspring, there is a 1/3 chance of a homozygous normal and a 2/3 chance of a heterozygous carrier state.

Fig. 1.15. Autosomal recessive inheritance

On occasion, families are observed where both parents have a recessive single gene disorder and yet have normal offspring. For example, two deaf parents can have all normal children if the deafness in one parent is due to a homozygous abnormal recessive gene (aa) and the other deaf parent is homozygous for another abnormal recessive gene (bb). If the first parent is homozygous for the normal dominant hearing gene BB, and the other parent is homozygous for the normal dominant hearing gene AA, the union of these two individuals will result in offspring with AaBb since one parent has aaBB and the other parent has AAbb. The resulting offspring are all normal by virtue of complementation.

AUTOSOMAL DOMINANT INHERITANCE

In conditions that are inherited in an autosomal dominant fashion, affected individuals are heterozygous for an autosomal dominant disease gene and a normal gene. In such cases, the presence of the abnormal gene results in the clinical expression of a disease or a condition.

Roughly, there are four times more dominant traits than recessive traits recognized in humans. This is because a recessive trait can be carried through generations "hidden" from view. A dominant trait is invariably expressed in the phenotype. All individuals with a dominant trait must carry the abnormal gene with a 50% chance that they will pass this gene on to their offspring. An example is Huntington disease (HD) where individuals with the abnormal gene will invariably develop clinical signs and symptoms.

There are, however, several variations to this relatively simple inheritance pattern. It is not uncommon to find pedigrees where an index case has an autosomal dominant trait and clearly normal parents.

New (de novo) mutation refers to a DNA change that transforms the gene from normal to abnormal in the egg or sperm that forms the zygote. Realize that the other germ cells of the parent are usually unaffected or normal and the risk of recurrence in future offspring is virtually the same as the general population. The affected individual, however, will have a 50% risk of having affected offspring. A good example is achondroplasia. Eight out of 10 cases of achondroplasia are secondary to new mutations. Only two out of 10 individuals with achondroplasia have a similarly affected parent.

On occasion, two or more sibs with an autosomal dominant trait have normal parents. This can be explained on the basis of germline or gonadal mosaicism. Conceivably, early in development, an individual could have a mutation that is limited to the germline (germ cells-egg or sperm) while sparing the somatic cells. Such individuals are phenotypically normal; however, they have a greater risk of recurrence than the general population. This phenomenon has been described in osteogenesis imperfecta, achondroplasia and Duchenne muscular dystrophy.

Finally, an affected child with normal parents can be explained on the basis of incomplete penetrance. The premise in autosomal dominant inheritance is that an individual who carries an abnormal gene will have an observable abnormal phenotype, however, there are exceptions. On occasion, a person who carries an autosomal dominant gene may be physically normal.

For autosomal dominant traits, the term "penetrance" refers to the number of gene carriers who are affected, divided by the total number of gene carriers who are affected and unaffected. Thus, a gene can have an 80% penetrance rate (80 affected people among 100 with the gene).

The nonpenetrant carrier is a loose term used to describe an individual who carries the abnormal gene, but does not express the disease or the trait. About 20% of individuals who carry the gene for retinoblastoma (Rb) are nonpenetrant carriers. This lack of penetrance can be explained as follows:

Retinoblastoma (Rb) is a malignant tumor of the retina. The inherited form of Rb is bilateral and multifocal; that is, it affects both eyes at several sites within each eye. The gene coding for Rb has been mapped to chromosome 13q14 and consists of a 100 kb DNA sequence with 12 exons. The gene codes for a tumor suppressor protein with 816 amino acids. The Rb protein has DNA binding properties and regulates a transcription factor (the copying of DNA into messenger RNA). The loss of this protein leads to neoplastic growth. However, one abnormal Rb gene is not sufficient to cause retinoblastoma. The normal Rb gene also needs to be eliminated by somatic mutation to produce a retinal cell with no functional Rb protein and, therefore, no regulatory control. Thus, not everyone who inherits the gene coding for retinoblastoma will develop malignant tumors. A second event, or "hit", must occur for tumors to form.

In this example, susceptibility to retinoblastoma is inherited as a dominant trait; however, the expression of the tumor within the eye, which requires the presence of two abnormal genes, is technically recessive. This concept of multi-hit somatic mutations (in local tissue or organs) on top of a constitutional mutation (present in all of the cells of the body) forms the basic concept for the heritable forms of cancers-colon cancer, breast cancer, etc.

Variable expressivity refers to the severity of the disease or trait: mild, moderate, or severe. Very often, variable penetrance and expressivity are used synonymously. Penetrance is an all or none phenomenon-either the abnormal phenotype is present or it is absent. If the phenotype is absent, then it is nonpenetrant. If the phenotype is apparent, then it is penetrant and can have variable expressivity.

Variable expressivity is a common feature in autosomal dominant traits. Even within the same family, members can have varying degrees of clinical involvement. A good example is neurofibromatosis (NF), which is caused by a change in a large gene on chromosome 17q that codes for the production of a tumor suppressor protein, neurofibromin. NF is 100% penetrant. All individuals who carry the gene are clinically identifiable. However, people with NF will have a variety of clinical features. Most will have at least some cafe-au-lait spots (areas of brown skin pigment), Lisch nodules (benign growths on the iris), and neurofibromas (nonmalignant peripheral nerve tumors). However, optic gliomas (benign tumor of the optic nerve), learning disabilities, hypertension, scoliosis (lateral curvature of the spine), and malignant neurofibrosarcomas are only occasional findings.

The explanations for variable expressivity of a gene include:

In autosomal dominant traits with complete penetrance, the chance that an affected person will have an affected child is 50%, providing the affected individual has an unaffected partner. There is also a 50% chance that the affected individual will have an unaffected child.



Fig. 1.16. Autosomal dominant inheritance

X-LINKED INHERITANCE

Diseases caused by genes on the X chromosome are said to be X-linked. Most X-linked diseases are recessive, but a few are X-linked dominant. In contrast to the X chromosome, the Y chromosome is small. The Y chromosome is mostly inactive heterochromatin with a small active portion coding for the testis determining factor.

Females have two X chromosomes and males have only one. In the XX female, one X chromosome in each cell becomes genetically inactive at an early stage in embryogenesis. The inactive X becomes a Barr body. The inactivation of the X chromosome is random. Generally, maternally and paternally derived X chromosomes are inactivated in equal numbers. Therefore, females produce X-linked gene products (e.g., factor VIII protein in hemophilia, creatine phosphokinase enzyme in Duchenne muscular dystrophy) in quantities roughly similar to males (dosage compensation).

Because males have only one X chromosome (hemizygous), the presence of an abnormal gene on the X chromosome is invariably expressed. However, in females who have two X chromosomes, the presence of one abnormal recessive gene is usually compensated by the presence of a normal gene on the other X chromosome (heterozygous). For this reason, X-linked conditions like hemophilia or muscular dystrophy are expressed in sons and transmitted by physically normal carrier mothers.

The concept of dominance and recessiveness is not particularly relevant in X-linked inheritance. Whether dominant or recessive, an abnormal gene on the X chromosome in males is invariably expressed. A recessive gene in a carrier female is occasionally expressed due to the inactivation of a significant number of the X chromosomes containing the normal gene. By the same token, a dominant trait in a carrier female can escape expression because of inactivation of a majority of the X chromosomes with the abnormal gene.

Since the X chromosome inactivation is random, it is just as likely that either the normal X or the abnormal X is inactivated. At the gene level, the cell either does or does not produce a gene product. Since an organ (e.g., the liver) originates from a small cluster of cells, by chance alone, a large number of the cells within the organ could have a normal functioning X (or an abnormal functioning X). Thus, X chromosome inactivation, or lyonization, creates normal cells and abnormal cells depending on whether the normal X or the abnormal X is active, on average, 50% of each. The extreme, however, is possible. While unlikely, it is possible that X chromosome inactivation will result in the formation of 90% abnormal cells and 10% normal cells. There are well documented reports of female hemophilia carriers who produce very low levels of factor VIII and for practical purposes can be considered mild hemophiliacs. Thus lyonization can modify the expression of abnormal genes, whether dominant or recessive, on the X chromosomes in females.

In most cases women who carry X-linked recessive disease genes are physically normal. There is a 50% chance with each pregnancy that a carrier female will pass on the abnormal recessive gene. With a Y chromosome from her partner, she will have an affected son. With an X chromosome from her partner, she will have a carrier daughter. There is also a 50% chance that a carrier female will pass on the normal X gene. If this is the case, her son will not be affected and her daughter will not be a carrier.

Fig. 1.17. X-linked inheritance (mother carrier)

Affected males have normal offspring. Their sons, receiving the Y, are free of the trait. Their daughters, receiving the abnormal X, are obligate carriers.


Fig. 1.18. X-linked inheritance (father affected)

SUMMARY

Each chromosome is made up of thousands of genes that are strung together like beads on a string. Each gene is made up of segments of DNA that code for a particular protein. Changes in a gene may alter the production or function of a protein. Such changes can result in obvious physical defects or progressive deterioration in individuals with inborn errors of metabolism.

Genes on the autosomal chromosomes (1 through 22) are inherited in pairs, one from each parent. An autosomal recessive disorder occurs when both genes of a pair are abnormal. Everyone carries a certain number of abnormal recessive genes, usually as a single copy. In most cases, it is not until after the birth of a child with a recessive genetic condition that a couple is identified as carriers with a 25% recurrence risk in future offspring of either sex.

An autosomal dominant disorder is caused by a single abnormal gene. Individuals who carry a dominant gene will usually show signs of the disorder. They have a 50% occurrence risk in future offspring of either sex.

In some cases, children with dominant single gene disorders are born to normal parents. This occurs if (1) a "new" gene mutation occurs in the egg (or sperm) prior to fertilization, (2) a collection of eggs (or sperm) in the gonads of one parent carry a "new" mutation, (3) one of the parents is a nonpenetrant carrier, or (4) one of the parents with subtle features of the disorder passes for normal.

An X-linked disorder is due to an abnormal gene on the X chromosome and is usually limited to males. While females inherit two copies of the X chromosome from each parent, males inherit one X chromosome from the mother and a Y chromosome from the father. With a nonfunctional gene on the X chromosome, a male will develop signs of the disorder. His mother, on the other hand, will most likely be physically normal. There is, however, a 25% chance that a carrier female will have (1) an affected son, (2) a carrier daughter, (3) an unaffected son, or (4) a daughter who does not carry the gene. Males who have an X-linked disorder will have normal sons. However, all of their daughters will carry the X-linked gene and are at risk of having affected sons.

PRACTICE ACTIVITY 4

Define the following terms:

1. gene

2. homozygote

3. heterozygote

4. genotype

5. phenotype

6. nonpenetrance

7. expressivity

Use a T or F to show whether each statement is true or false.

8. It is possible to diagnoses PKU by doing a routine chromosome study.

9. The parents of a child with PKU will be physically and intellectually normal.

10. A child with an autosomal dominant single gene disorder will always have at least one affected parent.

11. If the first child born to a person with Marfan syndrome is affected, his next child will be unaffected.

12. Males with hemophilia have a 50% chance of having a son with hemophilia.

13. Women will never develop X-linked recessive single gene disorders.

PRACTICE ACTIVITY 4: ANSWERS

1. A gene is a submicroscopic segment of DNA that codes for the synthesis of a protein.

2. A homozygote is a person who has a pair of similar genes (or alleles) at a particular locus or site.

3. A heterozygote is a person who has two different genes (or alleles) at a particular location on a chromosome.

4. Genotype refers to the pair of genes (or alleles) a person inherits that code for a particular trait.

5. Phenotype refers to a person's observable physical, biochemical or physiological characteristics. A person's phenotype is determined by the interaction between genes and the environment. One phenotype may be due to different genotypes, as was described in the PKU example.

6. When an individual who inherits a gene coding for an abnormal dominant trait is phenotypically normal, the trait is said to be nonpenetrant.

7. Expressivity refers to the severity of a particular genetic disorder. In the case of some autosomal dominant single gene disorders, a parent may have only a few subtle characteristics that are suggestive of the disorder, whereas the child may have more obvious physical features. This would be an example of variable expressivity.

8. False PKU is caused by a change in a single gene. As each chromosome is made up of thousands of genes, it is impossible to distinguish one gene from another on chromosome study. A child with PKU would have a normal karyotype.

9. True While it is true that the parents of a child with PKU carry the abnormal gene coding for this condition, in the majority of cases, they will also carry the normal gene coding for PAH production. Therefore, they are able to break down phenylalanine and will have no obvious signs of phenylketonuria.

10. False A dominant disorder may be caused by a new mutation, or gonadal mosaicism. It is also possible that one of the parents is a nonpenetrant carrier, or has subtle signs of the disorder and is considered unaffected.

11. False Each pregnancy is an independent event. Given that each gene pair separates in meiosis, we know that 50% of his sperm contain the gene coding for Marfan syndrome and 50% of his sperm contain the gene coding for normal development. Whether his next child is affected or not depends on which gene is present in the sperm that fertilizes the egg.

12. False To have a son, a man must pass on his Y chromosome. Therefore, male children born to men with hemophilia will not inherit the X-linked gene coding for this condition.

13. False While unlikely, some women who carry a gene coding for an X-linked recessive genetic condition may develop signs of this condition, due to unequal X inactivation of the normal X chromosome. Women who inherit only one X chromosome may also have an X-linked disorder, such as Duchenne muscular dystrophy, in addition to Turner syndrome.


Table of Contents- Lesson 1) ( Next) (Glossary)