Genetics Exam 2 Chapter 24

% Penetrance Equation

(# of individuals w correct phenotype) / (# of individuals with genotype coding for phenotype)

What is Marfan syndrome?

(Gene product: Fibrillin-1 (15q)) An autosomal dominant disorder where the disease-causing allele results in tall and thin individuals with abnormalities in the skeletal, ocular, and cardiovascular systems due to a weakening in elasticity of certain body tissues.

Phocomelia

- Suppression of limb development - Caused by a dominant allele with variable expressivity - Autosomal recessive

What are the symptoms and signs associated with Hemophilia?

- The major symptom of the disease is that the blood cannot clot properly when a wound occurs. - For hemophiliacs, common accidental injuries pose a threat of severe internal or external bleeding - This disease has also been called the "royal disease" because it has affected many members of European royal families

What are six autosomal recessive disorders?

1. Albinism (type I) 2. Cystic Fibrosis (CF) 3. Phenylketonuria (PKU) 4. Sickle cell disease 5. Tay-Sachs Disease (TSD) 6. Hemophilia C

What are some disorders inherited in an Autosomal Dominant manner?

1. Aniridia 2. Achondroplasia 3. Marfan syndrome 4. Familial hypercholesterolemia 5. Huntington disease 6. Polydactyly 7. Brachydactyly 8. Syndactyly 9. Compelling helo-ophthalmic outburst syndrome 10. Neurofibromatosis

What are the five major inheritance patterns of traits or diseases controlled by single genes?

1. Autosomal Dominant 2. Autosomal Recessive 3. X-linked Dominant 4. X-linked Recessive 5. Y-linked

What are the possible inheritance patterns of monogenic disorders?

1. Autosomal Dominant 2. Autosomal Recessive 3. X-linked Dominant 4. X-linked Recessive 5. Y-linked

What are some difficulties associated with determining the inheritance pattern of human traits?

1. Controlled matings are not possible 2. Sibship (a group of offspring having the same two parents) sizes are relatively small 3. Complete penetrance is sometimes lacking 4. Degrees of expressivity sometimes vary

Name 5 X-linked recessive disorders.

1. Duchenne muscular dystrophy 2. Hemophilia A 3. Hemophilia B 4. Androgen insensitivity syndrome 5. Red-green colorblindness

What are two examples of phenocopies?

1. Phocomelia 2. Thalidomide

What are the characteristics of X-linked dominant traits?

1. Trait does not skip generations 2. Affected males must come from affected mothers 3. Affected females come from affected mothers or fathers 4. Affected males have no normal daughters and no affected sons 5. Affected heterozygous females transmit the trait to approximately half of their children of either sex 6. Affected homozygous females transmit the trait to all of their children 7. Males are often more severely affected

What are the characteristics of X-linked recessive traits?

1. Trait may skip generations 2. Most affected individuals are male 3. Affected males result from affected mothers or mothers who are carriers 4. Affected females come from affected fathers and affected or carrier mothers 5. Affected females will have affected sons. 6. Trait can never be transmitted directly from father to son.

List the seven characteristics associated with diseases that have a genetic basis.

1. When an individual exhibits a disease, the disorder is more likely to occur in blood relatives than in the general population. 2. Identical twins share the disease more often than fraternal twins. 3. The disease does not spread to individuals sharing similar environmental situations. 4. Different populations tend to have different frequencies of the disease. 5. The disease tends to develop at a characteristic age 6. The human disorder may resemble a genetic disorder that is already known to have a genetic basis in an animal. 7. A correlation is observed between a disease and a mutant human gene or a chromosomal alteration.

Theoretically, for disease caused by a single gene, concordance among identical twins should be...

100%

For recessive diseases, concordance among fraternal twins would be ______ if we assume both parents are heterozygous carriers.

25%

For fraternal twins, concordance for dominant disorders is expected to be ______, assuming only one parent is heterozygous for the disease.

50%

What is a multi-genic or polygenic disorder?

A genetic disorder that is caused by the combined action of more than one gene.

What are monogenic disorders?

A result of a single defective gene on the autosomes.

What does the acronym ACHOO stand for?

A-utosomal-dominant C-ompelling H-elio- O-phthalmic O-utburst syndrome

Out of the autosomal dominant disorders, which displays Gain-of-Function mutations?

Achondroplasia - Caused by a mutation that occurs in the fibroblast growth factor receptor-3 gene. The mutant form of the receptor is overactive and this overactivity disrupts the normal signaling pathway and leads to severely shortened bones.

Summary of Phenylketonuria (PKU)

Affected individuals cannot metabolize phenylalanine - phenylalanine will accumulate and be converted to PHENYLPYRUVIC ACID - These are toxic and will cause mental and physical abnormalities Newborns are now routinely screened for PKU - Individuals w the disease are put on a strict dietary regimen (their diet is very low on phenylalanine) - These individuals tend to develop normally

Name an example of a human disorder that is known to have a genetic basis in animals.

Albinism

Temperature-sensitive allele

An allele in which the resulting phenotype depends on the environmental temperature. - In most cases, colder temperatures will yield a higher expressivity for the allele. - Warmer temperatures will decrease the functionality of the protein encoding for pigment.

What is autosomal-dominant compelling helio-ophthalmic outburst syndrome?

An autosomal dominant disorder in which people experience difficulty in controlling sneezing in response to numerous stimuli

Disorders that involve defective enzymes typically have what mode of inheritance?

Autosomal recessive

Why does red-green colorblindness often affect males?

Because it is an X-linked recessive disorder

Why are males termed hemizygous?

Because they have a single copy of the X gene

(S)- Thalidomide teratogenic

Causes birth defects

Pedigrees

Diagrams that show the relationship among members of a family, as well as their status with respect to a particular hereditary condition

Which mechanism is Huntington's Disease thought to result from?

Either: - dominant-negative effect of mutant huntingtin, leading to a loss-of-function of the wild-type protein OR - gain-of-function of mutant huntigtin, possibly through an interaction with a protein binding partner expressed in vulnerable neurons.

Age of Onset

For alleles that cause genetic diseases, the time of life at which disease symptoms appear.

Why is the measure of penetrance described at the populational level?

For example, if 60% of the heterozygotes carrying a dominant allele exhibit the trait, we would say that this trait is 60% penetrant. At the individual level, the trait is either present or it's not.

What is the affected gene, pattern of inheritance, and effect on the cell of Cystic Fibrosis?

Gene product: - CF transmembrane conductance regulator (CFTR) Chromosomal location of affected gene: - 7q Effect of disease-causing allele: - Water imbalance in tissues of the pancreas, intestine, sweat glands, and lungs due to impaired ion transport; leads to lung damage

What is the affected gene, pattern of inheritance, and effect on the cell of Tay-Sachs Disease?

Gene product: - Hexosaminidase A Chromosomal location of affected gene: - 15q Effect of disease-causing allele: - Progressive neurodegeneration

What is the affected gene, pattern of inheritance, and effect on the cell of Phenylketonuria?

Gene product: - Phenylalanine hydroxylase Chromosomal location of affected gene: - 12q Effect of disease-causing allele: - Foul-smelling urine, neurological abnormalities, mental impairment; may be remedied by diet modification at birth.

What is the affected gene, pattern of inheritance, and effect on the cell of Albinism?

Gene product: - Tyrosinase Chromosomal location of affected gene: - 11q Effect of disease-causing allele: - Inability to synthesize melanin, resulting in white skin, hair, etc.

Which mechanism is Familial hypercholesterolemia thought to result from?

Haploinsufficiency - the only functional copy of the LDL gene is jacked up

What is an example of a multi-genic or polygenic disorder?

Hemophilia

Which genetic disorder exhibits at a specific age of onset?

Huntington's Disease

What is an example of a Y-linked trait?

Hypertrichosis of the ear (excessive hair growth within or on the ear)

How can expressivity be explained for Polydactyly?

In the case of this disorder, the number of extra digits can vary; one individual may have an extra toe on only one foot whereas the second individual may have extra digits on both the hands and feet. A person with several extra digits would have a high expressivity for this trait, while a person with only one digit would have a low expressivity for the trait.

When would incomplete penetrance occur for recessive traits?

It would occur if the homozygote carrying the recessive allele did not exhibit the recessive trait.

Is actual concordance often more or less than theoretical values?

Less

Out of the autosomal dominant disorders, which displays Dominant-Negative mutations?

Marfan Syndrome - Due to a mutation in the fibrillin-1 gene. - This gene encodes a glycoprotein that is a structural component of the extracellular matrix that provides structure and elasticity to tissues. The mutant gene encodes a fibrillin-1 protein that antagonizes the effects of the normal protein, thereby weakening the elasticity of certain body parts. - For example, the walls of the major arteries such as the aorta, the largest artery that leaves the heart, are often affected.

Why do X-linked recessive disorders affect males so easily?

Most x-linked genes lack a counterpart on the Y chromosome. Males are hemizygous—have a single copy—for these genes. Therefore, a female heterozygous for an X-linked recessive gene passes this trait on to 50% of her sons.

Gain-of-Function Mutations

Mutation changes protein so it gains a new function or is overactive in comparison to the normal protein

How can modifier genes be responsible for incomplete penetrance and variable expressivity?

One or more genes alter the phenotypic effects of another gene.

Why may one fraternal twin have a recessive disorder and not the other?

One twin may have a disorder due to a new mutation that occurred after fertilization. It would be very unlikely for the other twin to have the same mutation.

When individuals cannot metabolize phenylalinine, what will happen to it?

Phenylalanine will accumulate and be converted to phenylpyruvic acid - these are toxic and will cause mental and physical abnormalities

Which X-linked Dominant disorders are fatal in males?

Rett syndrome Aicardi syndrome Incontinentia pigmenti

What are fraternal twins (dizygotic twins) formed from?

Separate pairs of sperm and egg

Dominant-Negative Mutations

The altered gene PRODUCT acts antagonistically (in opposition) to the normal product

Expressivity

The degree to which a trait is expressed. Example: flowers with deep red color have high expressivity for the red allele.

What is the concordance of a genetic disorder?

The degree to which it is inherited

Haploinsufficiency

The phenomenon in which a person has only a single functional copy of a gene, and that single functional copy does not produce a normal phenotype. - The heterozygote has 50% of the normal protein - This is not sufficient for a normal phenotype

Locus heterogeneity

The phenomenon that a disease can be caused by mutations in two or more different genes

Penetrance

The proportion of individuals with a specific genotype who manifest the corresponding phenotype

What are the two possible reasons for incomplete penetrance and variable expressivity?

The range of phenotypes is often due to environmental influences and/or due to effects of modifier genes in which one or more genes alter the phenotypic effects of another gene.

What accounts for the useful effects of the drug thalidomide and its teratogenic effects?

The reason for the horrific side effects of underdeveloped or absent limbs of children is due to the conformation of the drug. - The conformation that caused the birth defect was (S) - The desired conformation (sedative and antinausea drug) of the drug was (R)

What are identical twins (monozygotic twins) formed from?

The same sperm and egg

Explain why Polydactyly is considered to exhibit incomplete penetrance.

This disorder is due to an autosomal dominant allele and a single copy of this allele is sufficient to cause this condition. Sometimes, however, individuals carry the dominant allele but do not exhibit the trait. The dominant allele does not always "penetrate" into the phenotype of the individual.

How were toxicity studies of thalidomide in model animals useful for the FDA to block the use of this drug in the United States?

Toxicity studies showed that rats who were given thalidomide developed birth defects, sensorimotor peripheral neuropathy, somnolence, rash, fatigue, and constipation. - Frances Kelsey worked for the FDA and reviewed the approval of thalidomide use in the US. She withheld approval for the drug and requested further studies due to the results of a study that documented nervous system side effects

Incomplete penetrance

a pattern of inheritance in which a dominant allele does not always control the phenotype of the individual

What is Neurofibromatosis?

an Autosomal Dominant disorder that, if it penetrates, may be exhibited in different forms: - Mildest form (cafe-au-lait spots) - Intermediate form (cafe-au-lait spots; freckling) - Severe form (Neurofibromas of various sizes; speech impediments) - Shows 50-80% penetrance

Complete penetrance

identical genotypes have an expected produced phenotype percentage of 100%

Aggregation

the formation of a number of things into a cluster

Concordance refers to...

the percentage of twin pairs in which both twins exhibit the disorder or trait.

What is Achondroplasia?

(Gene product: Fibroblast growth factor receptor-3 (4p)) An autosomal dominant disorder where the disease-causing allele causes a common form of dwarfism associated with a defect in the growth of long bones.

What is Familial hypercholesterolemia?

(Gene product: LDL Receptor (19p)) An autosomal dominant disorder where the disease-causing allele causes very high serum levels of low-density lipoprotein (LDL), a predisposing factor in heart diseases.

What is Aniridia?

(Gene product: Pax6 Transcription Factor (11p)) An autosomal dominant disorder where the disease-causing allele causes an absence of the iris of the eye, leading to visual impairment and sometimes blindness.

Which traits are more likely to occur in consanguineous marriages?

Autosomal Recessive Traits

Tay-Sach's Disease Summary

- Affected individuals appear healthy at birth, but then develop neurodegenerative symptoms at 4 to 6 months. -Cerebral degeneration, blindness and loss of motor function - patients typically die at 3 or 4 years of age - It is the result of a mutation in the gene that encodes the ENZYME hexosaminidase A (hexA) (HexA BREAKS DOWN a category of lipids called Gm2-gangliosides) - An excessive accumulation of this lipid in cells of the CNS causes the neurodegenerative symptoms

Explain the inheritance pattern of Phenylketonuria, the exact molecular nature of the defect and consequence of taking a diet rich in proteins vs the consequence of taking a diet that is well controlled for phenylalanine during childhood.

- Autosomal Recessive - Caused by a defect in the gene that encodes the enzyme phenylalanine hydroxylase - Given a standard diet containing phenylalanine (found in protein-rich foods) PKU individuals manifest a variety of detrimental traits including mental impairment, underdeveloped teeth, and foul-smelling urine. - When PKU is diagnosed early and patients follow a restricted diet free of phenylalanine, they develop normally.

Summary of Albinism

- Autosomal Recessive disorder - Absence or partial deficiency of melanin in the skin, eyes, and hair - Occurs in a wide variety of animals

Hemophilia C

- Autosomal recessive disorder - Gene product: Clotting factor XI - Defect in blood clotting due to factor XI deficiency.

Explain hemophilia in regards to locus heterogeneity.

- Blood clotting involves a cellular cascade that involves several different proteins. - Thus, a defect in any of these proteins can cause the disease. - Hemophilia A is a defect in clotting Factor VIII - Hemophilia B is caused by a defect in clotting factor IX -Both are X-linked recessive disorders - Hemophilia C is caused by a defect in clotting factor XI -Found on chromosome 4

Thalidomide

- Sedative - Between 1959-1962, children with shortened limbs were born to mothers who took the drug early in their pregnancy - Phenotypes of children similar to the phenotypes of children with phocomelia - Drug-induced

Explain how screening for phenylketonuria (eg. By checking for the activity of the Phenylalanine hydroxylase enzyme in blood of newborns) helps in preventing the development of phenylketonuria.

- Since the 1960s, testing methods have been developed that can determine if an individual is lacking the phenylalanine hydroxylase enzyme. These tests permit the identification of infants who have PKU, and their diets can then be modified before the harmful effects of phenylalanine ingestion have occurred. - As a result of government legislation, more than 90% of infants born in the USA are now tested for PKU. This test prevents a great deal of human suffering and is also cost-effective. In the US, the annual cost of PKU testing is estimated to be a few million dollars, whereas the cost of treating severely affected individuals with the disease would be hundreds of millions of dollars.

Huntington Disease (summary)

- The major symptom of the disease is the degeneration of certain types of neurons in the brain. - This leads to personality changes, dementia, and early death (usually in middle age) - It is the result of a mutation in a gene that encodes a protein termed huntingtin. - The mutation adds a polyglutamine tract to the protein - This causes an aggregation of the protein in neurons.

Summary of Cystic Fibrosis (CF)

- The most common lethal genetic disease among caucasians. -about 3% of caucasians are carriers - The gene encodes a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) -the CFTR protein regulates ion transport across the cell membrane - The mutant allele creates an altered CFTR protein that ultimately causes ion imbalance -leads to serious digestive and respiratory problems - Average life expectancy ~38 years

Vitamin D-resistant rickets

- X-linked Dominant disorder - Gene product: Metallopeptidase - A disorder involving softening and weakening of the bones (of children) primarily caused by lack of vitamin D - Defects in bone mineralization at the sites of bone growth or remodeling, leading to bone deformity and stunted growth in children - Caused by lack of PHOSPHATE

Rett syndrome

- X-linked Dominant disorder - Gene product: Methyl-CpG-binding protein-2 - A neurodevelopmental disorder that includes a deceleration of head growth and small hands and feet; FATAL IN MALES

Incontinentia pigmenti

- X-linked Dominant disorder - Gene product: NFkB essential modulator - Characterized by morphological and pigmentation abnormalities in the skin, hair, teeth, and nails; FATAL IN MALES

Alcardi syndrome

- X-linked Dominant disorder - Gene product: Unknown - Characterized by the partial or complete absence of a key structure in the brain called the corpus callosum, and the presence of retinal abnormalities; FATAL IN MALES

Androgen insensitivity syndrome

- X-linked Recessive disorder - Gene product: Androgen receptor - Missing male steroid hormone receptor; XY individuals have external features that are feminine but internally have undescended testes and no uterus

Hemophilia B

- X-linked recessive disorder - Gene product: Clotting factor IX - Defect in blood clotting due to deficiency in factor IX

Hemophilia A

- X-linked recessive disorder - Gene product: Clotting factor VIII - Defect in blood clotting due to the missing protein factor VIII.

Duchenne muscular dystrophy

- X-linked recessive disorder - Gene product: Dystrophin - Progressive degeneration of muscles that begins in early childhood

What are the characteristics of Y-linked traits?

1. Trait only affects males 2. Affected males get it from their fathers and give it to their sons

What are the characteristics of autosomal recessive traits?

1. Trait tends to skip generations. 2. Members of both sexes affected equally. 3. Unaffected parents can have an affected child. 4. Two affected parents cannot have an unaffected child. 5. Traits are more likely to occur in consanguineous marriages.

What are the characteristics of autosomal dominant traits?

1. Trait usually present in every generation 2. Members of both sexes affected equally 3. Unaffected parents produce unaffected offspring 4. Two affected parents can produce unaffected offspring 5. On average, half the children of an affected parent will be affected 6. The homozygote for the disease-causing allele is GENERALLY more severely affected than the heterozygote.

List the X-linked Dominant disorders.

1. Vitamin D-resistant rickets 2. Rett syndrome 3. Aicardi syndrome 4. Incontinentia pigmenti

What is Huntington disease?

An autosomal dominant disorder where the disease-causing allele causes neurodegeneration that occurs relatively late in life, usually in middle age.

Phenocopy

An organism whose phenotype has been modified to resemble the phenotype of a different mutant organism.

Pedigree Symbols

And a diagonal arrow means Propositus/proposita, or the person from whom the pedigree is traced

Out of the autosomal dominant disorders, which displays haploinsufficiency?

Aniridia - with only one normal allele and one inactive allele, the result is an absence of the iris of the eye which leads to visual impairment and blindness in severe cases.

Penetrance and expressivity are used most often with what kind of traits?

Autosomal Dominant

What pattern of inheritance does Polydactyly exhibit?

Autosomal Dominant

Give an example of how environmental influences can be responsible for incomplete penetrance and variable expressivity.

Phenylketonuria (PKU), an autosomal recessive disease caused by a defect in a gene that encodes the enzyme phenylalanine hydroxylase, causes affected homozygous individuals to be unable to metabolize the amino acid phenylalanine properly. When given a standard diet containing phenylalanine (found in most protein-rich foods), PKU individuals manifest a variety of detrimental traits including mental impairment, underdeveloped teeth, and foul-smelling urine. Therefore, the phenotype of the disease will not be observed for those who find the disease early and maintain a diet free of phenylalanine, while those who were not as lucky suffer the harmful effects.