Deck 22: Genomics I: Analysis of Dna

Question 1

With regard to pedigree analysis, make a list of the patterns that distinguish among recessive, dominant, and X-linked genetic diseases.

Answer 1

The pattern of inheritance of human diseases can be analyzed by human pedigree analysis. This gives the information about the inheritance of disease from one generation to another generation. The pedigree analysis clearly distinguishes the differences between pattern of inheritance of human diseases in the manner of recessive, dominant and X - linked genetic diseases from one another.
In the Autosomal recessive inheritance pattern, the affected offspring is produced from two unaffected parents with rare recessive traits and they do not exhibit the disease. The recessive alleles are many times deleterious and lead to death or infertility. Hence, the parents in such cases are unaffected. The unaffected heterozygotes can produce 25% of affected children. Affected parents produce 100% affected children. The recessive traits unable to produce fertile and viable individuals so there is no possibility of affected parents producing affected children. The recessive trait is exhibited in the same frequency in both male and females. Tay - Sachs disease is the example of Autosomal recessive inheritance pattern.
In Autosomal dominant inheritance, offspring are affected when one or both parents are affected. In some dominant traits the heterozygote exhibits incomplete penetration due to which the affected offspring may not exhibit the trait. The affected offspring may also produced by occurring a dominant mutation during the gametogenesis. When one of the parents is affected, the progeny produced will be 50% affected and when both parents are affected the chance of unaffected offspring would be 25%. The trait is a dominant and expressed in the same frequency in both males and females. The Autosomal dominant traits mainly exhibited due to haploinsufficiency, a gain - of - function mutation or a dominant - negative mutation. Huntington disease is the example of Autosomal dominant inheritance.
In X - linked recessive inheritance males are more prone to disease because they carry the disease trait. If the affected offspring's mother has brother or father containing the same trait then the mother pass the trait to her offspring. The affected males produce unaffected daughters who can produce 50% affected sons. Hemophilia is the example of X - linked recessive trait.
In X - linked dominant trait females are more prone to trait and even it is lethal to males. The affected females pass the trait to their daughters with 50% frequency. Also there is a 50% chance of producing affected males. Diseases like Rett syndrome and Aicardi syndrome are the examples of the X - linked dominant traits.

Question 2

Which of the following experimental observations would suggest that a disease has a genetic basis
A. The frequency of the disease is less likely in relatives that live apart compared with relatives that live together.
B. The frequency of the disease is unusually high in a small group of genetically related individuals who live in southern Spain.
C. The disease symptoms usually begin around the age of 40.
D. It is more likely that both monozygotic twins will be affected by the disease than will dizygotic twins.

Answer 2

The genetic diseases have genetic basis. With regard to genetic basis of diseases the statements are as follows:
The frequency of disease is less likely in relatives that live apart compared to relatives that live together-such type of diseases have less genetic basis.
The frequency of disease is unusually high in a small group of genetically related individuals who live in southern Spain-such type of diseases will have more because people living in one location may be more related genetically. Also there is a possibility for an infectious agent found in only southern Spain but not else where. This suggests the high incidence of disease in specific region.
The disease symptoms begin around the age of 40-this has strong genetic base because most of genetic diseases show a characteristic age of on set of disease symptoms and tend to develop at later age in the life.
It is more likely that the monozygotic twins will be affected by the disease compared to dizygotic twins-this has genetical basis because, often genetical diseases mostly affect the monozygotic or identical twins than dizygotic or non identical twins.

Question 3

Make a list of the benefits that may arise from genetic testing as well as possible negative consequences. Discuss the items on your list.

Answer 3

Genetic testing can be done to know the gene mutations and any alterations in the chromosome during embryo or fetal development. There are many advantages like having the knowledge of fetal growth and to trace the genetic defects of fetus. The parents who are carriers of a genetic disorder can undergo testing to know about progeny birth defects during the fetal development (for example cystic fibrosis can be known during pregnancy itself). Other genetic disorders gene mutations leading to cancer can also be known which may make a way to prevention treatment prior the disease affects the body.
There are some disadvantages or negative aspects that are concerned with ethical issues are also part of genetic testing. Main disadvantage is false positive results which make the parents to take unwanted decisions like pregnancy termination and many times subject them to anxiety without possibility of causing the disorder. False negative results also sometimes cause worry in individuals because, genetic defects may be identified after the birth of child causing suffering to parents and as well to new born. Thus, the negative aspects are mainly concerned with ethical issues.

Question 4

Explain, at the molecular level, why human genetic diseases often follow a simple Mendelian pattern of inheritance, whereas most normal traits, such as the shape of your nose or the size of your head, are governed by multiple gene interactions.

Question 5

At the beginning of this chapter, we discussed the types of experimental observations that suggest a disease is inherited. Which of these observations do you find the least convincing Which do you find the most convincing Explain your answer.

Question 6

Our government has finite funds to devote to cancer research. Discuss which aspects of cancer biology you would spend the most money pursuing.
A. Identifying and characterizing oncogenes and tumor-suppressor genes
B. Identifying agents in our environment that cause cancer
C. Identifying viruses that cause cancer
D. Devising methods aimed at killing cancer cells in the body
E. Informing the public of the risks involved in exposure to carcinogens
In the long run, which of these areas would you expect to be the most effective in decreasing mortality due to human cancer

Question 7

Many genetic disorders exhibit locus heterogeneity. Define and give two examples of locus heterogeneity. How does locus heterogeneity confound a pedigree analysis

Question 8

What is meant by the term genetic testing What is different between testing at the protein level versus testing at the DNA level Describe five different techniques used in genetic testing.

Question 9

In general, why do changes in chromosome structure or number tend to affect an individual's phenotype Explain why some changes in chromosome structure, such as reciprocal translocations, do not.

Question 10

A particular disease is found in a group of South American Indians. During the 1920s, many of these people migrated to Central America. In the Central American group, the disease is never found.
Discuss whether or not you think the disease has a genetic component. What types of further observations would you make

Question 11

We often speak of diseases such as phenylketonuria (PKU) and achondroplasia as having a "genetic basis." Explain whether the following statements are accurate with regard to the genetic basis of any human disease (not just PKU and achondroplasia).
A. An individual must inherit two copies of a mutant allele to have disease symptoms.
B. A genetic predisposition means that an individual has inherited one or more alleles that make it more likely that he or she will develop disease symptoms than other individuals in a population will.
C. A genetic predisposition to develop a disease may be passed from parents to offspring.
D. The genetic basis for a disease is always more important than the environment.

Question 12

Chapter 20 describes a blotting method known as Western blotting that can be used to detect a polypeptide that is translated from a particular mRNA. In this method, a particular polypeptide or protein is detected by an antibody that specifically recognizes a segment of its amino acid sequence. After the antibody binds to the polypeptide within a gel, a secondary antibody (which is labeled) is used to visualize the polypeptide as a dark band. For example, an antibody that recognizes -galactosidase A could be used to specifically detect the amount of -galactosidase A protein on a gel. The enzyme -galactosidase A is defective in individuals with Fabry disease, which shows an X-linked recessive pattern of inheritance. Amy, Nan, and Pete are siblings, and Pete has Fabry disease. Aileen, Jason, and Jerry are brothers and sister, and Jerry has Fabry disease. Amy, Nan, and Pete are not related to Aileen, Jason, and Jerry. Amy, Nan, and Aileen are concerned that they could be carriers of a defective -galactosidase A gene. A sample of cells was obtained from each of these six individuals and subjected to Western blotting, using an antibody against -galactosidase A. Samples were also obtained from two unrelated normal individuals (lanes 7 and 8). The results are shown here.

Note: Due to X inactivation in females, the amount of expression of genes on the single X chromosome in males is equal to the amount of expression from genes on both X chromosomes in females.
A. Explain the type of mutation (i.e., missense, nonsense, promoter, etc.) that causes Fabry disease in Pete and Jerry.
B. What would you tell Amy, Nan, and Aileen regarding the likelihood that they are carriers of the mutant allele and the probability of having affected offspring

Question 13

Figure 24.1 illustrates albinism in two different species. Describe two other genetic disorders found in both humans and animals.
FIGURE 24.1 The albino phenotype in a human and a wildebeest.

Question 14

An experimental assay for the blood-clotting protein called factor IX is available. A blood sample was obtained from each member of the pedigree shown here. The amount of factor IX protein is shown within the symbol of each member and is expressed as a percent of the amount observed in normal individuals who do not carry a mutant copy of the gene.

What are the likely genotypes of each member of this pedigree

Question 15

Discuss why a genetic disease might have a particular age of onset. Would an infectious disease have an age of onset Explain why or why not.

Question 16

Let's suppose a cell line has become malignant because it has accumulated mutations that inactivate two different tumor-suppressor genes. A researcher followed the protocol described in the experiment of Figure 24.12 and isolated DNA from this mutant cell line. The DNA was used to transform normal fibroblast (NIH3T3) cells. What results would you expect Would you expect a high number of malignant foci or not Explain your answer.
FIGURE 24.12 Identification of chromosomal oncogenes.
Starting material: Several mouse cell lines. Some of the cell lines were malignant due to exposure to chemical or physical mutagens, whereas others were normal. It was known that none of the cell lines in this experiment were infected with oncogenic viruses.

Question 17

Gaucher disease (type I) is due to a defect in a gene that encodes a protein called acid -glucosidase. This enzyme plays a role in carbohydrate metabolism within the lysosome. The gene is located on the long arm of chromosome 1. People who inherit two defective copies of this gene exhibit Gaucher disease, the major symptoms of which include an enlarged spleen, bone lesions, and changes in skin pigmentation. Let's suppose a phenotypically unaffected woman, whose father had Gaucher disease, has a child with a phenotypically unaffected man, whose mother had Gaucher disease.
A. What is the probability that this child will have the disease
B. What is the probability that this child will have two normal copies of this gene
C. If this couple has five children, what is the probability that one of them will have Gaucher disease and four will be phenotypically unaffected

Question 18

What is a transformed cell Describe three different methods to transform cells in a laboratory.

Question 19

Ehler-Danlos syndrome is a relatively rare disorder caused by a mutation in a gene that encodes a protein called collagen (type 3 A1). Collagen is a protein found in the extracellular matrix that plays an important role in the formation of skin, joints, and other connective tissues. People with this syndrome have extraordinarily flexible skin and very loose joints. The pedigree shown here contains several members affected with Ehler-Danlos syndrome, shown with black symbols. Based on this pedigree, does this syndrome appear to be an autosomal recessive, autosomal dominant, X-linked recessive, or X-linked dominant trait Explain your reasoning.

Question 20

In the experiment of Figure 24.12, what would be the results if the DNA sample had been treated with DNase, RNase, or protease prior to the treatment with calcium and phosphate ions
FIGURE 24.12 Identification of chromosomal oncogenes.
Starting material: Several mouse cell lines. Some of the cell lines were malignant due to exposure to chemical or physical mutagens, whereas others were normal. It was known that none of the cell lines in this experiment were infected with oncogenic viruses.

Question 21

Hurler syndrome is due to a mutation in a gene that encodes a protein called -L-iduronidase. This protein functions within the lysosome as an enzyme that breaks down mucopolysaccharides (a type of polysaccharide that has many acidic groups attached). When this enzyme is defective, excessive amounts of the mucopolysaccharides dermatan sulfate and heparin sulfate accumulate within the lysosomes, especially in liver cells and connective tissue cells. This leads to symptoms such as an enlarged liver and spleen, bone abnormalities, corneal clouding, heart problems, and severe neurological problems. The pedigree shown here contains three members affected with Hurler syndrome, indicated with black symbols. Based on this pedigree, does this syndrome appear to be an autosomal recessive, autosomal dominant, X-linked recessive, or X-linked dominant trait Explain your reasoning.

Question 22

Explain how the experimental study of cancer-causing viruses has increased our understanding of cancer.

Question 23

Like Hurler syndrome, Fabry disease involves an abnormal accumulation of substances within lysosomes. However, the lysosomes of individuals with Fabry disease show an abnormal accumulation of lipids. The defective enzyme is -galactosidase A, which is a lysosomal enzyme that functions in lipid metabolism. This defect causes cell damage, especially to the kidneys, heart, and eyes. The gene that encodes -galactosidase A is found on the X chromosome. Let's suppose a phenotypically unaffected couple produces two sons with Fabry disease and one phenotypically unaffected daughter. What is the probability that the daughter will have an affected son

Question 24

Discuss ways to distinguish whether a particular form of cancer involves an inherited predisposition or is due strictly to (postzy-gotic) somatic mutations. In your answer, consider that only one mutation may be inherited, but the cancer might develop only after several somatic mutations.

Question 25

Achondroplasia is a rare form of dwarfism caused by an autosomal dominant mutation that affects the gene that encodes a fibroblast growth factor receptor. Among 1,422,000 live births, the number of babies born with achondroplasia was 31. Among those 31 babies, 18 of them had one parent with achondroplasia. The remaining babies had two unaffected parents. How do you explain these 13 babies, assuming that the mutant allele has 100% penetrance What are the odds that these 13 individuals will pass this mutant gene to their offspring

Question 26

The codon change (Gly-12 to Val-12) in human ras H that converts it to oncogenic ras H has been associated with many types of cancers. For this reason, researchers would like to develop drugs to inhibit oncogenic ras H. Based on your molecular understanding of the Ras protein, what types of drugs might you develop In other words, what would be the structure of the drugs, and how would they inhibit Ras protein How would you test the efficacy of the drugs What might be some side effects

Question 27

Lesch-Nyhan syndrome is due to a mutation in a gene that encodes a protein called hypoxanthine-guanine phosphoribosyltransferase (HPRT). HPRT is an enzyme that functions in purine metabolism. People afflicted with this syndrome have severe neurodegeneration and loss of motor control. The pedigree shown here contains several members with Lesch-Nyhan syndrome. Affected members are shown with black symbols. Based on this pedigree, does this syndrome appear to be an autosomal recessive, autosomal dominant, X-linked recessive, or X-linked dominant trait Explain your reasoning.

Question 28

Describe how normal mammalian cells grow on solid media in a laboratory and how cancer cells grow. Is a malignant focus derived from a single cancer cell or from many independent cancer cells that happen to be in the same region of a tissue culture plate

Question 29

Marfan syndrome is due to a mutation in a gene that encodes a protein called fibrillin-1. It is inherited as a dominant trait. The fibrillin-1 protein is the main constituent of extracellular microfibrils. These microfibrils can exist as individual fibers or associate with a protein called elastin to form elastic fibers. The gene that encodes fibrillin-1 is located on the long arm of chromosome 15. Let's suppose a phenotypically unaffected woman has a child with a man who has Marfan syndrome.
A. What is the probability this child will have the disease
B. If this couple has three children, what is the probability none of them will have Marfan syndrome

Question 30

Sandhoff disease is due to a mutation in a gene that encodes a protein called hexosaminidase B. This disease has symptoms that are similar to Tay-Sachs disease. Weakness begins in the first 6 months of life. Individuals exhibit early blindness and progressive mental and motor deterioration. The pedigree shown here contains three members with Sandhoff disease. Affected members are shown with black symbols.

A. Based on this pedigree, does this syndrome appear to be an autosomal recessive, autosomal dominant, X-linked recessive, or X-linked dominant trait Explain your reasoning.
B. What is the likelihood that II-1, II-2, II-3, II-4, II-5, II-6, and II-7 carry a mutant allele for the hexosaminidase B gene

Question 31

What is a prion Explain how a prion relies on normal cellular proteins to cause a disease such as mad cow disease.

Question 32

Some people have a genetic predisposition for developing prion diseases. Examples are described in Table 24.6. In the case of Gerstmann-Straüssler-Scheinker disease, the age of onset is typically at 30-50 years, and the duration of the disease (which leads to death) is about 5 years. Suggest a possible explanation why someone can live for a relatively long time without symptoms and then succumb to the disease in a relatively short time.
Table 24.6 Neurodegenerative Diseases Caused by Prions*

Question 33

Familial fatal insomnia (described in Table 24.6) is a prion disease inherited as an autosomal dominant trait. Researchers have identified the PrP gene, located on the short arm of chromosome 20, and tried to understand the relationship between the PrP gene sequence and the molecular basis of familial fatal insomnia.
A. It has been found that a rare mutation at codon 178, changing an aspartic acid to an asparagine, can cause this disease. In addition, codon 129 seems to play a role. The human population is polymorphic at codon 129, which may encode valine or methionine. If codon 178 is the normal aspartic acid (Asp) codon, it does not seem to matter if valine or methionine is found at position 129. In other words, if codon 178 is aspartic acid, Met-129 and Val-129 codons are not associated with disease symptoms. However, if codon 178 specifies asparagine (Asn), then it does matter. Familial fatal insomnia seems to require an asparagine at codon 178 and a methionine at codon 129 in the PrP gene sequence. Suggest a possible reason why this is the case.
B. Also, researchers have compared the sequences of the PrP gene in many people with familial fatal insomnia. Keep in mind that this is a dominant autosomal trait, so people with this disorder have one mutant copy of the PrP gene and one normal copy. People with familial fatal insomnia must have one abnormal copy of the gene that contains Asn-178 and Met-129. The second copy of the gene has Asp-178, and it may have Met-129 or Val-129. Some results suggest that people having a Met-129 codon in this second copy of the PrP gene causes the disease to develop more rapidly than in people who have Val-129 in the second copy. Propose an explanation why disease symptoms may occur more rapidly when Met-129 is found in the second copy of the PrP gene.
Table 24.6 Neurodegenerative Diseases Caused by Prions*

Question 34

What is the difference between an oncogene and a tumorsuppressor gene Give two examples.

Question 35

What is a proto-oncogene What are the typical functions of proteins encoded by proto-oncogenes At the level of protein function, what are the general ways that proto-oncogenes can be converted into oncogenes

Question 36

What is a retroviral oncogene Is it necessary for viral infection and proliferation How have retroviruses acquired oncogenes

Question 37

A genetic predisposition to developing cancer is usually inherited as a dominant trait. At the level of cellular function, are the alleles involved actually dominant Explain why some individuals who have inherited these dominant alleles do not develop cancer during their lifetimes.

Question 38

Describe the types of genetic changes that commonly convert a proto-oncogene into an oncogene. Give three examples. Explain how the genetic changes are expected to alter the activity of the gene product.

Question 39

Relatively few inherited forms of cancer involve the inheritance of mutant oncogenes. Instead, most inherited forms of cancer are defects in tumor-suppressor genes. Give two or more reasons why we seldom see inherited forms of cancer involving activated oncogenes.

Question 40

The rb gene encodes a protein that inhibits E2F, a transcription factor that activates several genes involved in cell division. Mutations in rb are associated with certain forms of cancer, such as retinoblastoma. Under each of the following conditions, would you expect cancer to occur
A. One copy of rb is defective; both copies of E2F are functional.
B. Both copies of rb are defective; both copies of E2F are functional.
C. Both copies of rb are defective; one copy of E2F is defective.
D. Both copies of rb and E2F are defective.

Question 41

A p53 knockout mouse in which both copies of p53 are defective has been produced by researchers. This type of mouse appears normal at birth. However, it is highly sensitive to UV light. Based on your knowledge of p53, explain the normal appearance at birth and the high sensitivity to UV light.

Question 42

With regard to cancer cells, which of the following statements are true
A. Cancer cells are clonal, which means they are derived from a single mutant cell.
B. To become cancerous, cells usually accumulate multiple genetic changes that eventually result in uncontrolled growth.
C. Most cancers are caused by oncogenic viruses.
D. Cancer cells have lost the ability to properly regulate cell division.

Question 43

When the DNA of a human cell becomes damaged, the p53 gene is activated. What is the general function of the p53 protein Is it an enzyme, transcription factor, cell-cycle protein, or something else Describe three ways that the synthesis of the p53 protein affects cellular function. Why is it beneficial for these three things to happen when a cell's DNA has been damaged