Ch. 23 & 24 Long answers

Know the four common types of genetic changes that produce oncogenes

Missense mutation, gene amplification, chromosomal translocations, viral integration.

Know the three common ways that the function of tumor-suppressor genes is lost.

1. A mutation in the tumor-suppressor gene itself The promoter could be inactivated An early stop codon could be introduced in the coding sequence 2. DNA methylation 3. Aneuploidy Chromosome loss may contribute to the progression of cancer if the lost chromosome carries one or more tumor-suppressor genes

Five common features of autosomal dominant inheritance are as follows:

1. An affected offspring usually has one or both affected parents 2. An affected individual with only one affected parent is expected to produce (on average) 50% affected offspring 3. Two affected, heterozygous individuals will have (on average) 25% unaffected offspring 4. The trait occurs with the same frequency in both sexes 5. For most dominant disease-casing alleles, the homozygote is more severely affected with the disorder

Know the seven observations that suggest a disease is caused

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

Understand the concept of homology.

2 sequences that are derived from the same ancestor

Be able to describe what a DNA microarray is, and how it is used to study gene expression patterns

A DNA microarray is a small silica, glass or plastic slide that is dotted with many sequences of DNA. A mixture of mRNA is used to create cDNAs that are fluorescently labeled. The cDNAs are applied to the microarray and any unbound cDNAs are washed off. The rest are hybridized and can be visualized using a laser.

For a rare genetic disease that is equally probable in males and females, the concordance for identical twins is 91% and for fraternal twins it is 45%. Do these values indicate a recessive or dominant pattern of inheritance? Suggest two reasons why the concordance value between identical twins is not 100%.

Because the genetic disorder is equally probable in both males and female, the disorder is likely autosomal. Because the disease has a concordance of approximately 50% for fraternal twins (assuming one parent is heterozygous), it is likely that the disease is inherited in a dominant fashion. Additionally, there are several possible explanations for why the concordance values in identical twins are not 100%, including the possibility that the disease occurs as a result of a gene mutation that has occurred after fertilization or that the disease is not completely penetrate and no obvious symptoms are seen.

Knockout mice are often generated to model human genetic disorders. Many years ago, researchers generated p53 knockout mice. Mice heterozygous for the p53 knockout allele were expected to have similar phenotypes as their human counterparts, patients with Li-Fraumeni syndrome. Given the characteristics of p53 as a tumor suppressor, describe an expected phenotype for p53 heterozygous mice.

Knocking out a gene may fail to produce an observable change in a mouse. P53 gene mutations are associated with many human cancers and often times lead to tumors in certain tissues. When the P53 gene is knocked out in mice, the animals develop tumors in a different set of tissues than in humans. However, it is likely that no observable phenotypic changes will be seen.

Explain why most inherited forms of cancer show a dominant pattern of inheritance in a pedigree even though they are recessive at the cellular level.

Most inherited forms of cancer show a dominant pattern of inheritance because cancer commonly results from the loss of the normal copy allele in heterozygous individuals, which is known as loss of heterozygosity. Therefore, although they are recessive at the cellular level, they will still exhibit a dominant inheritance pattern.

How would a mutation that prevents the Ras protein from hydrolyzing GTP affect the EGF pathway described in Figure 24.13? How would this affect cell growth?

The mutation would cause the Ras protein to stay in its active state. This would turn on the EGF pathway. The protein staying in its active state would promote cancer cell growth.

Know that the underlying cause of most recessive patterns of inheritance is

a loss-of-function mutation

for dominant patterns, it may be due to

haploinsufficiency, gain-of-function, or a dominant negative mutation.

Know that most cancers involve a progression of

multiple mutations

Experimentally, how would you distinguish between haploinsufficiency, gain-of-function, or a dominant negative mutation.

Haploinsufficiency: The heterozygote has 50% of the normal protein, which is not sufficient for a normal phenotype. Gain-of-function mutations: Mutation changes protein so it gains a new function. Dominant negative mutations: The altered gene product acts antagonistically to the normal product.

tumor-suppressor genes involve

a loss-of-function

To cause cancer, know that oncogenes involve a

gain-of-function

Four common features of autosomal recessive inheritance are as follows:

1. Frequently, an affected offspring will have two unaffected parents 2. When two unaffected heterozygotes have children, the percentage of affected children is (on average) 25% 3. Two affected individuals will have 100% affected children 4. The trait occurs with the same frequency in both sexes

Three common features of X-linked recessive inheritance are as follows:

1. Males are much more likely to exhibit the trait 2. The mothers of affected males often have brothers or fathers who are affected with the same trait 3. The daughters of affected males will produce (on average) 50% affected sons