(8) Mutation

Question 1

What are mutations?

Answer 1

Heritable changes in the base-pair composition of DNA.

Question 2

What three conclusions can be drawn from studies into the frequency of mutations?

Answer 2

Mutation frequencies are low in all genomes
Mutation frequencies differ considerably among organisms
Mutation frequencies among different genes of a single species show variation

Question 3

What can we assume from the following statement: Mutation frequencies are low in all genomes.

Answer 3

Mutations contribute slowly to the inherited diversity

Question 4

What can we assume from the following statement: Mutation frequencies differ considerably among organisms

Answer 4

There are differences in mutation tolerance and/or the efficiency of DNA repair mechanisms

Question 5

What can we assume from the following statement: Mutation frequencies among different genes of a single species show variation

Answer 5

There are intrinsic characteristics of DNA sequences that lead to different mutation rates among the genes on a genome
There are “hotspots of mutation”

Question 6

Why might we find higher rates of mutation among RNA viruses?

Answer 6

RNA strands are more prone to breakage
Replication of these genomes lack a proofreading function

Question 7

How often do errors in DNA replication occur in multicellular organisms?

Answer 7

About 1 nucleotide in every 10 billion nucleotides

Question 8

What does OMIM stand for?

Answer 8

Online Mendelian Inheritance in Man

Question 9

What are the factors that influence mutation rates and how?

Answer 9

Size of the gene: larger genes have higher mutation rates
Nucleotide sequence: presence of nucleotide repeats are associated with higher mutation rates
Spontaneous chemical changes: C/G base pairs are more likely to mutate than A/T pairs

Question 10

The CFTR protein (produced by the cystic fibrosis gene (CFTR)) contains five domains; what are they?

Answer 10

Two membrane-spanning domains, a regulatory domain, and two nucleotide-binding domains that interact with ATP

Question 11

What does an abnormal CFTR protein result in?

Answer 11

Defective electrolyte transport and defective chloride ion transport in the apical membrane epithelial cells of the sweat gland, airway, pancreas, and intestine

Question 12

What are the exceptions to the average mutation rate in DNA replication?

Answer 12

Certain regions of the genome are prone to mutation
Differences between the sexes (males experiences a greater mutation rate than females)
Differences in cell type (Somatic cells experience greater mutation rates than germ-line cells (i.e., gametes))

Question 13

What is more important, rate of mutation per cycle of DNA replication or the rate of mutation per organism all generation?

Answer 13

For germ-line mutations, rate of mutation per organism all generation. Important to evolutionary processes because through transmission between generations they may become present in many individuals
For somatic mutations, the rate of mutation per cycle of DNA replication is most important. Not transmitted to future generations, only progeny cells in mitotic divisions.

Question 14

Describe the experiment that was made to answer this question: How do mutations arise (spontaneously or in response to the environment)?

Answer 14

The Lederbergs isolated a pure culture of antibiotic-resistant bacteria even though the original bacteria had never been exposed to antibiotics. This result supported the hypothesis that mutations occur randomly and without regard to the needs of the organism (in this case, to survive in an environment containing antibiotics).

Question 15

How do organisms reduce the frequency of errors during replication?

Answer 15

Proofreading: DNA polymerases can proofread their work.
Mismatch repair enzymes: fixes most errors that were missed by the DNA polymerases

Question 16

What are the four DNA repair mechanisms?

Answer 16

DNA ligase, mismatch repair, base excision repair, nucleotide excision repair

Question 17

Describe DNA ligase as a DNA repair mechanism

Answer 17

Seals breaks in the sugar-phosphate backbone

Question 18

Describe mismatch repair

Answer 18

Single mis-paired base repaired by removing and replacing a DNA segment

Question 19

Describe base excision repair

Answer 19

Incorrect base and its sugar excised from the strand, then replaced

Question 20

What is the name of the repair enzymes required for mismatch repair?

Answer 20

Mut Proteins

Question 21

What plays a key role in the elimination of DNA lesions and how?

Answer 21

DNA glycosylase
Recognizes and excises damaged bases, thereby initiating a repair process that restores the regular DNA structure with high accuracy

Question 22

Describe nucleotide excision repair

Answer 22

Recognizes multiple mismatched bases in a region

Question 23

What is an endonuclease?

Answer 23

Nuclear that removes nucleotides from within a polynucleotide strand

Question 24

What is an exonuclease?

Answer 24

Nuclear that removes nucleotides at the end of a polynucleotide strand

Question 25

Which repair mechanism is critical for the repair of pyramidine diners caused by UV radiation?

Answer 25

Nucleotide excision repair

Question 26

What disease are mutations in genes coding for nucleotide excision enzymes associated with?

Answer 26

Xeroderma Pigmentosum

Question 27

Name the different categories of mutation

Answer 27

Nucleotide substitution or point mutation (silent, missense & nonsense mutations) Frame shift mutations (insertion, deletion) Large scale (chromosomal mutations): (Insertion, deletion, translocation)

Question 28

Explain point mutations

Answer 28

Bro you know this

Question 29

Explain how mutations affect the phenotype.

Answer 29

Mutations -> Change in amino acid sequence -> change in protein folding -> change in phenotype

Question 30

What are the three types of nucleotide substitutions?

Answer 30

Missense mutations, sense mutations, nonsense mutations

Question 31

Explain how sickle cell anemia is caused.

Answer 31

It is caused by a change in only a single amino acid: Glu (polar) is replaced by Val (non-polar). The result is the mis-folding of the hemoglobin subunit beta-globin. Individuals who inherit two copies of the mutant beta-globin gene have sickle cell anemia.

Question 32

Explain the symptoms of sickle cell anemia.

Answer 32

Hemoglobin crystallizes in low levels of oxygen, causing the cell to collapse; oxygen is not carried through the body effectively, causing anemia, and sickles cells block capillary vessels, causing pain and low oxygen levels.

Question 33

What is a sense mutation?

Answer 33

A mutation in a single nucleotide that changes a stop codon into one that codes for an amino acid, producing elongated proteins.

Question 34

What is a nonsense mutation?

Answer 34

A mutation that changes an amino acid specifying a codon to one of three termination codons

Question 35

What is the beta-39 mutation?

Answer 35

A relatively common mutation in Mediterranean populations. A nonsense mutation at the 39th codon of the human beta-globin

Question 36

What is a frame shift mutation?

Answer 36

Insertion or deletion of 1 or 2 bases resulting in disruption/shifting of the reading frame.

Question 37

What is the most common cause of cystic fibrosis and what are its symptoms?

Answer 37

The deletion of 3 nucleotides in the CFTR gene (the “delta-f508” mutation). Results in abnormal secretions in the lungs, liver, pancreas, and other glands.

Question 38

Provide an example of trinucleotide repeats.

Answer 38

CAG repeats associated with Huntington’s disease

Question 39

What is an allelic expansion?

Answer 39

Increase in gene size caused by an increase in the number of trinucleotide sequences. Potential for expansion is a characteristic of a specific allele.

Question 40

What number of CAG repeats corresponds to severity of symptoms for Huntington’s disease

Answer 40

26: normal 27-35: normal, but number may increase in children 36-39: may or may not develop symptoms (incomplete penetrance), but likely later onset or slower progression 40-60: definitely affected 60+: symptoms in childhood

Question 41

What is ‘anticipation’?

Answer 41

The phenomenon in which increasing disease severity or decreasing age of onset is observed in successive generations. Known to occur in Huntington’s disease.

Question 42

Explain how anticipation works in Huntington’s disease.

Answer 42

Occurs more commonly in paternal transmission of the mutated allele. Arises from the instability of the CAG repeat during spermatogenesis. Large expansions occur almost exclusively through paternal transmission.

Question 43

How does transmission of fragile-X syndrome differ between sexes? Additionally, how does the phenotype differ between sexes?

Answer 43

1. Maternal transmission: Repeats expand Paternal transmission: Repeats remain constant or decrease 2. Heterozygous mothers are phenotypically normal. 20-50% of hemizygous males are phenotypically normal (transmitter males)

Question 44

What is the cause and symptoms of Fragile-X syndrome?

Answer 44

Caused by the allelic expansion of the FMR gene. Alleles of the FMR-1 gene contain CGG repeats (normal 6-52 repeats, pre-mutation 60-200 repeats, fully mutant 230+) Symptoms include mental retardation

Question 45

What are transposable elements?

Answer 45

DNA sequences that can move from one position to another in the genome. Can insert into a gene and disrupt its function.

Question 46

How were transposable elements discovered?

Answer 46

Discovered by Barbara McClintock in 1944 Hypothesized that a transposable element called Dissociator would alter the coloration of purple corn kernels by inserting itself in the anthocyanin gene, causing the kernels to be yellow instead of purple. By setting up genetic crosses, she showed that another transposable element, Activator, on another chromosome to revert back to their original purple color.

Question 47

What is the most common transposable element in the human genome? Explain it.

Answer 47

The “Alu” transposon. ~300bp transposon, a particular Alu insertion at the PV92 locus occurred relatively recently in humans, allele frequencies of +/- PV92 can be used for population genetics.

Question 48

What are inborn errors of metabolism?

Answer 48

The idea that many genetic traits result from alterations in biochemical pathways

Question 49

Provide an example of inborn errors of metabolism and explain it.

Answer 49

Alkaptonuria: An autosomal recessive trait with altered metabolism of homogentisic acid Affected individuals do not produce the enzyme needed to metabolize this acid, and their urine turns black.

Question 50

What are essential amino acids?

Answer 50

Amino acids, like phenylalanine, that cannot be synthesized in the body and must be supplied in the diet.

Question 51

What does PKU stand for?

Answer 51

Phenylketonuria

Question 52

What is PKU?

Answer 52

An autosomal recessive disorder of amino acid metabolism that results in mental retardation if untreated.

Question 53

Explain the cause of PKU and how it develops.

Answer 53

Phenotype caused by buildup of phenylalanine and the products of secondary reactions. Infants with PKU may develop normally before birth, then develop neurological damage when fed a diet containing protein.

Question 54

What does a PKU diet consist of?

Answer 54

Must contain enough phenylalanine for normal development, but low enough to prevent mental retardation.

Question 55

What happens when women with PKU have children?

Answer 55

A pregnant woman with PKU who eats a normal diet has high levels of phenylalanine in her blood. Excess phenylalanine does not affect the mother because her nervous system has already formed. Excess phenylalanine crosses the placenta and damages the fetus, no matter what its genotype is

Question 56

What was sickle cell anemia the first example of?

Answer 56

Inherited variation in protein structure. It was the first direct proof that mutations result in a change in amino acid sequence in proteins. Was also evidence that a change in a single nucleotide can cause a genetic disorder.

Question 57

What does molecular organization of globin gene clusters show?

Answer 57

How gene expression is regulated.

Question 58

What is a pseudogene?

Answer 58

Nonfunctional genes that are closely related (by DNA sequence) to functional genes present elsewhere in the genome.

Question 59

What is thalassemia?

Answer 59

A disorder associated with an imbalance in the production of alpha or beta globin. Synthesis of alpha or beta globin is reduced or absent (usually equal amounts produced). Effects on oxygen binding can be lethal.

Question 60

What does the Alpha-Globin cluster on chromosome 16 contain?

Answer 60

Two copies of alpha-globin genes, the zeta gene, and pseudogenes (Zeta is active during embryogenesis only)

Question 61

Provide an example of genes active in fetal development, and some that are transcribed after birth.

Answer 61

1. G & A Gamma 2. Beta

Question 62

Explain alpha & beta thalassemia and explain them.

Answer 62

Genetic disorder associated with an imbalance in the ratio of alpha and beta globin caused by reduced or absent synthesis of: alpha globin (alpha thalassemia) or beta globin (beta thalassemia)

Question 63

What does fetal hemoglobin have?

Answer 63

Two alpha globins and two gamma globins

Question 64

Which globins are switched off at birth?

Answer 64

Gamma globins, part of the beta cluster. Then, the beta gene is activated.

Question 65

What causes fetal hemoglobin to reappear in red blood cells?

Answer 65

Treatment with an anti cancer drug, hydroxyurea reactivated gamma genes.

Question 66

Explain the example of colorectal cancer in relation to pharmacogenomics.

Answer 66

It is treated with the drug Irinotecan. In some people, genetic variations cause a shortage of the UGT1A1 enzyme responsible for metabolizing irinotecan. With a UGT1A1 shortage, higher levels of irinotecan remain in the body, which leads to potentially life-threatening side effects. Risk is greater with higher doses of the drug. Doctors may use a pharmacogenomic test called the UGT1A1 test. It shows which people have this genetic variation.