Mutation: The source of genetic variation

Question 1

What is a mutation?

Answer 1

The ultimate source of genetic variation

Question 2

What are the two major types of mutations focused on in this document?

Answer 2

Base-pair substitutions and deletions/insertions

Question 3

What is a base-pair substitution?

Answer 3

A mutation where one base pair is replaced by another

Question 4

What are silent substitutions?

Answer 4

Base-pair substitutions that do not change the amino acid sequence

Question 5

What is a missense mutation?

Answer 5

A mutation that produces a change in a single amino acid

Question 6

What is a nonsense mutation?

Answer 6

A mutation that produces one of the three stop codons in mRNA

Question 7

What is the result of a premature nonsense mutation?

Answer 7

Early termination of the polypeptide chain or destruction of the transcript

Question 8

What is a stop-loss mutation?

Answer 8

An alteration of a stop codon so that it encodes an amino acid

Question 9

What is a frameshift mutation?

Answer 9

Mutations caused by deletions or insertions not in multiples of three

Question 10

What is an example of a disease caused by a deletion mutation?

Answer 10

Cystic fibrosis

Question 11

What is Charcot–Marie–Tooth disease associated with?

Answer 11

A 1.5 million-bp duplication on chromosome 17

Question 12

What is dosage sensitivity in genetics?

Answer 12

When a reduction or increase in gene product produces disease

Question 13

What is a promoter mutation?

Answer 13

A mutation that decreases the affinity of RNA polymerase for a promoter site

Question 14

What are splice-site mutations?

Answer 14

Mutations that alter the splicing signal at intron-exon boundaries

Question 15

What are cryptic splice sites?

Answer 15

Splice sites that differ slightly from normal splice sites and are ordinarily unused

Question 16

What are mobile elements in genetics?

Answer 16

DNA sequences capable of propagating copies of themselves and causing mutations

Question 17

What are tandem repeated DNA sequences?

Answer 17

DNA sequences that can increase in number and potentially cause genetic disease

Question 18

What is the difference between gain-of-function and loss-of-function mutations?

Answer 18

Gain-of-function produces overexpression or novel proteins; loss-of-function results in reduced protein activity

Question 19

What is haploinsufficiency?

Answer 19

When 50% of the gene product is insufficient for normal function

Question 20

What is a dominant negative mutation?

Answer 20

A mutation that results in an abnormal protein product that inhibits the normal protein function

Question 21

What are the two broad categories of hemoglobin disorders?

Answer 21

Structural abnormalities and thalassemias

Question 22

What is hereditary persistence of fetal hemoglobin (HPFH)?

Answer 22

A condition where fetal hemoglobin continues to be produced after birth

Question 23

What causes sickle cell disease?

Answer 23

A missense mutation substituting valine for glutamic acid in the β-globin chain

Question 24

What is the characteristic shape of erythrocytes in sickle cell disease?

Answer 24

Sickle shape under low oxygen tension

Question 25

What is the consequence of sickled erythrocytes in capillaries?

Answer 25

They are less flexible and unable to pass through

Question 26

What are the major features of sickle cell disease?

Answer 26

Anemia

Question 27

What are the characteristics of capillaries?

Answer 27

Tiny vessels whose diameter is smaller than that of erythrocytes.

Question 28

What is the main issue with sickled erythrocytes in capillaries?

Answer 28

Less flexible and unable to squeeze through capillaries.

Question 29

What is vascular endothelium?

Answer 29

The innermost lining of blood vessels.

Question 30

What are the major disease features of sickle cell disease?

Answer 30

* Anemia * Tissue infarctions * Infections

Question 31

What causes sickle cell disease?

Answer 31

A single β-globin missense mutation that produces an amino acid substitution.

Question 32

What is HbH disease?

Answer 32

Deletion or abnormality of three of the four α-globin genes causing moderately severe anemia and splenomegaly.

Question 33

What are the effects of hydrops fetalis (Hb Barts)?

Answer 33

Severe anemia or hypoxemia, congestive heart failure, stillbirth or neonatal death.

Question 34

What mutations typically cause β0-thalassemia?

Answer 34

Nonsense, frameshift, or splice-site mutations; no β-globin produced.

Question 35

What are the common features of β+-thalassemia?

Answer 35

Features similar to β0-thalassemia but usually milder due to small amounts of β-globin produced.

Question 36

What happens to erythrocytes in sickle cell disease?

Answer 36

Localized hypoxemia, painful sickling crises, and infarctions of various tissues.

Question 37

What is splenomegaly?

Answer 37

Enlargement of the spleen.

Question 38

What is the estimated life expectancy reduction for persons with sickle cell disease in North America?

Answer 38

About 30 years.

Question 39

What causes premature destruction of sickled erythrocytes?

Answer 39

Decreased number of circulating erythrocytes and hemoglobin level, leading to anemia.

Question 40

What is the primary cause of α-thalassemia?

Answer 40

Deletions of the α-globin genes.

Question 41

What is the clinical effect of losing one or two α-globin genes?

Answer 41

No clinical effect.

Question 42

What is the condition associated with the loss of all four α-globin genes?

Answer 42

Hydrops fetalis.

Question 43

What is β-thalassemia minor?

Answer 43

A condition with little or no anemia caused by a β-globin mutation in one copy of chromosome 11.

Question 44

What is the main cause of β-thalassemia major?

Answer 44

Both copies of the chromosome carry a β-globin mutation.

Question 45

When do the effects of β-thalassemia major typically become clinically evident?

Answer 45

At the age of 2 to 6 months.

Question 46

What is a common treatment for patients with sickle cell disease?

Answer 46

Blood transfusions and chelating agents.

Question 47

What is the mortality rate of bone marrow transplantation for severe β-thalassemia or sickle cell disease?

Answer 47

Approximately 5% to 30%.

Question 48

What are mutagens?

Answer 48

Agents that cause induced mutations.

Question 49

What type of radiation is known to cause mutations?

Answer 49

Ionizing radiation.

Question 50

What effect does ionizing radiation have on DNA?

Answer 50

It can eject electrons from atoms, forming ions that can change DNA bases.

Question 51

What is the difference between ionizing and non-ionizing radiation?

Answer 51

Ionizing radiation forms charged particles; non-ionizing radiation does not.

Question 52

What are mutagens?

Answer 52

Substances that cause induced mutations ## Footnote This includes radiation and chemicals

Question 53

What type of radiation is considered an important class of mutagen?

Answer 53

Ionizing radiation ## Footnote Examples include x-rays and nuclear fallout

Question 54

How does ionizing radiation affect DNA?

Answer 54

It can eject electrons, forming charged ions that can change DNA bases and break double-stranded DNA bonds

Question 55

What is nonionizing radiation?

Answer 55

Radiation that does not form charged ions but can move electrons within an atom ## Footnote Example: Ultraviolet (UV) radiation

Question 56

What are pyrimidine dimers?

Answer 56

Covalent bonds formed between adjacent pyrimidine bases due to UV radiation ## Footnote These dimers disrupt proper pairing during DNA replication

Question 57

What is a base analog?

Answer 57

A chemical that can substitute for a true DNA base during replication ## Footnote Example: 5-bromouracil

Question 58

What is the effect of nitrous acid on DNA?

Answer 58

It removes an amino group from cytosine, converting it to uracil, leading to base-pair substitution

Question 59

What is xeroderma pigmentosum (XP)?

Answer 59

A rare autosomal recessive disease caused by faulty DNA repair mechanisms, leading to skin tumors and photosensitivity

Question 60

What is nucleotide excision repair (NER)?

Answer 60

A DNA repair system that removes pyrimidine dimers and other DNA damage ## Footnote It is encoded by at least 28 different genes

Question 61

What are the common symptoms of xeroderma pigmentosum?

Answer 61

Dry skin, freckling, abnormal pigmentation, and increased risk of skin tumors

Question 62

What is the mutation rate at the nucleotide level?

Answer 62

Approximately 1.3 x 10 −8 per base pair per generation

Question 63

What factors contribute to the variability of mutation rates at the gene level?

Answer 63

Gene size and susceptibility of certain nucleotide sequences ## Footnote Larger genes usually have higher mutation rates

Question 64

What are mutation hot spots?

Answer 64

Regions of DNA that have a higher likelihood of mutation ## Footnote Example: CG dinucleotide sequences

Question 65

What is the paternal age effect?

Answer 65

The increased probability of transmitting mutations to offspring as a father ages

Question 66

What is the estimated additional mutation rate per year of paternal age?

Answer 66

Approximately one to two additional mutations per year

Question 67

What is the significance of methylated CG dinucleotides?

Answer 67

They experience elevated mutation rates due to easy conversion from cytosine to thymine

Question 68

What are some diseases caused by defects in DNA repair mechanisms?

Answer 68

* Xeroderma pigmentosum * Cockayne syndrome * Fanconi anemia * Bloom syndrome * Werner syndrome * Ataxia-telangiectasia * Hereditary nonpolyposis colorectal cancer

Question 69

What is the role of DNA repair mechanisms?

Answer 69

To correct replication errors, repair double-stranded DNA breaks, and excise damaged nucleotides

Question 70

True or False: All mutations are harmful.

Answer 70

False ## Footnote Some mutations can be neutral or beneficial