10/19: DNA Repair and How Mutations Occur?

Question 1

What are types of genetic disorders?

Answer 1

Single gene disorders
Chromosome disorders
Multifactorial or complex disorders

Question 2

What are chromosome disorders?

Answer 2

Rearragnements/translocaitons, deletions, insertions, duplications, anomalies in chromosome number: trisomies, monosomies

Question 3

What are specific examples of genetic chromosome disorders?

Answer 3

• Autosomal, sex linked, and mitochondrial
• Germline (heritable) or somatic (non-heritable)
• Dominant, recessive, co-dominant

Question 4

What are multifactorial or complex disorders?

Answer 4

Multiple gene variants, gene variant x environment interactions

Question 5

What is a mutation

Answer 5

Inherent association with disease, pathology, or mutant
**negative connotations for patients

Question 6

Most phenotypes are on a _________

Answer 6

spectrum (bell curve)

Question 7

What is a variant?

Answer 7

Implies nothing about a disease state, just a different form

Question 8

Variants still arise by

Answer 8

mutation process

Question 9

What can a variant be described as?

Answer 9

• novel, rare, common
• having low or high impact
• benign, likely pathogenic, or pathogenic

Question 10

What are multigenic or multifactorial diseases typically caused by

Answer 10

combined effect of numerous common, low impact variants that individually would not cause the disease

Question 11

What can risk be influenced more by?

Answer 11

New genetic variants and environmental factors

Question 12

What are two causes of mutations?

Answer 12

Spontaneous mutation
Induced mutation

Question 13

What are spontaneous mutations

Answer 13

Arise naturally during DNA replication (mitosis or meiosis)

Question 14

What are examples of enduced mutations

Answer 14

Radiation
Chemicals

Question 15

Where can mutations occur?

Answer 15

Anywhere in the nuclear (or mitochondrial) DNA

Question 16

Where else can mutations cause a disease?

Answer 16

Outside the exons of a gene

Question 17

Where can SNVs or point mutations be present?

Answer 17

Coding and non-coding DNA

Question 18

What does non-coding DNA include?

Answer 18

Gene regulatory elements, introns, repetitive elements (viral DNA, transposons)

Question 19

What are the 3 types of coding SNVs?

Answer 19

SIlent (synonymous)
Nonsense
Missense (non-synonymous)

Question 20

What are silent mutations?

Answer 20

have no effect on the amino acid produced by a codon

Question 21

What are nonsense mutations?

Answer 21

No amino acid is produced; causes a stop codon to occur

Question 22

What are missense mutations?

Answer 22

still code for an amino acid, but not the correct amino acid

Question 23

What are the ways that SNVs can be described?

Answer 23

• in terms of significance of the resulting change in the amino acid side chain
• by the chemical nature of the nucleotide change

Question 24

What can deletions/insertions involve?

Answer 24

A single amino acids (3bp) or many base pairs, removing or disrupting exons and/or regulatory sequences

Question 25

What do rearrangements involve?

Answer 25

Large segments of DNA

Question 26

What do framshift variants involve?

Answer 26

Deletion or insertion of <3bp (i.e. 1 or 2bp) within the coding sequence, disrupting the codon reading frame and thus the amino acid sequence

Question 27

What can a reading frameshift also arise from?

Answer 27

A larger deletion ex: a deletion that removes one or more exons

Question 28

What are other types of mutations?

Answer 28

Promoter/enhancer/silencer Splice acceptor/donor site splice enhancer/silencer element Repeat expansion Transposons

Question 29

The nomenclature of variants can be represented as:

Answer 29

Genomic coordinate mRNA (cDNA) coordinate Protein (amino acid) coordinate

Question 30

What is genomic coordinate?

Answer 30

Citing the version of the genome sequence used

Question 31

What is mRNA coordinate?

Answer 31

Citing the reference cDNA sequence used

Question 32

What is protein (amino acid) coordinate?

Answer 32

Citing the reference protein sequence used

Question 33

What is more commony used when referring to variants that are very common in a population, hence "polymorphism"

Answer 33

SNP

Question 34

SNP = ________

Answer 34

SNV

Question 35

What are usually benign?

Answer 35

SNPs

Question 36

What is an allele?

Answer 36

One of the two copies of a gene - you inherit one allele of each autosomal gene from your mother and one from your father

Question 37

If each member of a chromosome carries the same allele, the individual is called __________ for that allele

Answer 37

homozygous

Question 38

If each member of a chromosome carries the different allele, the individual is called __________ for that allele

Answer 38

heterozygous

Question 39

The phenotype of a dominant allele can be observed in a ____________ individual

Answer 39

heterozygous

Question 40

The phenotype of a recessive allele can be observed in a ____________ individual

Answer 40

homozygous

Question 41

How do mutations occur?

Answer 41

1. oxidative damage by reactive oxygen species 2. uncontrolled methylation (CH3-) 3. hydrolytic attack - deamination and depurination, most frequent reactions

Question 42

How can DNA bases be damaged?

Answer 42

1. reactive metabolites 2. exposure to chemicals 3. UV radiation

Question 43

What happens when methylated cytosines are accidentally deaminated?

Answer 43

They form the natural nucleotide thymidine, so NOT removed by base excission repair

Question 44

Mismatched bases are corrected through a process called_____________

Answer 44

Nucleotide excision repair

Question 45

What is base excision repair?

Answer 45

Specific glycosylases remove damaged bases

Question 46

A location in DNA that has neither a purine nor a pyrimidine base

Answer 46

AP site (apurinic/apyrimidinic site)

Question 47

How do modifications of nucleotides produce mutations?

Answer 47

In case of deamination: DNA substitution In case of deputination: DNA deletion

Question 48

What is the "quick and dirty" mechanism

Answer 48

non-homologous end joining

Question 49

When does homologous recombination occur?

Answer 49

During meiosis

Question 50

What does homologous recombination involve?

Answer 50

Base pairing between DNA strands

Question 51

What is homologous recombination used to facilitate?

Answer 51

Genetic exchange between homologous chromosomes

Question 52

What does DNA base pairing guide?

Answer 52

Homologous recombination *highly accurate repair mechanism

Question 53

When is homologous recombination deployed?

Answer 53

To repair double strand DNA breaks as well as single strand breaks that arise during DNA replication

Question 54

What does repair involve?

Answer 54

Number of enzymes and accessory proteins - any loss of these repair proteins is lethal - loss or mutation of accessory proteins leads to cancer

Question 55

Most spontaneous changes to nucleotides are repaired when?

Answer 55

Before they become a stable part of the DNA

Question 56

When mutations occur in somatic tissues, can they be inherited?

Answer 56

No, but can give rise to diseases such as cancer

Question 57

When mutations arise in the DNA of the gametes, where are the passed on to?

Answer 57

Offspring