CPPS403 - GeneticVariation - 3

Question 1

What is the role of HDAC IIa in a healthy heart?

Answer 1

HDAC IIa is in the nucleus and usually inhibits MEF2

MEF2 promotes hypertrophy

Question 2

What happens to HDAC IIa in a stressed heart?

Answer 2

HDAC IIa moves to the cytoplasm and HAT and BET turn on hypertrophic genes

MEF2 can recruit HAT to promote acetylation and BETs recognize histone acetylation

Question 3

What is the function of HDAC I?

Answer 3

HDAC I has catalytic activity and inhibits the expression of cardioprotective genes

HDAC I is overexpressed in the stressed heart

Question 4

How does HDAC I affect anti-hypertrophy genes in a stressed heart?

Answer 4

HDAC I represses the expression of anti-hypertrophy genes

Question 5

What is the effect of HDAC inhibitors (HDACi) on HDAC II?

Answer 5

HDACi can stop the transport of HDAC II to the cytoplasm

Question 6

What is the outcome of using HDAC inhibitors on hypertrophy gene expression?

Answer 6

Hypertrophy gene expression is attenuated

Question 7

What is the effect of HDAC inhibitors on HDAC I catalytic activity?

Answer 7

HDACi can inhibit HDAC I catalytic activity

Question 8

What happens to anti-hypertrophy gene expression with HDAC inhibitors?

Answer 8

Anti-hypertrophy gene expression increases

Question 9

Define ‘locus’ in genetic terms.

Answer 9

Region/segment of DNA

Question 10

What is an allele?

Answer 10

Alternative versions of the DNA sequence at a locus

Question 11

What does ‘wild-type’ refer to?

Answer 11

Common allele

Question 12

What is a polymorphism?

Answer 12

Variations in an allele that are relatively common in a population

Question 13

Define ‘mutation’.

Answer 13

Permanent change in nucleotide sequence or DNA arrangement

Question 14

What is genetic variation?

Answer 14

Generated constantly; effects may be neutral, convey selective advantages, or have deleterious consequences

Question 15

What is a single nucleotide polymorphism (SNP)?

Answer 15

A single nucleotide variant that occurs in at least 1% of human genomes

Question 16

What are rare variants?

Answer 16

Variants that occur with lower allele frequency; can be benign, pathogenic, or variants of unknown significance (VUS)

Question 17

What does ‘indel’ refer to?

Answer 17

Deletions, duplications, or insertions of a small number of bases

Question 18

What is an example of variation nomenclature?

Answer 18

ACTN1: c.4375C>T, p.R1459*

Question 19

What does ‘c’ represent in variation nomenclature?

Answer 19

Coding DNA reference sequence position

Question 20

What does ‘R1459*’ indicate in variation nomenclature?

Answer 20

Arginine (R) at position 1459 is replaced by a stop codon (*)

Question 21

What is a frameshift mutation?

Answer 21

Misreading of codons until a stop is reached

Question 22

What is a nonsense mutation?

Answer 22

Causes a premature stop codon

Question 23

What is a silent mutation?

Answer 23

No change in the amino acid

Question 24

What is a missense mutation?

Answer 24

Amino acid substitution

Question 25

What is a conservative substitution/mutation?

Answer 25

Substituting an AA with one of similar properties (charge, hydrophobicity, size)

Question 26

What is a non-conservative substitution/mutation?

Answer 26

Substituting an AA with one with different properties

Question 27

What are the three classifications of short tandem repeats based on size?

Answer 27

* Satellite DNA arrays * Minisatellite DNA arrays * Microsatellite DNA arrays ## Footnote Satellite DNA is often found at centromeres, minisatellite DNA at telomeres, and microsatellite DNA is usually less than 100bp and found throughout the genome.

Question 28

What causes variation in copy number of short tandem repeats?

Answer 28

Replication slippage ## Footnote Replication slippage refers to the misplacement of strands during DNA replication, leading to differences in length between individuals.

Question 29

How many times is the CAG segment normally repeated in a healthy gene compared to in Huntington's disease?

Answer 29

10 to 35 times in healthy individuals; 36 to more than 120 times in Huntington's disease ## Footnote This expansion of the CAG segment is linked to the pathology of Huntington's disease.

Question 30

What impact do altered regulatory elements have on gene expression?

Answer 30

They affect the amount of mRNA transcript produced ## Footnote Changes in regulatory elements can lead to increased or decreased transcription levels.

Question 31

What are the two types of mutations that alter the amount of gene product?

Answer 31

* Promoter mutations * Other regulatory mutations ## Footnote Promoter mutations can block transcription or create new binding sites that increase transcription.

Question 32

What types of mutations can alter the sequence of gene products?

Answer 32

* Nonsynonymous mutations * Synonymous (silent) substitutions * Frameshift mutations * Splice site mutations ## Footnote These mutations can lead to different protein sequences and functions.

Question 33

What are the two main effects of pathogenic variants on gene function?

Answer 33

* Final gene product is not produced or does not function like the wild-type product * Mutations can give rise to harmful gene products ## Footnote This can occur through mechanisms like null alleles or missense mutations affecting critical functional domains.

Question 34

What is haploinsufficiency?

Answer 34

The dosage of normal product from the wild-type allele is insufficient for complete function ## Footnote This condition can lead to a dominant phenotype despite only one mutated allele being present.

Question 35

How does a loss-of-function (LOF) allele lead to a dominant phenotype?

Answer 35

* Imprinted loci * Dosage-sensitive genes * Dominant negative effects ## Footnote LOF alleles can disrupt the normal function of the wild-type allele, leading to a dominant phenotype.

Question 36

What is a dominant negative effect?

Answer 36

A mutant protein antagonizes the wild-type protein produced from the wild-type allele ## Footnote This results in a reduced functional capacity of the resulting protein complexes.

Question 37

What clinical condition is associated with mutations in the COL1A1 gene?

Answer 37

Osteogenesis imperfecta ## Footnote Osteogenesis imperfecta is characterized by brittle bones and is caused by mutations affecting collagen production.

Question 38

What is the effect of a null allele in the COL1A1 gene on procollagen production?

Answer 38

Reduces the amount of procollagen by half ## Footnote This reduction can lead to mild osteogenesis imperfecta.

Question 39

What can a missense mutation in the COL1A1 gene lead to?

Answer 39

Severe osteogenesis imperfecta due to a strong dominant negative effect ## Footnote This disrupts the packing of collagen chains, rendering a significant portion of procollagen nonfunctional.

Question 40

What is the role of nonsense mediated decay in genetics?

Answer 40

It degrades mRNA transcripts that contain premature stop codons ## Footnote This process prevents the production of truncated proteins that could be harmful.

Question 41

What does the term 'gain-of-function' mean in genetics?

Answer 41

Mutations that increase the activity or function of a gene product ## Footnote Gain-of-function mutations can lead to phenotypes that differ from the wild type.