Genomics sequence variation

Question 1

What is a mutation/variant?

Answer 1

A change in the genetic material

Question 2

What does a pathogenic mutation result in?

Answer 2

A pathogenic mutation (pathogenic variant) results in an alteration of the function of
the gene product and can cause a disease phenotype

Question 3

What are the different variants types?

Answer 3

– Single base substitutions (point mutations)
– Deletions
– Insertions

Question 4

What is synonymous base substitution?

Answer 4

It is also known as a silent mutation
-Nucleotide change –> w/o amino acid change: synonymous substitution

Question 5

What is a missense mutation?

Answer 5

-Replacement of a single nucleotide
-Results in an incorrect amino acid, which may produce a malfunctioning protein

Question 6

What is a nonsense mutation?

Answer 6

-Replacement of a single nucleotide
-Results in incorrect sequence which causes shortening of protein

Question 7

What can insertion/deletions of genomic sequences alter and lead to?

Answer 7

Can alter the subsequent reading frame, may lead to loss/gain of amino acids

Question 8

What are the 2 types of insertion and what can this produce?

Answer 8

-the 2 types are in-frame(multiple of three) or frameshift (not multiple of three)
-Insertion of a single nucleotide
–This results in incorrect amino acid sequence, which may produce a malfunctioning protein

Question 9

What are the 2 types of deletion and what can this produce?

Answer 9

-the 2 types ar in frame(multiple of three) or frameshift (not multiple of three)
-Deletion of a single nucleotide
–This results in incorrect amino acid sequence, which may produce a malfunctioning protein

Question 10

What is open reading frame?

Answer 10

Same nucleotide sequence can be used differently

Question 11

What are the functional effects of variants in terms of loss of function?

Answer 11

-Loss of function
* Reduced activity/decrease stability = hypomorph
* Complete loss of gene product = null allele/amorph

Question 12

What are the functional effects of variants in terms of gain of function?

Answer 12

• Increased levels of gene expression
• New function for protein product

Question 13

What are the functional effects of variants in terms of dominant negative?

Answer 13

Mutant allele produces gene product that interferes with correct role

Question 14

What is an example of a dominant loss of function?

Answer 14

MonoMac syndrome (lack of GATA2 leads to monocyte and B cell deficiencies)

Question 15

What happens in a gain of function due to genetic sequence variation?

Answer 15

Mutant allele produces a mutant protein which is damaging to individual
(upregulated or different role)

Question 16

What is an example of a gain of function from genetic sequence variation?

Answer 16

Achondroplasia (gain of function mutation in FGFR3 leads to decreased bone
mass by altered regulation of osteoblast/clast activity)

Question 17

What is a dominant negative mutation?

Answer 17

Protein produced by mutant allele interferes with role of wildtype allele

Question 18

What does a mutation in transcription factor in dominant negative mutation result in?

Answer 18

Mutation in transcription factor removes activation domain but still contains DNA
binding domain therefore binds to DNA as it should but can’t trigger transcription;
blocks wild type from binding

Question 19

What does a mutation in protein that is functional as a dimer in a dominant negative mutation result in?

Answer 19

Mutation in protein that is functional as a dimer; lacks functional domain but keeps
dimerization domain; forms dimer with wildtype protein but resulting dimer is non-
functional (example sodium channels)

Question 20

What would a mutation that produces a hypomorph/amorph(LOF) but has one healthy allele that produces sufficient protein presented as?

Answer 20

If a mutation produces a hypomorph/amorph (LOF) but having one healthy allele
produces sufficient protein for the individual to be healthy, then this would present
in a family as a recessive disease (i.e. heterozygotes are healthy carriers,
homozygotes are affected)

Question 21

What would a mutation in an individual with only one health allele present as?

Answer 21

But if someone with just one healthy allele is affected then this is
haploinsufficiency/gain of function/dominant negative and this would present in a
family as a dominant disease (i.e. heterozygotes are affected)

Question 22

What is germline mutaiton?

Answer 22

Germline affects the gametes therefore can be inherited and passed down through
the generations