Genomics sequence variation Flashcards
What is a mutation/variant?
A change in the genetic material
What does a pathogenic mutation result in?
A pathogenic mutation (pathogenic variant) results in an alteration of the function of
the gene product and can cause a disease phenotype
What are the different variants types?
– Single base substitutions (point mutations)
– Deletions
– Insertions
What is synonymous base substitution?
It is also known as a silent mutation
-Nucleotide change –> w/o amino acid change: synonymous substitution
What is a missense mutation?
-Replacement of a single nucleotide
-Results in an incorrect amino acid, which may produce a malfunctioning protein
What is a nonsense mutation?
-Replacement of a single nucleotide
-Results in incorrect sequence which causes shortening of protein
What can insertion/deletions of genomic sequences alter and lead to?
Can alter the subsequent reading frame, may lead to loss/gain of amino acids
What are the 2 types of insertion and what can this produce?
-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
What are the 2 types of deletion and what can this produce?
-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
What is open reading frame?
Same nucleotide sequence can be used differently
What are the functional effects of variants in terms of loss of function?
-Loss of function
* Reduced activity/decrease stability = hypomorph
* Complete loss of gene product = null allele/amorph
What are the functional effects of variants in terms of gain of function?
- Increased levels of gene expression
- New function for protein product
What are the functional effects of variants in terms of dominant negative?
Mutant allele produces gene product that interferes with correct role
What is an example of a dominant loss of function?
MonoMac syndrome (lack of GATA2 leads to monocyte and B cell deficiencies)
What happens in a gain of function due to genetic sequence variation?
Mutant allele produces a mutant protein which is damaging to individual
(upregulated or different role)
What is an example of a gain of function from genetic sequence variation?
Achondroplasia (gain of function mutation in FGFR3 leads to decreased bone
mass by altered regulation of osteoblast/clast activity)
What is a dominant negative mutation?
Protein produced by mutant allele interferes with role of wildtype allele
What does a mutation in transcription factor in dominant negative mutation result in?
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
What does a mutation in protein that is functional as a dimer in a dominant negative mutation result in?
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)
What would a mutation that produces a hypomorph/amorph(LOF) but has one healthy allele that produces sufficient protein presented as?
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)
What would a mutation in an individual with only one health allele present as?
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)
What is germline mutaiton?
Germline affects the gametes therefore can be inherited and passed down through
the generations
