What are three primary ways genetic variation can disrupt normal biological processes by affecting the gene product?
By changing the amino acid sequence, altering the amount of gene product, or affecting gene regulation.
What are the three main classes of pathogenic variants mentioned in the lecture?
Small-scale mutations, variation in tandem repeat copy number, and chromosome abnormalities.
A mutation that occurs at a splice-site affects which biological process?
RNA processing.
A _____ mutation is a substitution that results in the same amino acid being coded.
silent (synonymous)
What is the outcome of a missense mutation?
It results in a different amino acid being coded in the protein.
What type of substitution mutation introduces a premature stop codon?
A nonsense mutation.
What is the collective term for small insertions or deletions of nucleotides?
Indels.
Which type of mutation alters the reading frame of the genetic code, often leading to a completely different protein sequence downstream?
A frameshift mutation.
What is another name for a Premature Termination Codon (PTC)?
Premature Stop Codon.
Name three types of mutations that can introduce a Premature Termination Codon (PTC) into mRNA.
Nonsense mutations, insertions, and deletions (which can cause frameshift mutations).
What is the process called where mRNA containing a PTC is degraded, resulting in no protein production?
Nonsense-Mediated Decay (NMD).
Under what condition is an mRNA with a PTC likely to undergo Nonsense-Mediated Decay (NMD)?
If the PTC is located more than approximately 50–55 nucleotides upstream of the last exon-exon junction.
The degradation of mRNA via NMD often results in _____, a condition where a single functional copy of a gene is insufficient to produce a normal phenotype.
haploinsufficiency
NMD is considered what type of mutation effect in terms of protein function?
A loss of function mutation.
What is the likely outcome if a PTC occurs less than 55bp upstream of the last exon and escapes NMD?
A truncated protein is produced.
What is a ‘gain of function’ mutation in the context of a PTC that escapes NMD?
The resulting truncated protein acquires a new, potentially harmful, activity.
Splicing mutations disrupt the highly conserved 5’ _____ or 3’ _____ sequences at exon-intron boundaries.
GT (GU in RNA); AG
What are the two primary consequences of mutations in the conserved 5’ GT or 3’ AG splice sites?
Exon skipping or intron retention.
Mutations within an exon or intron that activate a new, illegitimate splice site are known as _____.
cryptic splice sites
A synonymous mutation [GC>GT] that activates a splice donor site within an exon can lead to what structural change in the final mRNA?
A truncated exon.
An intronic mutation [AC > AG] that activates a splice acceptor site can lead to what structural change in the final mRNA?
Partial intron inclusion, leading to an ‘extended’ exon.
What is the ‘Paternal Age Effect’ in genetics?
The increased risk of de novo point mutations in offspring associated with advancing paternal age.
Why do DNA replication errors accumulate in sperm DNA as a man ages?
Spermatogenesis begins at puberty and continues throughout life, with each cell division presenting a chance for errors.
What is the pathogenic mechanism of Short Tandem Repeat (STR) mutations?
The expansion of short tandem repeats beyond a pathogenic threshold.
