Genet 302 lec 10 & 11
What chromosome region is commonly deleted or duplicated in Dr. McDermid’s lab research?
22q11
What molecular mechanism commonly causes deletions/duplications at 22q11?
Non-allelic homologous recombination (NAHR) during meiosis.
What is non-allelic homologous recombination (NAHR)?
Recombination between similar DNA sequences at different locations, leading to unequal crossover → deletion in one chromosome and duplication in the other.
What is the genotype of DiGeorge syndrome?
46,XX,del(22)(q11q11)
or
46,XY,del(22)(q11q11)
Major phenotypes of DiGeorge syndrome?
Learning & behavioural problems
Characteristic facial features
Congenital heart defects
What is the genotype of Cat-eye syndrome?
46,XX,dup(22)(q11q11)
or
46,XY,dup(22)(q11q11)
Major phenotypes of Cat-eye syndrome?
Ocular coloboma
Heart defects
Other developmental features
Compared to deletions, how severe are duplications usually?
Phenotypes of duplications are generally milder than deletions.
What is a contiguous gene syndrome?
A disorder caused by deletion or duplication of multiple adjacent genes, producing a complex phenotype.
Why do contiguous gene syndromes produce complex phenotypes?
Because multiple genes are lost or gained simultaneously.
What example shows a known gene cause within a deletion?
Deletion of Xp21 removing:
DMD → muscular dystrophy
CYBB → chronic granulomatous disease
Why is this a contiguous gene syndrome?
: Because loss of adjacent genes produces multiple independent disorders in the same patient.
Why is it harder to identify the responsible gene(s) in 22q11 syndromes?
The region contains 30+ genes, making phenotype-gene mapping complex.
In Cat-eye syndrome, which gene is implicated in heart defects?
CECR2 (OMIM entry highlights CECR2).
Main causes of aneuploidy?
Non-disjunction in mitosis
Non-disjunction in meiosis I
Non-disjunction in meiosis II
Main causes of chromosome rearrangements?
Improper repair of two or more DNA breaks
Non-allelic homologous recombination (NAHR)
What is the key difference between single-gene disorders and contiguous gene syndromes?
Single-gene disorder → mutation in one gene
Contiguous gene syndrome → deletion/duplication of multiple adjacent genes
If two patients have deletions of slightly different sizes in the same region, why might their phenotypes differ?
Different genes may be included/excluded in the deletion.
Why can duplications sometimes have milder phenotypes than deletions?
Extra gene dosage is often less disruptive than complete loss of gene function.
What are the three major steps of mRNA processing?
Splicing (introns removed, exons ligated), export from nucleus, and translation in cytoplasm.
What happens during splicing?
Introns are cut out of pre-mRNA and exons are ligated together to form mature mRNA.
What marks exon/intron and intron/exon boundaries during transcription?
Splicing factors mark the boundaries during mRNA synthesis.
What is the spliceosome?
A large RNA-protein complex that cuts introns at splice sites and joins exons together.
What is the exon/intron junction called?
The splice donor site.
What is the intron/exon junction called?
The splice acceptor site.
What is the conserved sequence at the 5′ splice donor site?
GU at the start of the intron.
What is found at the 3′ splice acceptor site?
A conserved AG preceded by a polypyrimidine tract.
How is coding DNA numbering determined in humans?
Relative to the A of the ATG start codon.
What does a + number mean in splice site nomenclature (e.g., c.657+1)?
It indicates nucleotides into the intron.
What does a – number mean in splice site nomenclature?
It indicates nucleotides upstream into the exon.
Why are splice site mutations often severe?
Splice sites are highly conserved; mutation can prevent proper intron removal and disrupt mRNA.
What is an intron phase?
The position of the intron relative to the codon reading frame.
What is a phase 0 intron?
An intron located between codons.
What is a phase 1 intron?
An intron located after the first nucleotide of a codon.
What is a phase 2 intron?
An intron located after the second nucleotide of a codon.
Why are intron phases important?
They determine whether exon deletion preserves the reading frame.
Why is a frameshift deletion usually worse than an in-frame deletion?
Frameshift alters the reading frame and often creates a premature stop codon.
What is nonsense mediated decay (NMD)?
A quality-control mechanism that degrades mRNAs containing premature stop codons.
What mutations can trigger NMD?
Nonsense mutations and frameshift mutations that create premature stop codons.
Why can truncated proteins be dangerous?
They may retain active domains but lose regulatory domains, causing abnormal function.
When does NMD surveillance occur?
During the pioneer round of translation as mRNA exits the nucleus.
What are Exon Junction Complexes (EJCs)?
Protein complexes deposited at exon-exon junctions after splicing.
What happens to EJCs during normal translation?
They are displaced by the ribosome as it moves along the mRNA.
When is NMD triggered relative to EJCs?
If a stop codon occurs before the final EJC, remaining EJCs signal abnormal termination and trigger degradation.
How is defective mRNA degraded during NMD?
The 5′ cap and/or poly(A) tail are removed and the mRNA is degraded by nucleases.