Chromosomal rearrangements Flashcards
How can Karyotyping be obtained ?
- “Karyotype” also refers to the actual collection of chromosomes being examined
- Can be obtained by staining of condensed chromosome with various agents that have different affinities of binding for DNA depending on sequence composition.
What are some different types of chromosomes ?
- Classification based on position of centromere relative to arm length
1. Metacentric
2. Submetacentric
3. Acrocentric
4. Telocentric
What are some different types of chromosomal rearrangements (deletion)?
- Duplication
- Inversion
- Translocation
What are the effects of chromosomal deletions ?
Will cause looping in meiosis in heterozygotes, and a similar effect is observed for duplications
When does Haploinsufficiency occur?
Haploinsufficiency can occur in hemizygosity
What is Hemizygosity ?
Hemizygosity is when a diploid organism has a single copy of a gene, a situation that can of course occur when chromosome deletions are present
What is Haploinsufficiency?
If the single copy of the remaining gene, even if normal, is insufficient to provide function
What can incorrect DSB repair lead to ?
Various types of chromosomal abberation, including deletions
What is Nonallelic homologous recombination?
The presence of homologous repeats can cause problems also if they are distantly spaced, with potential loss (or duplication) of the intervening sequence
Unequal crossing over results in ?
A recombinant with a duplication for the region and a recombinant with a deletion. The deletion will give rise to William’s Syndrome
What are some types of chromosomal duplications?
- Tandem duplication
- Displaced duplication
- Reverse duplication
- Displaced reverse duplication
Intra-chromosomal recombination in tandem duplications can lead to?
The excision of the duplicated segment
What are some types of chromosomal inversions?
- Paracentric inversion
- Pericentric inversion
Explain chromosomal inversions ?
- Although no DNA is lost in inversions, phenotypic effects can be observed
- For example, the inversion points can disrupt (or fuse) genes at those loci
- Or the genes within the inversion can have their expression altered by position effects
What are some types of chromosomal interactions?
- Reciprocal translocation
- Non-reciprocal translocation
- Robertsonian translocation
If the damage involves both strands then a double-strand break (DSB) can occur and this is then often repaired by ?
The non-homologous end-joining pathway (NHEJ) which only relies on the two free ends bring brought together
Alternatively, a more faithful homology-dependent pathway (HDR) which relies on? what does the require?
Recombination with intact DNA can be employed to repair DSBs. This requires the presence of a homologous chromosome, or of a sister chromatid
DSBs are a major cause of chromosomal rearrangements. These are normally DSBs which are caused by ?
DNA damage, in itself induced by agents such as ionising radiation or by reactive oxygen species and DNA replication (SSBs turned into DSBs)
When are Spo11-dependent DSBs generated and normally repaired by ?
Spo11-dependent DSBs are generated only during meiosis and are normally repaired correctly by HDR
Explain some alterations of the genome that could occur?
- Small scale changes (point mutations, replication fork slippage, indels, etc)
- Chromosomal rearrangements (duplications, deletions, translocations, inversions)
- Chromosome number variations (aneuploidy)
What is Chromothripsis?
Chromotripsis (the shattering of the chromosome followed by rejoining by NHEJ or replication-based mechanisms) can also occur in cancer cells
Because of the 3 bp periodicity of the code, small indels that are not multiples of 3 bp will lead to?
Frameshift mutations that change the code of the entire sequence downstream of the mutation itself
Because the code is redundant, and the third base often not discriminant, several point mutations are?
Synonymous (or silent) substitutions that do not lead to amino acid changes.
Nonsynonymous (or missense) substitutions instead lead to ?
AA changes (nonsense substitutions create new stop codons)
Nonsense and frameshift mutations lead to ?
Truncated proteins, or to degradation of the RNA by nonsense-mediated decay (NMD)
What do nonsense and frameshift mutations cause?
Both these mutation frequently give rise to premature termination codons, which can be dangerous and act as dominant negative alleles
What does the NMD pathway takes care of ?
Eliminating most of these transcripts
Explain the Pathogenic splicing mutations ?
- Mutations in dinucleotides required for splicing can result in exon skipping or intron retention
- Mutations can also lead to creation of new splice (cryptic) place sites, producing truncated or extended exons
Loss of function:
Amorph ?
Hypomorph ?
- Amorph (genetic null) = complete loss of gene function
- Hypomorph = reduced gene function
Gain of function:
Hypermorph ?
Neomorph ?
Antimorph ?
- Hypermorph = increased gene function
- Neomorph - new gene function
- Antimorph (dominant negative): dominant allele inhibiting function of wild-type gene
What has a stronger phenotype than null alleles (in heterozygote form) ?
Dominant negative alleles
What does a null mutation often imply ?
A null mutation often implies complete loss of the gene, but not always, as null alleles can result from nonsense or splicing mutations that cause early termination or partial deletions. Missense mutations can also give rise to null alleles
Explain a gain of function mutation ?
Gain of function mutations are rarer mutations. They typically do not produce radically new products but more often instead tend to make products that are expressed inappropriately (for example are constitutionally active, activated in the the wrong cell type, at the wrong time, or in response to the wrong signal)
What is a classical example of a gain of function ?
The reciprocal translocation seen in chronic myeloid leukaemia between chromosomes 9 and 22
Are nonsense and frameshift mutations easy to identify ?
Nonsense and frameshift mutations are relatively easy to identify as pathogenic. For missense mutations one can resort to conservation to evaluate the likelihood of the change being harmful
Why are changes in noncoding RNAs much harder to evaluate ?
Changes in noncoding RNAs are much are harder to evaluate, also because of poor conservation and the role of secondary structure in RNA function. Often changes in these RNA affect complex diseases such as cancer (by affecting gene expression), rather than single-gene disorders
