From whole chromosomes to single bases Flashcards
Revision (37 cards)
How is a chromosome recognised?
Banding pattern with specific stains
Length
Position of centromere
Acrocentric chromosomes
Most chromosomes have a telomere at both ends of the chromosome, a short arm, a long arm and a centromere.
The short arm doesn’t really matter
Some chromosomes only have a long arm these are celled acrocentric chromosomes e.g. satellite ribosomal genes, tRNAs etc. Therefore they only have a centromere and long arm.
What are some chromosome changes that cause disease?
Balanced chromosome rearrangement is where all the chromosomal material is present.
Unbalanced chromosome rearrangement is where there is extra or missing chromosomal material. Usually 1 or 3 copies of some of the genome.
(Having 1 or 3 copies of a part of your genome is developmentally bad news).
what is the definition of Robertsonian Translocation?
This is where two acrocentric chromosomes are stuck end to end.
There is an increased risk of trisomy in a pregnancy.
If the father is considered normal and the mother has balanced robertsonian translocation chromosomes there are 4 possible outcomes,
Normal
Balanced Translocation
Trisomy 14 (Miscarriage)
Trisomy 21 (Down Syndrome)
What does Trisomy 18 result in?
Edwards Syndrome.
It’s rarer than down syndrome and is a fatal condition and so all with the condition either miscarry or normally die within the first month of life.
Why is X chromosome aneuploidy is better tolerated?
Because of X chromosome inactivation.
45X Turner syndrome
47XXX Triple X
47XXY Klinefelter syndrome
Why is having a big translocation possibly better than having a small translocation?
If an embryo has a big translocation causing a big imbalance, it will most likely miscarry.
If an embryo has a small translocation, there is a greater chance of the embryo surviving but resulting in a child with a developmental abnormality.
If the mother is considered normal and the father has reciprocal translocations in his chromosomes, what are possible outcomes for offspring?
Normal
Balanced 1:9 Translocation
Partial Trisomy 9 + Monosomy 1
Partial Trisomy 1 + Monosomy 9
What are the reproductive risks for someone with Reciprocal Translocations?
For most translocations estimated 50% of concepts will either have normal chromosomes or the balanced translocation.
Unbalanced products result in
- miscarriage (large segments)
- dysmorphic delayed child (small segments)
If the translocation is smaller than 5 million bases, It’s too small to see what is this called?
This is microdeletion
Molecular Cytogenetics
You no longer need to see chromosomes to count them - molecular techniques are quicker, cheaper and more sensitive.
You will only detect imbalance.
You can detect tiny changes.
Some small changes are polymorphisms.
What is Array CGH (aCGH)?
Now the first line chromosome test
It is genome wide
It also finds lots of polymorphisms
Technique is “DNA based” - reflects underlying chromosomes.
In aCGH - if there is half as much DNA present it indicates a deletion.
aCGH can detect any size of imbalance.
aCGH does not detect balanced rearrangements.
What is Mosaicism?
Different cells have a different genetic constitution.
This could be a mosaic chromosome abnormality or mosaicism for a point mutation.
What is Somatic Mosaicism?
(Everyone starts off as one cell which then proliferates and the cells differentiate. if one cell develops a mutation, it will then pass it onto it’s daughter cells and so on causing somatic mosaicism).
All cells suffer mutations as they divide
- At meiosis and at mitosis
- Approx. 10 to the power of -6 per gene per cell division.
However, repair mechanisms exist.
Chromosome changes could cause what?
Chromosome changes could
- Activate an oncogene (a cell becomes cancerous)
- Delete a tumour suppressor (a tumour suppressor stops a cancerous cell dividing so by deleting it this would cause cancer).
What is Philadelphia chromosome?
This is where chromosomes 9 and 22 translocate.
How do Chromosome changes indicate treatment in cancer?
HER2 amplification:
Monoclonal antibody: Trastuzamab
Philadelphia Chromosome:
Tyrosine Kinase inhibitor: Imatinib
How else do we analyse DNA?
aCGH - for deletions/ duplications (Chromosome/ Karyotype analysis for balanced rearrangements only)
Polymerase chain reaction (PCR) and Sanger sequencing or Next Generation Sequencing (NGS).
How is Next Generation Sequencing carried out?
- extracted gDNA
- gDNA is fragmented into a library of small segments that are each sequenced I parallel.
- Individual sequence reads are reassembled by aligning to a reference genome.
- The whole-genome sequence is derived from the consensus of aligned reads.
Alignment of multiple short reads shows that there is a different base in half the reads. This is because half the reads come from a variant allele which contains either a polymorphism or a disease causing mutation.
You can look at a person’s entire genome which costs about £1000 ($1000 genome).
The way to identify mutations is to line them up with the reference strand.
(NGS machines, are large, boring and need VERY big computers).
What is the final technique that can be used to look at the genome?
The sock technique.
What is the definition of Aneuploidy?
Whole extra or missing chromosome.
What is the definition of translocation?
Rearrangement of chromosomes.
What is the definition of insertions and deletions?
This is where there is missing or duplicated material.
What is the definition of microdeletions?
Microdeletions are chromosomal deletions that are too small to be detected by a microscope.
