Biology 3594A Lecture Notes - Lecture 13: Somatic Hypermutation, Genetic Load, Deprogramming
13 May 2018
School
Department
Course
Professor
Know the agents and what they do –matching and MC
Constitutional: Patients had too many CNVs in all of their cells –not a mosaicism (in some tissues but not others)
Homeology –a few nucleotides, nothing about their common ancestry. They are similar enough in sequence that low processivity of replication, they can get used as a
template when they shouldn’t
Replication stress low processivity –tend to have a mechanism that will generate more gains and duplications than deletions
Losses are more detrimental than gains –why we might tend to see more gains
Selective pressure –not fit to have copy number state of 0, might be more problems with downregulation vs upregulation of the gene
Where is the sister homolog and where are these microhomeologies that could cause chromosomal rearrangements?
Constitutive CNVs, has to be developmental
Where there were MHs that were both maternal –happened during the making of the egg oogenesis
Pat pat –evidence that they didn’t need a maternal copy, during spermatogenesis
If both maternal and paternal implicates early zygotic –in first few cleavages of cell post-zygotically
Perizygotic –a little bit before, a little bit after
MHs tell you about the mechanism, the chromosomes around at the time when it occurred (mediators of the mechanism?)
Constitutive means that it stopped somehow too, otherwise it would be more specific to certain tissues
One-off –can happen in a cell as its dividing
You’ll see chromosomal instabilities in some tumours, but these two can’t explain what we’re looking at right now
But relevant and affect cancer and neurogenerative disease
Broken and knitted back together, poorly
Can happen as a single event (transient part) and affects one or a few chromosomes, not all of them (doesn’t fit our model)
Can get disease in an instant, event happens within a replication of the DNA of that cell
Doesn’t fit our 5 people because they had 4 or more events spread out over the genome
Mechanism is very contained because only one chromosome here
Occurs in a point of time where replication was happening, low processivity
Low processivity –performing the function and not, pause. Adducts, damage, stress are reasons why you get low processivity. Cancer –rate of replication is stressful
Cancer and embryology are replication dependent, and can be chaotic and stressful
Synthesis part of word –reconstitution. Lots of chromosome breaks and stalling (Low processivity), synthesis needs to knit it back together again, but with a lot of
errors
Doesn’t fit our story – patterns don’t work..?
Fig 3 legend is important!
Proposed model for mdnCNVs in the 5 patients –explain constitutive nature, gains, perizygotic
Oogonium, events bring in CNVs maybe
Primary oocyte (more maternal than paternal events) (or spermatogenesis) and just as starting zygote divisions
Proposed a driver mutation happens to start a mutator phenotype
Driver mutation is blue, creates a product that is red
First polar body takes away driver mutation –something happens to make a factor that has a lifespan around development
First polar body is an example of how you can exclude the driver mutation from the cell
In a cell for a period of time then excluded from the cell –perizygotic
Epigenetics of pat and mat genomes have deprogramming and reprogramming at diff times –could be a way a gene is expressed for a certain period of time and then
stop
Bottom graph: blue is mutant DNA –goes away when polar body is excluded
CNVs increasing when the factor is around and during all the cell divisions that occur, constitutive level that continues
Red is the mutant RNA that particular factor –mRNA and protein has half-life and then goes away
Mutagenesis isn’t always predictable – need to look at outliers
When they have a phenomenon then it becomes important
Look at areas with a lot of aggregate mutations, mutation burden
Might find genes that drive cancer -> figure out how disease progresses
If we know the tumours better in terms of mutation load, we can….
Classify tumours better based on this hypermutation, design genetic tests, screen tumours, and maybe fine therapies
Strategy: sequence a lot to find out stuff
Lec 13 Mutator Model and Hypermutation
May 13, 2018
2:43 PM
3594 Page 1
Document Summary
Know the agents and what they do matching and mc. Constitutional: patients had too many cnvs in all of their cells not a mosaicism (in some tissues but not others) Homeology a few nucleotides, nothing about their common ancestry. They are similar enough in sequence that low processivity of replication, they can get used as a template when they shouldn"t. Replication stress low processivity tend to have a mechanism that will generate more gains and duplications than deletions. Losses are more detrimental than gains why we might tend to see more gains. Selective pressure not fit to have copy number state of 0, might be more problems with downregulation vs upregulation of the gene. Where there were mhs that were both maternal happened during the making of the egg oogenesis. Pat pat evidence that they didn"t need a maternal copy, during spermatogenesis. If both maternal and paternal implicates early zygotic in first few cleavages of cell post-zygotically.
