13 Mutations Flashcards
What is a mutation?
- A heritable alteration in a gene or chromosome
E.g. Change in sequence of nucleotides
What is exogenous DNA damage?
- Radiation
- Free radicals (uncharged molecule with unpaired valency electron)
- Chemicals
- Anti-cancer agents
All these can cause problems, and with a defective/error prone DNA repair, cause mutations!
What is endogenous DNA damage?
- DNA replication defects
- Transposable elements
All these can cause problems, and with a defective/error prone DNA repair, cause mutations!
What are transposable elements?
- Specific DNA sequences contained within DNA molecule
- Move as discrete unit to random sites
- Inseritionally inactive target gene
- Ubiquitous (found everywhere)
Why is it not a problem that 50% of our genome is made of transposable elements?
Because a lot of our DNA is non-coding
Small genes aren’t affected as much as less chance of it being interrupted
More chance with larger genes like BRCA1,2
What are the three types of mutation on a micro level?
- Deletion
- shorten, -1 frame shift, can affect stop codon being read - Insertion
- lengthen, +1 frame shift, can affect stop codon being read - Substitution
- missense - 1 nucleotide changes and changes AA coded
- nonsense - 1 nucleotide changes and results in premature stop codon
Mutations that occur within gene expression could start with a mutation of initial code in DNA, what affect would this have?
Wrong DNA, wrong mRNA, wrong polypeptide, wrong affects
Why would insertions and deletions disturb genetic code?
Genetic code is 3 letter and non-overlapping.
Would shift reading frame +1, -1
What are silent/neutral mutations?
Mutations that do not have an effect
What is a transition mutation? What is a transversion mutation?
- Change to same type of base e.g. Purine to purine
(A==>G) - Change to different type of base e.g purine to pyramidine (A/G==>C/T)
What affects could a mutation have in
i) a promoter sequence for transcription
ii) polyadenlyation
iii) splicing
i) activators may not bind so could cease transcription
ii) mutation of AAUAA (polyadenylation sequence), affect stability of RNA, affect amt of protein that is made
iii) mutation of donor site GU or acceptor site AG which would change the length of mature mRNA and hence proteins made. Could be degraded as non-functional
What affects could deletion, insertions of 3/6 bp have?
These do not form frameshift mutations as the same amino acids are still formed, just added/deleted one.
The effect they have depends hugely on the importance of the information the deleted/inserted AA has.
What are the 5 types of mutation on a macro level?
- Deletion
- Insertion
- Inversion - section flipped
- substitution
- Translocation - one piece on each chromosome swapped
What disease can be caused by translocation, and how?
Leukaemia - cancer of blood cells
End of q arm of chrom 9 now on 22
Chromosome 9 suffers no problems as hasn’t affected genes
22 - BCR and ABL genes now so close together that they form another gene (Gene fusion) - makes new protein - tyrosinekinase
Tyrosine kinase - plays key roles in growth, differentiation, metabolism, apoptosis
What is a germ line mutation?
Egg/sperm
Affect all cells in body
Passed on
What is a somatic mutation?
Body cell
Not passed onto offspring
Error in mitosis
Can be genetic (DNA replication error) or chromosomal
What is a spontaneous mutation?
- Autosomal dominant
- parent not affected then affected child must be from spontaneous mutation - Autosomal recessive
- v. Small chance that same mutation, both genes occurs
- spontaneous mutation commonly affect one gene producing a heterozygote. Two heterozygote = affected baby.
Briefly describe sickle cell mutation
Mutation in codon 7 (6th AA) glu==>val
Base substitution
Describe germ line and somatic mitochondrial mutations
- Germ line
- involve multiple organ systems (most pronounced in tissues requiring a lot of energy)
- muscle weakness, wasting, problems with movement etc - Somatic
- not inherited
- ltd ability to repair and so mutations build up
- cause cancer, age-related disorders - heart disease, Alzheimer’s, Parkinson’s
How does a cell end up with two copies of a chromosome? What effects does this have?
- Errors occur during metaphase when chromosomes line up on metaphase plate
- Duplicate chromosomes do not pair properly at metaphase plate, pair will not move properly to each pole during anaphase causing anaphase lag
- One cell has two copies of chromosome while other has none
- fatal to daughter cell lacking
- Increase in expression of extra chromosome genes in other cell. Its fate depends on what is being expressed e.g. Slow growth - extra copy may be fatal, fast growth - may lead to cancer
What are PGCs?
Primordial Germ Cells
Common origins of spermatozoa and oocytes
How do PGC’s turn into egg cells? What is this process called?
Oogenesis
PGC’s arrive at fetal female gonad
Differentiate into oogonia
1. Oogonium goes through mitosis and forms more oogonium (before birth) but after birth forms primary oocyte
2. Primary oocyte goes through meiosis I and pauses at prophase I
3. Monthly, 1 primary oocyte finishes meiosis I becoming a secondary oocyte (other one from oogonium becomes a polar body)
4. Release from ovary and fertilisation
5. Meiosis II produces one big egg cell and one small polar body which stays attached to egg cell
6. One daughter cell gets all of cytoplasm , containing all nutrients forming zygote
How do PGC’s form sperm cells? What is this process called?
Spermatogenesis
PGCs arrive in male gonad and remain there until puberty when spermatogenesis starts
1. Spermatogonium, mitosis, more spermatogonium. OR
Spermatogonium, mitosis, 1 spermatogonium, diploid primary spermatocyte
2. Meiosis I forms secondary spermatocyte
3. Meiosis II forms 4 spermatids
4. Maturation forms 4 mature sperm cells
Why is the mutation rate higher in male gametes?
5 times more like as more divisions than female germ line cells
What would happen if there was a mitotic chromosomal mutation in one of 2 cells at 2 cell stage of zygote?
Death/aborted
Teratogenesis (congenital malformation produced in embryo/foetus)
Cancer when born
What allows germ cell mutations to be inheritable?
- Not lethal to gamete
- Not impair gamete function
- Not be lethal at fertilisation
- Production of viable adult with normal reproductive capacity
What do recessive mutations cause?
Loss of function as both alleles (maternal and paternal) affected
If someone was a heterozygous carrier, the normal allele would compensate for the affected allele and therefore not show phenotype
What do dominant mutations cause?
Increased function (as normal gene cant “compensate”)
Often show structural abnormalities
What effect can mutations have on drug treatment?
No, reduced, side, allergic effects
What is a benign tumour?
Non cancerous mass of cells that grows slowly, doesn’t usually spread
What is a malignant tumour?
Mass of cells that are cancerous and grow out of control, invade nearby tissues and usually spreads
What does a successfully fertilised oocyte (zygote) cleave to form?
A morula
