13 - Mutations Flashcards
What is a mutation and what is mutagenesis?
Mutation - A change in the nucleotide sequence
Mutagenesis - Process of mutation generation
What is deanimation mutation?
Removal of an amino group from a molecule causing a change in base
What are some DNA level mutations and how do they occur?
- Exogenous sources (radiation, free radicals etc)
- Endogenous sources (transposable elements, replication defects)
- Spontaneously
Why does spontaneous deanimation always result in a mutation?
What are transposons?
- Sit within chromosome
- Greater length than one gene
- Can move as discrete unit and insert themselves into another location (transposition)
- Issue if inserted into genes as can cause non-functional polypeptide, inactive/activate gene
- Bigger the gene bigger the risk of transposition, e.g DMD
What is a SNiP?
Single nucleotide polymorphism
- Where one nucleotide is different to the rest of the population
- Anonymous SNP, coding SNP, non-coding SNP (not in gene)
What are micro mutations?
What are the two types of substitution?
Transition - Same base for same base
Transversion - Change to different base (pyramidine to purine)
What can a single nucleotide change result in?
- No effect
- Change polypeptide length
- Change amount of product
- Change gene product
What is the genetics behind sickle cell anaemia?
- Autosomal recessive
- Base substitution in codon 7 of HBB, changing 6th AA
What is a non-sense mutation?
Mutation causes a change in the stop codon so it is not recognised so polypeptide longer than should be
What is a missense mutation?
Mutation that results in a different amino acid being coded for
What is a synonymous mutation?
Substitution, same amino acid coded for. (could be due to wobble)
What is a frameshift mutation?
When there is a change in the number of nucleotides, not in the multiple of 3, so all the amino acids downstream are different
Why might a deletion of three bases not cause any affect, and why may it cause a drastic effect?
- No frameshift so only one amino acid missing
- If amino acid usually located in active site will cause non-functional protein but if not, not much difference to overall structure of protein
What is haemoglobin wayne and haemoglobin CS?
- Normal alpha Hb: 141 aa
- alpha wayne: 147 aa (deletion of A at 139 causing frameshift so stop codon not read)
- alpha cs: 172aa (substitution in 142 stop codon so not read)
NON-SENSE MUTATIONS
How could a mutation lead to a change in the amount of a gene product?
- Mutation in regulatory sequence
- Alter promoter activity
- Prevent mRNA splicing (splicing sites change)
- Reduce mRNA stability (mutations in tails and caps)
- Earlier start codon
What are haemoglobin lyon and leiden?
- Leiden: Loss of Glu at 6
- Lyon: Loss of Lys and Val at 17/18
What are the types of chromosome mutation?
- Translocation (reciprocal/robertsonian)
- Inversion (para/pericentric)
- Duplication
- Substitution
- Deletion
What are the two types of chromosome inversion?
Paracentric: on one side of the centromere, within one arm
Pericentric: inversion occurs over the centromere
What happens during chromosome substitution (insertion)?
One part of a chromosome is moved from one chromosome to another
What are the two types of protein translocation?
Reciprocal: Swapping of genetic material
Robertsonian: Breaking at the centromere on two acrocentric chromosomes. Lose the p arms, two q-arms fuse. Individual has 45 chromosomes
Apart from the main chromosome mutations, what are three other structural mutations that can occur?
- Ring chromosomes (end break and fuse to ring)
- Isochromosomes (two p together, abnormal centromere split)
- Marker chromosomes (small fragements of chromosomes)
What is polyploidy?
- more than two sets of homologous chromosomes (3n=69)
- usually due to polyspermy
- triploidy occurs in 2-3% of pregnancies and causes 15% of miscarriages
What is aneuploidy?
- Abnormal number of chromosomes
- Due to non-disjunction in meiosis
- Not always lethal like polyploidy
- Doesn’t involve more than two sets of homologous chromosomes
What are some examples of monosomy and trisomy?
Mono:
_-_Turners Syndrome 45,X
Tri:
- Down Syndrome 47,+21
- Patau 47,+13
- Edwards 47,+18
- Klinefelter Syndrome 47,XXY
Does chromosome non-disjunction only occur in some chromosomes?
No, all of them. Only some are visible as they are the only ones viable for life, rest can’t live
What is Turner’s syndrome?
- Lack of X chromosome
- Only affects female
- Only known monosomy
What is Patau syndrome?
- Trisomy 13
- Mostly miscarry/still birth. 90% die in first year
What is Edward’s syndrome?
- Trisomy 18
- Life span: 5-15 days
- Maternal meiosis II error
What is Klinefelter syndrome?
- Trisomy XXY
- Male with two X’s
- Infertile
What is Down syndrome?
- Trisomy 21
- Early alzheimers, hypotonia, heart defects, facial features distinct, increased risk of leukemia
- Critical region: 21q22 (don’t have to have full chromosome duplication to have downs)
What is mosaicism?
- When chromosome non-disjunction occurs in mitosis. Results in two or more cell lines
- Occurs after first mitotic division and can save trisomy, reducing the number of cells in the body with trisomy
What are balanced and unbalance chromosomal abnormalities?
Balanced - No genetic information is lost or gained and the phenotype is normal
Unbalanced - Abnormal chromosome has led to abnormal phenotype
What is balanced translocation?
Reciprocal Translocation
- 2 chromosomes clean broken and material is swapped.
- Leads to issues in meiosis as quadrivalents are formed
- During meiosis balanced and unbalanced gametes can be produced depending on segregation
When can reciprocal translocation be an issue?
- Philadelphia Chromosome
- Fusion of BCR-ABL gene on chromosome 22, kinase signally gene constantly on so cell uncontrollably divides
- Associated with leukemia
What is the issue with balanced translocation?
- In meiosis a quadrivalent is formed rather than bivalent so different types of segregation
- 3:1 non-disjunction
- Alternate segregation
- (Non-homologous) Adjacent 1 segregation
- (Homologous) Adjacent 2 segregation
What are the consequences of different types of segregation when meiosis occurs with chromosomes that have undergone translocation?
If a couple with one being a carrier for reciprocal translocation, how would you work out the risk that they would have a child with an imbalance?
- Analyse couples genes to see which chromosomes have been affected by translocation
- Look up if anyone else has had the same translocation before and quote the risks
- Work out based on the knowledge known
What happens during meiosis with a person with a Robertsonian translocation and what happens to their offspring?
- Person has 45 chromosomes
- Trivalent formed at meiosis
- Leads to risk of aneuploidy
- Females with 45 at higher risk than males (oogenesis pauses in meiosis and trivalent very unstable)
Why can people appear phenotypically normal but be infertile or have abnormal children?
- They have balanced translocation which is not picked up on microarray
- Could have two 21’s fused so end up with trisomy and downs
- Infertile as odd number of chromosomes
What is cytogenetics and why is it carried out?
Study of the genetic make up of cells through visualisation and analysis of chromosomes
- Better clinical management (e.g hormones for XXY)
- Pre-natal diagnosis
- Accurate diagnosis (identify syndrome, account for pregnancy loss)
- Assess future reproductive risks (affected baby or risk of unalive birth)
How can cytogenetics be carried out?
- Karyotyping
- FISH
- Microarray hybridisation
- DNA sequencing
What are some referral reasons for cytogenetic testing?
- Delayed sexual development
- Pregnancy loss
- Prenatal diagnosis
- Birth defects
- Infertility
- Leukemia
- Tumours
- Prognostic info for specific translocations
What is a protooncogene and an oncogene?
Protooncogene - Gene that has the potential to become an oncogene if there are mutations
Oncogene - Gene that has the potential to cause cancer
Can a mutation in bases very upstream cause a change in the gene product?
Yes! Could affect a regulatory sequence that normally stimulates an effector to start transcription, therefore more or less gene expression
What is a gain of function mutation?
A mutation that leads to a new or enhanced function of a protein. Almost always dominant
What is nitrous acid and how is it formed?
- Sodium nitrate is a food additive in smoked meats
- When gets into stomach it reacts with HCl to form nitrous acid
- Nitrous acid is a mutagen which causes deanimation of C –> U
What is the relationship between sickle-cell trait and malaria?
- If you have sickle cell trait normally immune to malaria
- Malaria is caused by a parasite that normally replicates within red blood cells
- If red blood cells lysing then parasite killed before it can get to replicate
Can you test for Down Syndrome whilst a mother is pregnant?
Yes NIPT. Can take a blood test from the mother at 9-10 weeks as their blood will contain some fetal DNA, not all the fetal chromosomes but some
