Genetics 2 Flashcards
Describe dominant autosomal disorders with example
single gene disease multiple egenerations affected child of affected person = 1/2 chance m+f equally likely to be effecting vertical degree pattern gain of function-gene makes protein with a new function
huntingtons- proteins aggregate
Describe autosomal recessive disorders with example
two copies of non working gene loss of function mutations- sibling of affected child has 1/4 chance of being affected m+f equally effected horizontal pedigree pattern
cystic fibrosis- chloride channel is defective
Why in brittle bones does a mutation in collagen affect skeletal abnormalities
Skeleton initially laid down ad collagen, is mineralised later
if collagen is defective then bones are
Describe X linked recessive and dominant disorders
RECESSIVE- mainly affects males
brothers of affected son have 1/2 risk, sisters 1/2 risk of being a carrier
affected father= all sons will be healthy, all daughters carriers
carrier mother= 1/2 carrier daughter, 1/2 affected son
e.g haemophilia
DOMINANT-
affected father= all daughters and non sons affected
Affected mother= 1/2 chance son or daughter
Describe Y linked disorders
only males affected
all sons of affected father
vertical degree mater
Describe mitochondria disorders and the variability in them
Have their own DNA and all mitochondria maternally inherited
all children of affected woman are affected
variability as mitochondria replicate via binary fission so can lose or gain mutated genes due to random segregation , will only express the disease phenotype if over a threshold. can change with time and develop with age
In brittle bones what protein changes and how does this affect electrophoresis
From glycine to cysteine. Cysteine can from disulphide bridges to link chains together, 2-mercaptoethanol breaks these.
Glycine is more negative than cysteine so in electrophoresis one of the chains will move less than normal collagen chains.
How does the protein change in brittle bones change the assembly of type 1 collagen
glycine changes to cysteine, and cysteine can’t fit so fibrils will be affected.
even if only half colA1 protein is mutated all fibrils will be affected when they are packed together
If the patients are genetically identical what is the likely cause of variance in phenotype?
environment
Prenatal diagnostic tests for brittle bones/ osteogenesis imperfect
Sample from foetus: amniocentesis, chronic villus sampling
RFLP- mutation makes or breaks restriction site, gel electrophoresis
or
PCR- amplify, gel then probe for mutation
If the patients are related but NOT genetically identical what is the likely cause of variance?
Effect of other genes which interact with the disease
could be environment
If the patients are unrelated but the same mutation what is the likely cause of variance?
unstable mutations- change with time/age
different mutations in the same gene
What do the dark and light bands of karyotyped chromosomes mean
Bands have different staining, dark (heterochromatin) are more compact and have fewer genes, light 9euchromatin) are more open and have more genes
Describe basic nomenclature
p= short arm q=long arm del- deletion der- derivative (extra material dup ins \+/- BEFORE chromosome number is gain or loss of whole chromosome \+/- AFTER chromosome number is gain/loss of part of chromosome
normally put total number of chromosomes then where the gain or loss is
What is aneuploidy and how does it happen
Abnormal number of chromosomes: non disjunction
In normal meiosis the aim is to reduce from diploid 2n=46 to haploid n=23, allows genetic variation through random assortment and recombination
Non disjunction results in an uneven number of chromosomes In daughter cells if in Meiosis I all daughter cells affected, if meiosis 2 then half but it still results in a trisomy and monosomy
Why is sex chromosome aneuploidy tolerated
there is X inactivation of excess X chromosomes, only one is active
low gene content of Y chromosome
both X and Y have PAR (pseudo autosomal region) - regions of a chromosome that remain active even after inactivation
Where does trisomy 21 arise and what are the risk factors
in maternal non disjunction- the risk of this increases with age because the oocyte remains in meiosis 1 for a long time and the factors which hold chromatids together are degraded
Primary spermatocytes undergo many divisions per year and can accumulate defects.
paternal age doesn’t affect, only for some single gene disorders that enhance sperm viability
Paternal smoking is a risk factor
What is crossing over, when does it occur and how an it go wrong/lead to aneuploidy
In prophase 1, increases genetic diversity
pair of chromosomes aligns, chiasma forms and crossover occurs
If the chromosomes misalign then they can cross over wrongly leading to del - deletion of a gene in some and dup- duplication of a DNA region in others
What is chromosome inversion and what are the types
Paracentric - far from centromere
Pericentric- around centromere
people often unaffected, happens when the DNA that breaks off gets inverted
What is translocation and insertion
involve non homologous chromosomes
In an insertion, DNA from one chromosome is moved to a non-homologous chromosome in a unidirectional manner. In a translocation, the transfer of chromosomal segments is bidirectional and reciprocal – a reciprocal translocation.
What is Williams syndrome, what is the phenotype and how can it be detected
A deletion from one chromosome, will have short upturned nose, long philtre, arched eyebrows, friendly+ social cocktail party personality
7q11.23del
FISH (fluorescent thing) will detect a lack of elastin on effected chromosome
if its a 7q11.23 duplication then will be the opposite- delayed speech, autistic behaviours, flat eyebrows, broad nose
What are the three classes of chromosomes
Metacentric- has a short arm (p) and a long arm (q)
Submetacentric- short arm becomes shorter
Acrocentric- short arm replaced with a stalk and small bit of DNA
What is Robertsonian translocation
between Afrocentric chromosomes, homologous or non homologous
most show no effects but problems in offspring
13+14, 14+15, 14+21
What is mosaicism
Presence of two or more populations of cells with different genotypes
X inactivation leads to mosaic expression
Mosaicism can arise via: non disjunction or loss of extra chromosome: causes milder phenotype and some aneuploidy can survive if mosaic
What is the mendelian trait
controlled by a single gene, phenotype follows dominant e.g. ABO blood group
What is a complex trait
Controlled by multiple genes and the effect of the environment e.g height, weight, skin, eye colour
What are some examples of Complex and mendelian diseases
mendelian- cystic fibrosis, sickle cell anaemia
complex- diabetes, cardiovascular disease, asthma, mental health diseases
What are SNPs, how can they be used and why are they useful
Single Nucleotide Polymorphisms
they are DNA sequence variations that occur when a single nucleotide is changed, the single nucleotide polymorphism frequency between control groups ad ones with disease are found, if one is more frequent its likely to be a susceptibility gene
They are useful for public health, can target those who have susceptibility genes- high risk groups and have preventative strategies from the beginning which will save resources in the long term.
What is missing heritability and what could be the reason for it
genetic variants in Genome-Wide Association Studies (GWAS) cannot completely explain the heritability of complex traits. Traditionally, the heritability of a phenotype is measured through familial studies using twins, siblings and other close relatives, making assumptions on the genetic similarities between them. When this heritability is compared to the one obtained through GWAS for the same traits, a substantial gap between both measurements arise with genome wide studies reporting significantly smaller values.
could be due to :
rare variants of small effect, low frequency variants with intermediate effects, interactions between susceptibility genes, miscalculation of heritability
What is pharmacogenetics and why is personalised medicine a thing
The study of variability in drug response due to genetic difference, it may have no effect on some and a severe effect on others
The action of the drug is the same bu the response and how its metabolised is genetic
aims for increased efficacy and decreased adverse side effects
personalised medicine aims to treat patients depending on specific characteristic of their disease
What prenatal scans are there and why are they useful
Nuchal scan- 10-14 weeks gestation- dates pregnancy, diagnoses multiple pregnancy, major fatal abnormalities, early miscarriage or risk of Down syndrome and other chromosomal abnormalities by looking at maternal age, blood hormone levels, nuchal translucency thickness, blood flow through metal heart
Midtrimester anomoly scan
Ultrasound scans
What is nuchal translucency and what does it indicate
Thickness of fluid at back of neck higher than 3mm can indicate: 1) chromosomal abnormalities like downs 2) birth defects- cardiac anomalies, pulmonary defects, renal defects, abdominal wall defects 3) skeletal dysplasias
NT is a screening test and is not diagnostic
When is prenatal testing arranged and with what aim
Following abnormal nuchal or mid trimester scan
inc risk of downs
if previous pregnancy affected
if parents carrier of chromosome rearrangement or genetic condition
to inform and prepare parents, allow in utero treatment, manage remainder of pregnancy, prepared for complications after, allow termination of an affected foetus
What are some non invasive prenatal testing methods
Cell-free foetal DNA- analyses DNA fragments in maternal plasma, most of the DNA from the mother and 10-20% from foetus. Can test for aneuploidy T13, T18 and T21
Non Invasive Prenatal diagnosis methods:
achondroplasia, apert syndrome: test if runs in family
sexing if there is an X linked condition in condition - if male then test if female then no test
detect if maternal or paternal mutation has been inherited
What are the limitations and begets of non invasive pregnancy diagnosis and non invasive pregnancy testing
if have twins/multiple pregnancy its not possible to tell which fetus the NDA is from
proportion of cell-free foetal DNA is reduced in women with high BMI
Women must prepare themselves form the implications of an invasive test result and consider the consequences of the results- whether they want to know
however, non invasive testing reduces the amount of invasive testing
no increased risk of miscarriage
less expertise is required to perform a blood test than invasive
get a result much earlier as offered earlier
What are some invasive tests and when are they offered
offered if there is a known risk
Chronic villus sampling (from placenta)- 11-14 weeks, 1-2% chance of miscarriage, trans abdominal or transvaginal, samples of chorionic villi which is developing into placenta, faster result that amniocentesis
Amniocentesis (fluid from around baby)- 16 weeks, sample of amniotic fluid containing fetal cells, up to 1% risk of miscarriage, infection and rh sensitisation is a risk
With the DNA samples obtained from invasive tests, what tests are done
Test for genetic disorder worried about
karyotype if chromosomal abnormality in family
QF-PCR- looks for t13,18,21. quantitative fluorescence polymerase chain reaction. Small sections (markers) of DNA from the sample are amplified, labelled with fluorescent tags and the amounts measured by electrophoresis.
What test is offered if there are concerns on the 20 week scan
CGH array- looks for small/large imbalances in chromosomes like micro deletions and duplications
if something is found test the parents to see if they are a carrier
How is a CGH array done
DNA is extracted and labelled with different fluorescent dyes
Hybridised and washed
Scanned to detect red and green signals
analyse data to see gains and losses in DNA
What is trio exome
Exome is the coding region of DNA, DNA is taken from foetus/baby and parents
Identifies causal mutations
its considered when the foetus in previous pregnancy had significant anomalies
What are the options for family planning where there is a known reproductive risk and explain these
Conceive naturally no testing
conceive naturally with prenatal testing
egg/sperm donors - not anonymous, licensed fertility centre is better
adoption: registration and checks (medical and criminal background checks), assessment and approval (home visits, panel review and see if suitable)
choose not to have children
pre implantation genetic diagnosis- uses IVF and additional step to test embryo before implantation
What is the process of pre implantation genetic diagnosis and embryo testing
Stimulation of ovaries - hyper stimulation of ovaries to remove lots of eggs
Egg collection
Insemination - single sperm injected into centre of egg, reduced amount of non-embryo DNA which could inc risk of single faulty gene conditions
Fertilisation
Embryo biopsy (take one cell)- once blastocyst
embryo testing
embryo transfer of non defected ones
pregnancy test
What is pre implantation genetic diagnosis used for and what is the eligibility criteria
Genetic disorders: translocation carriers, HD, DMD, CF
Nationally funded for three rounds
HFEA requires license
Female under age 39, BMI of 19-30, both don’t smoke, stable relationship and living together, no living unaffected children, risk of having a child with serious condition, female has appropriate hormone levels and will respond to treatment, no welfare concerns,
What is the role of a genetic counsellor
Arrange and explain CVS, amniocentesis, PGD and cell free foetal DNA
facilitate decision making - previous experience, family situation, religion, personal beliefs, balancing miscarriage risk with genetic risk, dealing with indecision and couples not agreeing
give results
see patients in clinic following diagnosis in utero
arrange termination if necessary
What is phenylketonuria, how is it treated and what happens if untreated
Lack of phenylalanine hydroxylate, build up the amount of phenylalanine as it can’t be converted into to tyrosine as don’t have enzyme.
substrate build up due to lack of enzyme
as it can’t be converted phenylketones are produced instead
if untreated: cognitive impairment, fairer skin, hair and eyes due to lack of melanin, recurrent vomiting, behavioural difficulties
treatments- low protein diet with tyrosine supplement
What is haemophilia
Blood clotting disorder, uncontrolled bleeding, internal bleeding into joints/brain
if untreated then fatal
treatment- VIII clotting factor from freeze dried plasma derived factor concentrates
When there is a protein mutation, what should pharmacological therapies be targeting to achieve
treating condition not symptoms
treatments not cures
normalise function of mutant protein
What is a pharmacological chaperone
Protein folding in the endoplasmic reticulum sometimes fails, if it fails the ER degrades the misfolding proteins. Chaperones cause small molecules to enter the cell and correct the misfolded proteins so they can be active and exported out to use instead of degraded - a quality control check. If the defective protein bypasses these check then will lack activity in lysosomes
How are chaperones used in Fabry disease
Fabry disease is a deficiency of alpha galactosidase A, globotriaosylceramide (glycoside0 builds uo instead. Mutations cause misfiling
MIGALASTAT is a small molecule chaperone and stabilises the enzyme into the correct shape
What are pharmacological modulators
Commonly used drugs, receptor agonists or antagonists and ion channel activators or blockers
e.g can inhibit Bcl-abl kinase inhibitors
(Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia)
How can a pharmacological modulator be used to help cystic fibrosis
They have a defective chloride channel due to CFTR gene and the mutation causes them not to open
IVACAFTOR binds to the chloride channel and allows it to open which activated it. IS mutation specific as have to have the inactive Cl- channels
How can combination therapy be useful for cystic fibrosis
Has a mutation which causes a missing amino acid and therefore the channel is misfiled and inactivated
combination chaperone and activator/modulator
chaperone to stop the misfolding of the channel in the first place and activator/modulator to impact existing ones
ORKAMBI does this
What drugs can be used for diseases caused by nonsense mutations which have a premature stop codon, give an example a disease this works on
the premature stop codon prevents protein production as its shortened
AMINOGLYCOSIDE antibiotics can bind to the ribosome and cause mistranslation - stop them responding to the stop codons so the protein isn’t shortened
Duchenne muscular dystrophy- has a premature stop codon
Becker muscular dystrophy- missing section
using a amino glycoside (ataluren) means that instead of Duchenne they will have Beckers which is much less severe
Why is gene therapy difficult to achieve
hard to achieve specificity for mutation, getting therapy to right placenta too its easier in vitro/ ex vivo than in vivo
How does ex vivo/ in vitro gene therapy work
patients cells are collected, therapeutic gene is put into inactivated virus, viruses mixed with patients stem cells and the fixed stem cells are re introduced
for example in mitochondrial inherited diseases there are two methods
pronuclear transfer - DNA is taken from fertilised egg and transferred to a donor egg which has normal mitochondria
maternal spindle transfer- chromosomes removed from unfertilised egg that has the mitochondrial mutation and put into donor egg without nucleus then fertilised
How can viruses be utilised in gene therapy
Can engineer to carry therapeutic gene
virus choice depends on target tissue
How is in vitro gene therapy used in severe combined immune-deficiency
Have no B or T cell mediated response
can be X linked or due to adenosine deaminase deficiency
Bone marrow transplant kill the patients and replace with a donors if X linked
If due to ADA then - strimvelis is made which allows an autologous transplant to happen if there are no donors. Two samples of bone marrow are take, one is used to make strimvelis which expands the CD34+ cells, they infect this with lentivirus which carries the adenosine deaminase gene. these cells are grown. the patient is then treated with busulfan to kill their hameatopoeitic stem cells and the new rein fused transformed cells are implanted
What are examples of in vivo therapy
Supplementation - if they lack a functional gene then can inject a virus carrying a working copy of the gene. injected locally to eye, spine,brain or systematically
Leber congenital amaurosis type 2- mutation in RPE65 causes progressive blindness as loses retinal cells, can have supplemental injection into back of eye with cells that express RPE65 so there may be some restoration of vision
What is gene silencing
For dominant diseases that have gain of function
can be used for recessive genes if has effects on other proteins
can be used for non genetic diseases
what are the two methods of gene silencing with examples
1) Antisense oligonucelotides- are short modified nucleic acids complementary to targets. DNA in the cell is converted to RNA then to mRNA which s made into protein, antisense oligonucleotides bind to mRNA and destroy it which blocks translation. Can also alter after splicing.
e. g. intoresen is used in transthyretin related hereditary amyloidosis which has a mutation in transthyretin, cleaves it and stops build up
e. g.2 eteplirsen is an antisense oligonucleotide that can cause the skipping of exon 51 by causing splicing
2) RNAi- (siRNA) dsRNA that is complimentary to target, modification prevents degradation and allows it to enter the cell. The pathway of RNA interference starts when Dicer cuts dsRNA into small interfering RNAs (siRNAs) that subsequently target homologous mRNAs for destruction RISC formation. the target mRNA Is then cleaved.
e. g lumasiran is used in primary hyperoxaluria type 1. has a mutation in AGT so gylcooxelate builds up and is broken down to oxalate not glycine which causes kidney damage. doesn’t replace the gene but stops the conversion
What is exon skipping and when is it used
In pre-RNA processing, oligonucleotides cause and exon to be skipped, skips the disease coding exon and allows to put RNA back into reading frames.
To be used it has to be in large proteins and the exon can’t be vital proteins
e.g. in duchess muscular dystrophy there’s a premature stop, in Becker there’s a missing exon so by exon skipping it improves
What is a possible gene silencing therapy
Possible CRISPR-cas
a bacterial system disables bacteriophages, recognises and cleaves foreign DNA. may have off targets
already used to alter genome of IVF embryos
What is cancer
derived from single cells that have acquired characteristics of continually dividing in an unrestrained manner and invading the surrounding tissues, also avoid apoptosis.
This is acquired through changes to the DNA to cancer genes
What causes cancer
Chemicals like smoking
Radiation ENVIRONMENTAL FACTOR
Viruses can introduce their own genes EXOGENOUS FACTOR
SUSCEPTIBILITY FACTOR GENETICS - hereditary more susceptible
What is the difference between a benign and a malignant tumour
Benign- mass of well differentiated cells that grow slowly DOESNT INVADE tissue or metastasise
Malignant- not self limited in its growth, escapes apoptosis, poorly differentiated, invade surrounding tissues and spread- metastasis
What do cancer cells look like
Large number of dividing cells Large nucleus that's variably shaped variation in size and shape Lost normal features of cell Disorganized poorly defined boundary
What are the different types of cancer
Carcinomas: most common - lung breast and colon, epithelial
Sarcomas- cancers from cells found in supporting tissues of the body: bone, cartilage, fat, connective tissue and muscle
Lymphomas: cancers from lymph nodes and tissues of body immune system
Leukaemias: cancers of immature blood cells, grow in bone marrow and tend to accumulate in bloodstream
Six hallmarks of cancer
self sufficiency in growth signals- activate H-Ras oncogene
evade apoptosis- produce IGF survival factors
insensitivity to anti-growth signals- lose Rb suppressor
sustained angiogenesis- produce VEGF inducer
limitless replicative potential- telomerase tuned on
tissue invasion and metastasis - inactivate E-cadherin
What increases the risk of developing cancer
Correlated with how often stem cells in that tissue divide
Difference between germ-line and somatic mutations
Germline mutations are in the egg or sperm, will affect all offspring and are heritable
Somatic mutations- Non gremlin tissues, non-inheritable and very common happens when mutations accumulate in somatic cells over many years
What are the different types of mutations as well as genetic mutations
Single base substitutions- point mutations, missence
Deletions/insertions
duplications
inversions
translocations : reciprocal (both in the non homologous pair have parts switched), non reciprocal (only one has been given a segment)
Chromosome instability- higher rate of mis-segregation due to defective cell quality mechanism
Aneuploidy: loss in DNA repair system, allows chromosomal rearrangements
Overview of how cancers develop and how its multistep
Starts with an irreversible genetic alteration, can be inherited-germline mutation or as a Somali mutation, there is hyper proliferation due to defect in tumour suppressor genes e.g. APC , then early adenoma, intermediate adenoma, late adenoma, carcinoma and metastasis. It develops as they acquire additional mutations involving DNA repair genes like RB, K-ras and p53
What somatic mutation does UV light cause
crosslink adjacent pyrimidine bases like CC, CT, TC and TT to become dimers via covalent bonds. C to T is most common in UV light, if these DNA changes occur in critical genes like BRAF kinase then initiation begins
The light initiates a reaction between two molecules of thymine, one of the bases that make up DNA. The resulting thymine dimer is very stable, but repair of this kind of DNA damage–usually by excising or removing the two bases and filling in the gaps with new nucleotides–is fairly efficient. Even so, it breaks down when the damage is extensive. longer the exposure to UV light, the more thymine dimers are formed in the DNA and the greater the risk of an incorrect repair or a “missed” dimer. If cellular processes are disrupted because of an incorrect repair or remaining damage, the cell cannot carry out its normal functions. At this point, there are two possibilities, depending on the extent and location of the damage. If the damage is not too extensive, cancerous or precancerous cells are created from healthy cells. If it is widespread, the cell will die.
What distinct somatic mutation does smoking have
Changes G to T
What is a passenger mutation and a driver mutation
Passenger mutation- many mutations that are tolerated by somatic cells - often heterozygous state. don’t affect the fitness of clones no advantage bu associated with clonal expansion as they occur in the same cells that might have the driver mutation
Driver mutation- few mutations that can confer a selective advantage and are recurrently found -in a homozygous state. cause clonal expansions
Cancer is the continuous acquisition of genetic variation by random mutation, natural selection may eliminate cells that have acquired mutation or choose cells with mutations that might be able to survive and grow better-chooses the driver mutation
Driver mutations have a growth advantage- positively selected
oncogenes- cancer genes where driver mutations are activating or resulting in new functions
tumour supressors- cancer genes where mutations are inactivating their functions
candidate driver- cells with mutations of the gene more likely to become cancerous, has a greater impact on protein mutation that passenger
What are oncogenes
Genes that have the ability to cause cancer, begin as proto-oncogenes which are to prevent cancer and regulate cell proliferation but acquire a mutation. The mutation will activate oncogenes by chromosomal rearrangements,, gene amplification through MyC and mutation through Ras. Will usually be dominant and a gain of function mutation, will escape apoptosis and proliferate
ONE MUTATION IS ENOUGH TO CAUSE CANCER
What is an example of an acquired mutation in an oncogene
Chronic myeloid leukaemia
The BCR protein has serine threonine kinase activity. The ABL protein has many roles in the cellular pathway, it acts as an inactivating switch for tyrosine kinase. When translocation occurs within chromosomes 9 and 22 and create the Philadelphia gene, the tyrosine kinase activity is switched on indefinitely and will phosphorylase the Ras protein. Ras controls cellular signalling for many pathways like cell growth, adhesion, migration. Ras controls cell proliferation by being switched on/off when mutated it’s switched on and proliferates in an uncontrollable manner.
What is the activity of Ras governed by and mutation in the P12 gene causes what
When Ras is bound to GDP it is inactive, GEF catalyses the release of GDP, due to nucleotide exchange Ras has a higher affinity for GTP so will bind. This will switch on signalling pathways. The GAP protein will hydrolyse GTP and cause Ras to be inactive again
Mutation causes a switch to guanine or cysteine which makes the GDP domain of Ras insensitive and switches it on causing cell proliferation
What rare mutations in oncogenes can be inherited and what can it lead to
Mutation in KIT leads to GI stromal tumour
RET- thyroid cancer
CDK4-malignant melanoma
MET- papillary renal cancer
What are tumour suppressor genes and some examples
A gene that regulates the cell cycle during division. Mutation in tumour suppressors leads to a loss of function. One mutation makes them a susceptible carrier but a if ,mutations are accumulated it leads to the activation of oncogenes and cancer.
The function of tumour suppressor genes is to stop division if there is DNA damage and control apoptosis
For example the BRAC1 gene is needed as a cell checkpoint and DNA repair, if acquire a mutation it’s more likely that other tumour suppressor cells will be mutated too
What is retinoblastoma and the two hit hypothesis
Rb is a tumour suppressor and blocks the effect of the E2F family by binding to it and stops cells entering S phase of the cell cycle until it has passed all checks needed to move out of G1
When the cell passes these checks and is ready to bind Rb is phosphorylated by cyclin dependent kinase to become inactivated and release the E2F family
Rb belongs to the protein pocket family as E2F can bind
The two hit model suggests that bilateral inheritance of a Rb mutations means the onset of Rb cancer will be young and unavoidable, however unilateral inheritance is not enough to cause cancer and will need a second hit/mutation in the good gene to cause a cancer- this second one would be a somatic mutation
So chances for a hemline mutation carrier to get a somatic mutation is much greater than someone who doesn’t have a mutation in both to get two somatic mutations
What is p53 and how does it work
Tumour suppressor encoded by TP53
The function of p53 is to bind to DNA and regulate gene expression to prevent the accumulation of mutation- it can activate DNA repair, cause apoptosis, arrest growth and promote senescence if telomeres are shortened. P53 must be maintained at low levels as it is constantly ubiquinated by E3 kinases MDM2 and MDM4, and is only phosphorylated by ATM and ATR if damage is detected, causing it to detach from E3 ligands and function.
People who inherit one copy of p53 gene will most likely get tumours in childhood : Li-Fraumeni syndrome
Can also occur due to damage to DNA by mutagens
Unstable because they can’t stop cell cycle to repair DNA, and can’t induce apoptosis
What are the roles of BRCA1 and BRCA2 in DNA repair
BRCA1 is phosphorylated by ATM and CHK2 when double stranded DNA damage is sensed, BRCA1 binds to BRCA2 which interacts with RAD51 to form a complex that will repair DNA
Mutation means that there is increase unrepaired DNA damage which may lead to deletion or insertion which makes truncated proteins
How can viruses cause cancer
DNA of virus mixes with cell DNA and triggers changes in the cells to make them multiply and interferes with normal cellular programming.
E7 is a small protein with no intrinsic enzyme activity, but evolved a few amino acids that can bind to Rb and promote its degradation which leads to cell proliferation.
