Genetics 2 Flashcards

Question

What is the mendelian trait

Answer 1

controlled by a single gene, phenotype follows dominant e.g. ABO blood group

Answer 2

Controlled by multiple genes and the effect of the environment e.g height, weight, skin, eye colour

Answer 3

mendelian- cystic fibrosis, sickle cell anaemia complex- diabetes, cardiovascular disease, asthma, mental health diseases

Answer 4

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.

Answer 5

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

Answer 6

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

Answer 7

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

Answer 8

``` 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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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.

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

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,

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

treating condition not symptoms treatments not cures normalise function of mutant protein

Answer 24

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

Answer 25

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

Answer 26

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)

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

hard to achieve specificity for mutation, getting therapy to right placenta too its easier in vitro/ ex vivo than in vivo

Answer 31

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

Answer 32

Can engineer to carry therapeutic gene | virus choice depends on target tissue

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

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

Answer 40

Chemicals like smoking Radiation ENVIRONMENTAL FACTOR Viruses can introduce their own genes EXOGENOUS FACTOR SUSCEPTIBILITY FACTOR GENETICS - hereditary more susceptible

Answer 41

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

Answer 42

``` 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 ```

Answer 43

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

Answer 44

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

Answer 45

Correlated with how often stem cells in that tissue divide

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

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.

Answer 50

Changes G to T

Answer 51

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

Answer 52

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

Answer 53

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.

Answer 54

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

Answer 55

Mutation in KIT leads to GI stromal tumour RET- thyroid cancer CDK4-malignant melanoma MET- papillary renal cancer

Answer 56

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

Answer 57

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

Answer 58

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

Answer 59

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

Answer 60

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.