Genetics Flashcards

Question

How many major types of collagen are there?

Answer 1

There are at least five major types of collagen which occur in different tissues.

Answer 2

Each type of collagen has distinct properties, but they all have the same triple helix structure which is the special feature of collagen. Associated with this is the unusual amino acid composition with its high concentration of glycine. Glycine is the smallest of the amino acids and occurs at every third position in collagen where it faces the interior of the helix (Gly-x-y repeated). Other features are the presence of the modified amino acids hydroxyproline and hydroxylysine.

Answer 3

The main feature of this disease is repeated fracture of long bones, and for this reason it can easily be misdiagnosed as child abuse. There are also malformed bones. There is a whole range of genetic disorders which can lead to the disease.

Answer 4

Most cases of osteogenesis imperfecta result from mutations in the glycine residues producing defective structural assembly.

Answer 5

This substitution of the normal glycine at this residue, with a larger amino acid, in the mutant molecule, will cause steric hindrance which generates a kink in the normally straight triple helix, with a resulting defect in the assembly into fibres.

Answer 6

If the amino acid introduced is cysteine, inappropriate disulphide bonds would form between the two α1(I) chains in the helix, due to a reactive sulphydryl group in the cysteine side chain. Thus not only is formation of the collagen triple helix disrupted, but the resulting crosslinked polypeptide chains will migrate much more slowly than the individual chains when examined by gel electrophoresis in the presence of SDS.

Answer 7

The disulphides bonds will be cleaved in the presence of | 2-mercaptoethanol, allowing the chains to migrate according to their molecular weight.

Answer 8

Due to the patient being heterozygous, only some of their α1(I) chains will be abnormal while the other allele makes the normal α1(I) chains. In principle 50% of the chains would be normal and 50% abnormal, though in practice this exact ratio rarely occurs in real genetic diseases.

Answer 9

There may be differences in the rates of transcription of the gene, rate of translation, stability of mRNA or stability of the protein which lead to a different ratio.

Answer 10

Because the collagen triple helix contains two α1(I) chains and will be disrupted if only one is the mutant form, the majority of the collagen fibres will be affected leading to a dominant phenotype.

Answer 11

The major consequence is in the formation of bone. Bone is formed by laying down hydroxyapatite (a form of calcium phosphate) on an ordered scaffold of collagen-I. The abnormal collagen structure leads to defects in this mineralisation process, so that the patient ends up with skeletal abnormalities and generally weak bones.

Answer 12

Most patients suspected of having OI are investigated by direct study of their collagen protein. This would not be a suitable approach for prenatal diagnosis since sampling of collagen from a fetus would be impractical and risky (could lead to miscarriage).

Answer 13

The foetal DNA is obtained by chorionic villus sampling or amniocentesis and amplified by PCR. Specific probes could be used which were complementary to part of the DNA sequence where a mutation was known to occur: under the right conditions of temperature and ionic strength, the probe will only hybridise (bind to the DNA) if it has the exact complementary sequence, enabling normal and mutant genes to be distinguished.

Answer 14

If the mutation altered a restriction enzyme recognition site, that would allow identification of normal and mutated DNA since only one would be cleaved by the enzyme to shorter fragments.

Answer 15

1) Unaffected male = white square 2) Unaffected female =white circle 3) Affected male = black square 4) Affected female = black circle 5) Autosomal carrier male = half black-half white (vertically) square 6) Autosomal carrier female = white circle 7) X-linked carrier female = white circle with a central black dot 8) Deceased male = white square with a horizontal line across 9) Deceased female = white circle with a horizontal line across 10) Proband (seeking medical attention) male = white square with a small arrow on the bottom left pointing to the opposite corner 11) Proband (seeming medical attention) female = white circle with a small arrow on the bottom left pointing diagonally

Answer 16

1) Couple = mates linked by a horizontal line 2) Consanguineous couple = linked by two horizontal lines 3) Offspring = linked to parents by horizontal line 4) Dizygotic (non-identical) twins = linked to each other by diagonal lines 5) Monozygotic (identical) twins = linked to each other by diagonal lines, and a horizontal line joining the two diagonal lines 6) Generations = each one is on a separate line and denoted with Roman numerals (e.g. I = grandparents, II = parents, III = offspring) 7) Offspring = birth order general left to right, children can also be numbered left to right 8) Lineage = maternal on the left, paternal on the right

Answer 17

1) Provides a clear simple summary of information 2) Allows patterns to be spotted easily 3) Allows patterns to be explained to patients 4) Allows identification of potential carriers of risk gene 5) Allows the risk of passing on disease or being a carrier to be calculated 6) Permits informed choice, as many diseases are a mix of familial and sporadic (e.g. motor neurone is ~85% sporadic and ~15% familial - four known genes account for 65% of cases)

Answer 18

1) Drawn from the bottom, starting with the proband and siblings 2) One parent is chosen at a time, with their siblings, children and parents drawn 3) The other parent’s side of the family is then added 4) Children of other partners are then added

Answer 19

1) Incomplete information 2) May not have information on all or many relatives 3) Incorrect information 4) Family history may not be correct 5) Important in clinical setting

Answer 20

1) Vertical transmission 2) Not all offspring affected 3) Males and females affected (50% risk of inheritance) 4) At least one affected parent (mother or father)

Answer 21

1) Not all generations affected (affected fathers do not have affected offspring unless partner is affected/carrier) 2) Not all offspring affected (mutated gene has no effect on own, but some female offspring will be carriers) 2) Only Males affected (gain X chromosome from their mother) 2) Inherited from unaffected mother (carrier but unaffected)

Answer 22

1) Vertical transmission 2) All generations affected 3) All offspring affected (mutation inherited from affected mother) 4) Males and females affected (100% risk of inheritance)

Answer 23

Mitochondria have multiple copies genome some normal some mutant. Offspring inherit different numbers of mutated mitochondria from mother. Different tissues/cells can contain different number of mutated mitochondria and this can change with time. Some diseases develop with age due to accumulation of mutated mitochondria. all mitochondrial disease caused by mutations in mitochondrial DNA, most are caused by mutations in cell genome and have normal mendalian inheritance.

Answer 24

1) Usually no family history of disease 2) Parents unaffected (mutated gene has no effect on own) 3) Horizontal transmission –siblings, cousins affected 4) Not all offspring affected (require 2 mutated copies to express disease) 5) Males and females affected 6) Possibly consanguinity (incest) in pedigree 7) Obligate carriers

Answer 25

This is a calculation of the predicated chance of having the disease or being carrier. It is calculated by working from person with known phenotype to subject (closest relative on each side of family) and multiplying the risks together.

Answer 26

All information must be taken into account, including: • Phenotype • Disease characteristics • Family distribution for X-linked and mitochondrial disease • Which side of family disease is on • Which parent has the disease

Answer 27

``` • Which side of family disease is on > X-linked, mitochondrial • Ethnic background > Many diseases have different prevalence in different populations (e.g. CF, Sickle cell, Tay-Sachs) > Heterozygote advantage (e.g. sickle cell, CF) >Founder effect (e.g. Tay-Sachs) • Information about the patient > Their phenotype > Their biological sex ```

Answer 28

It is now classified into nine subtypes, which although they all result in fragile bones prone to fracture they have different disease outcomes, inheritance patterns and underlying causes (those caused by mutations in collagen genes and those caused by mutations in other genes).

Answer 29

Even though the underlying cause of these diseases are genetic there is an important role for the environment in the progress and outcome of the disease for each patient. Here, environment means factors external to the patient.

Answer 30

The condition is inherited in an autosomally dominant fashion, but despite this not all people with the mutation will develop the same types of adenoma or at the same time. This is because a second event has to occur to promote tumour formation. Some people develop many tumours at a young age whereas others do not develop any tumours until very late in life. The exact cause of this is unknow but there is clearly an effect of environmental impact on the course of the disease.

Answer 31

There are a number of physiological differences between males and females and these differences can affect the phenotype dispalyed by individuals harbouring the same mutations. At the most simple level this can be due to the presence or absence of organs and tissues. So for example men with mutations in BRCA-1 and BRCA-2 have an increased risk of prostate cancer. This is obviously not the case with females as they lack a prostate instead they have an icreased risk of ovarian cancer.

Answer 32

In men the symptoms begin to develop between 40 and 60 whilst in women symptoms do not develop until several years after menopause. The explanation for this is that females lose a significant amount of blood during menstruation and this prevents the build up of iron in other tissues. Men also tend to have more severe phenotypes. This though is not absolute as some men do not develop symptoms whilst some women do.

Answer 33

In addition to the presence of the disease gene the life course of a disease and the symptoms presnt are commonly modified by the presence of other genes. These genes can either improve the condition or make the condition worse.

Answer 34

The type of OCA-2 inherited is resonsible for approximatley 80% of eye colour. The rest is controllled by other genes. The second most important gene is one called HERC2, which controls the activity of OCA- In addition to HERC2 there are over 16 other genes that influence eye colour. The interaction of which produce a wide range on eye colours

Answer 35

Some diseases are associated with only a single mutation for example sickle cell anemia. Where as other disease can arise as the result of many mutations within the same gene. Both Duchenne and Becker muscular dystrophy are caused by mutations in the dystrophin gene; the largest known human gene. the diseases are similar in the distribution of muscle wasting and weakness, which is mainly proximal. The reason for these diffences in disease progression are the type of mutation in each. Both are the result of deletions in the dystrophin gene but in In DMD the mutation is a frame shift deletion, but in Becker Muscular dystophy the mutation does not result in a frame shift.

Answer 36

These are a large group of diseases caused by a trinucleotide repeat expansion. This is a mutation in which a region of three repeated nucleotides in the genome increases in number during DNA replication. If there are fewer than 27 repeats in the genome, these tend to be stable and the function of the protein remains normal. As the number of repeats increases, it reaches a thresehold above which they are no longer stable during DNA replication and the number of repeats increases during subsequent rounds of DNA replication. This increase in trinucleotide repeats changes the protein function and a greater number of repeats results in a more severe phenotype.

Answer 37

Huntington's disease is caused by expansion of a region of cytosine-adenine-guanine (CAG)—repeats, in the huntington gene. CAG is the codon for glutamine, so a series of these repeats results in the production of a chain of glutamine known as a polyglutamine tract or Poly Q tract (Q being the single letter code for glutamine). 1) < 27 repeats: normal phenotype and the region is stable. 2) 27–35 repeats: an Intermediate phenotype with some minor effects, however the region of the DNA is not longer stable and the numbers of repeats can increase. 3) 36–39 repeats: results in the characteristic phenotype but not all carriers will be affected by the disease. 4) 40 or more repeats: results in Huntington's disease in all carriers.

Answer 38

This is mainly a collection of a person’s chromosomes, which is most easily determined using a sample of peripheral blood, but can also be determined in amniotic cells and chronic villus sample.

Answer 39

1) Collect ~5ml heparinised venous blood > Can use amniotic cells, CVS 2) Isolate white cells 3) Culture in presence of phytohaemagglutinin >Stimulates T-lymphocyte growth/differentiation 4) After 48 hours add colchicine > Causes mitotic arrest – metaphase 5) Place in hypotonic saline 6) Place on slide 7) Fix and stain

Answer 40

Once the stained sample has been obtained, individual chromosomes are cut out and arranged. Karyotype is now often done in prophase rather than metaphase, as the chromosomes are less compact, allowing more detail from the karyotype.

Answer 41

DNA does not exist as a single double helix, but is compacted around his tones and further condensed into chromatin. The function of chromatin is not only fitting a lot of DNA into a cell, but the proteins bound to it affect its regulation. The 3D genome is important.

Answer 42

This allows the individual pattern of each chromosome, to be represented. Chromosomes have some common structural features such as: a centromere between the two arm, a telomere at either end, a short arm called the p (petite) arm and a long arm called the q arm. The gisema staining leaves a recognisable pattern of bands of numbered light and dark bands.

Answer 43

The bands themselves are caused by differently staining and originally identified with low level of resolution. Only a few bands were visible per chromosome (e.g. 1p, 2p, 3p). Improved technology has allowed more bands to become visible. These newly visible bands have been categorised as sub-bands (e.g. 1p11, 2p21, 3p22). Further technological improvements have allowed sub-sub-bands (e.g. 1p11.1, 3p21.1). Improved resolution helps identify smaller aberrations.

Answer 44

This identifies the improvement of the level of detail that can be seen on a chromosome, the higher the bphs, the more detail that can be seen. It is important to remember that bands do not represent genes or families of genes, but simply different areas of compaction: •Dark (heterochromatin) more compact fewer genes •Light (euchromatin) more open more genes

Answer 45

This describes an abnormal number of chromosomes. This causes problems, as the genome has developed such that having 2 copies of the chromosome is sufficient.

Answer 46

This is a special form of the cell cycle used to produce gametes and ensure their genetic variation. Meiosis enables random assortment of homologues and recombination. The purpose of meiosis is fundamentally the reduction from diploid (2n=46) to haploid (n=23).

Answer 47

This occurs when the process of meiosis goes wrong. Non-disjuncture results in uneven number of chromosomes in daughter cells and can occur in either meiosis I or meiosis II. If it occurs in meiosis I, then all the daughter cells are affected. But, if it occurs in meiosis I, then half of the daughter cells are affected. This means that it always results in either +1 (trisomy) or -1 (monosomy) chromosome.

Answer 48

Most common form of chromosomal abnormality, affecting 1 in 400 males and 1 in 650 females. The sex chromosome imbalance is tolerated because of: > X-inactivation of excess X chromosome, meaning only one X-chromosome is active > Low gene content of Y chromosome When inactivated the abnormal number X-chromosome can have effect, if both the X and Y chromosome have a PAR (pseudo-autosomal region), as this region is not inactivated with the rest of the chromosome.

Answer 49

This is trisomy 21, more common known as Down’s syndrome. It has this name due to the 3 copies of chromosome 21. Most cases of trisomy 21 arise due to non-disjunction during maternal meiosis.

Answer 50

Although the risk of Down’s syndrome increases significantly with the mothers age, 75% of children with Down’s syndrome are born to mothers under the age of 35. However, this may simply be due to the fact that 90% of all children are born to mothers under the age of 35.

Answer 51

This is due to inherent vulnerability of oogenesis. Paused in utero in prophase I until puberty, secondary oocyte arrests in metaphase II. Only competes if fertilized. One primary oocyte yields only one ovum, but there is a finite number of primary oocytes. In older mothers, the ovum would’ve been stuck in one stage or the other of meiosis, for decades, leading to the degradation of factors which hold homologous chromatids together.

Answer 52

Males have no equivalent to oocyte mitotic arrest. Their primary spermatocytes undergo ~23 mitotic divisions per year and potentially accumulate defects. Paternal Age not risk factor increased aneuploidy, but does affect a subset of single gene disorders, caused by point mutations in FGFR2, FGFR3 and RET, including: 1) Apert syndrome 2) Crouzon syndrome 3) Pfeiffer syndrome These syndromes are thought to be enhanced by ‘selfish spermatogonial selection’ resulting from a selective advantage over neighbouring wild type cells.

Answer 53

Although age does not have any effect on paternal aneuploidy, smoking has been found to be a risk factor, not associated with maternal aneuploidy.

Answer 54

Aneuploidy causes 5% still births and 50% of spontaneous abortions. It also effect 5% of all clinically recognized pregnancies. Trisomy of all chromosomes has been detected prenatally and can lead to miscarriages, as most are trisomies are not compatible with life. Monosomy is also very poorly tolerated. Aneuploidy is estimated 50% preimplantation embryos.

Answer 55

This occurs in prophase I and increases genetic diversity. The pairs of chromosomes align and chiasma form, allowing crossover to occur. This is a common process that occurs 1-3 times per chromosome per meiosis. Crossover can occur from a single point, so large portion of terminals of chromosomes are swapped, or it can it can occur within the middle of the chromosomal material in a double cross over., meaning portions in the centre of the chromosomes are swapped over. However it can sometimes go very wrong.

Answer 56

This is an abnormality that occurs during crossing over when pairs of chromosomes are aligned incorrectly. This results in daughter chromosomes receiving unequal material, one receiving extra material, and one having a deletion of its material.

Answer 57

1) Deletion: Can be the result of unequal cross over. Breaks in chromosome. Can occur at ends. 2) Duplication: Most often caused by unequal cross over, genetic material is duplicated during cross over. 3) Paracentric inversion: Carriers often unaffected. Estimated to occur in 1 in 1000 people. Can cause reproductive problems. Children with deletions/insertions.

Answer 58

If the train of material between non-homologous chromosomes occurs in a uni-directional manner, then insertion can occur. The mutual exchange of material can also occur, when translocation of material leads to each of the derivative chromosomes having parts of the other chromosome on them. If this occurs in a balanced manner, it does not affect the carrier, but may cause problems in off spring - such as partial trisomy or monosomy (e.g. Cri-du-chat syndrome). Can occur in Somatic cells cf Philadelphia chromosome t(9;22)(q34;q11) CML.

Answer 59

Many chromosomal abnormalities are de-novo. Some people are unidentified carriers as they are unaffected by their translocation of genetic material for instance. However, during gametogenesis, the homologous chromosomes could be partitioned in different ways to produce either normal, balanced translocation carrier or unbalanced offspring. The unbalanced offspring would be affected by the abnormality.

Answer 60

These are classified into two forms: 1) Microscopic – be detected easily in microscope > Cri-du-chat syndrome 46,XY, deletion of short arm (p) of chromosome 5 2) Microdeletion - seen in high resolution banding; molecular genetics > Despite name still 20+ genes deleted > Velocardiofacial/DiGeorge syndrome 22q11.2 del

Answer 61

The phenotypes of this syndrome are caused by an imbalance of genes which are unrelated apart from their genomic location. It is characterised by: 1) Long philtrum 2) Short, upturned nose 3) Arched eyebrows 4) Supravalvular aortic stenosis 5) Friendly, social ‘cocktail party’ personality – an absence of social anxiety

Answer 62

The deletion of 7q11.23 is too small to detect using standard karyotyping, but can be detected using targeted Fluorescent in situ hybridisation (FISH), as there is a lack of elastin on the affected chromosome 7.

Answer 63

Duplications usually have a milder phenotype than the reciprocal deletion. This duplication is characterised by: 1) Delayed speech development 2) Autistic behaviours that affect social interaction and communication 3) Dilatation of the aorta 4) Flat eyebrows 5) Broad nose and short philtrum

Answer 64

1) Metacentric: the short arm (p) and the long arm (a) are almost of equal length and the centromere is roughly in the middle of the chromosome. 2) Submetacentric: the short arm is considerably shorter than the long arm. 3) Acrocentric: where the short arm has been reduced down to a vestige stump (chromosomes 13, 14, 15, 21 and 22).

Answer 65

Acocentric chromosomes can undergo Robertsonian translocation. The short arm of each chrome is translocated to produce a derivative chromosome. This affects 1 in 1000 people and can be between homologous or non-homologous chromosomes. It is most common between 13 and 14, 14 and 15 and 14 and 21. Most carriers of the abnormality are unaffected, but it can cause problems in offspring due to the unbalanced segregation of chromosomes in the gametes.

Answer 66

This describes the presence of two or more populations of cells with different genotypes. X-inactivation results in mosaic expression. Mosaicism can arise two mechanisms: 1) Non disjuncture during early development 2) Loss of extra chromosome in early development Mosaicism results in generally milder phenotype, as some lethal aneuploidy survivable if mosaic. The most common mosaic 46,XX/45,X mosaic 46,XY/45,X. All humans are thought to be mosaic to a certain degree.

Answer 67

Mendelian diseases are controlled by a single gene and complex diseases are controlled by multiple genes.

Answer 68

These are controlled by a single gene and their inheritance follows Mendel’s principles, with dominant and recessive alleles.

Answer 69

``` The are controlled by multiple genes, as well as the effect of environment. In humans, these traits include: > Hair colour > Skin colour > Eye colour > Height > Weight > Personality ```

Answer 70

1) Diabetes 2) Cardiovascular Disease (CVD) 3) Cancer 4) Asthma 5) Hypertension 6) Mental Health Diseases

Answer 71

There is only 1% variation that exists in the human genome. SNPs are DNA sequence variations that occur when a single nucleotide is changed. SNPs are the most common form of variation in the human genome there being over 10,000,000 SNPs in the genome recognised so far.

Answer 72

1) A population is stratified according the genotypes and a specified SNP. 2) Statistical analysis is then conducted to see if the difference seen in the number of disease cases in each group, is significantly different from the rest of the groups. The statistical P values is 5%/0.05.

Answer 73

1) Understanding the structure of genomes 2) Understanding the biology of genomes 3) Understanding the biology of disease 4) Advancing the science of medicine 5) Improving the effectiveness of healthcare

Answer 74

These are association analyses that stratify the population into different genotype groups over the 10,000,000 SNPs in the genome, at the same time. These are agnostic searches, as there is a chance of false positiveness. When doing over 10,000,000 SNPs, the P value increases from 5% due to the concept of multiple testing. Testing correction allows the multiple testing effect to be adjusted to avoid false positiveness and finding results that are purely by chance and nothing to do with the biology of a disease. When correcting from multiple testing the known new P value for a GWAS is 5x10^-8. This means that much larger sample sizes are needed than normal, but allows very robust findings.

Answer 75

This is the allele that is more frequently observed in individuals who are suffering from a disease.

Answer 76

It’s a plot with the y axis showing the significance of the P value for the association or each with the disease of interest and the x axis showing the chromosome. This allows an overview of all the SNPs association across the genome.

Answer 77

1) It is the leading cause of mortality worldwide 2) It leads to 17 million annual deaths worldwide 3) It causes 30% of global mortality 4) It is estimated to keep rising

Answer 78

1) Stenosis and blockage of blood vessels (Atherosclerosis) 2) Coronary artery disease (CHD) 3) Myocardial infarction 4) Heart failure 5) Stroke 6) Diseases of peripheral vessels

Answer 79

1) Obesity 2) Type 2 Diabetes 3) High cholesterol 4) High blood pressure

Answer 80

1) Modifiable: drinking habits, eating habits, smoking habits, high blood pressure and sedentary lifestyle. 2) Non-modifiable: sex, age and genetics.

Answer 81

1) Understand the biology of CVD 2) Gaining the ability to predict CVD 3) Identifying high risk groups 4) Intensifying preventive strategies in high risk groups

Answer 82

H^2 = 2(rMz-rDz) > H = broad sense heritability/ heritability estimate > rMz = correlation of monozygotic twins (0.95) > rDz = correlation of dizygotic twins (0.52)

Answer 83

This is the phenomenon found when calculating the difference between the heritability found in broad sense heritability and and the smaller value for the SNPs based heritability/heritability based on GWAS data in a population. GWAs help identification of many genetic loci, but there is still a gap between what is known about the heritability of the disease and what is found by GWAs.

Answer 84

1) Rare variants (SNPs) 2) Low frequency variants with intermediate effect 3) Interactions 4) Miscalculated estimation of heritability 5) Diagnosis (accuracy and precision)

Answer 85

The study of variability in drug response due to genetic differences. It is believed that it well help improve drug therapy and prescribing in the future.

Answer 86

1) Recovery 2) No effect 3) Side effect 4) Death

Answer 87

When a drug enters the body, it is absorbed and then distributed throughout the body and connected to a target organ to exert its effect. Genetic factors may interfere at the very first stage of interaction between the drug and the target organ, effecting the drug response. Different individuals could have differences in their receptors which could be under the control of a gene. The drug will then be metabolised and removed from the body through the kidneys and liver, where genes can also effect the metabolism of the drug, by either decreasing its metabolism (leading to overdose) or increasing its metabolism (drug has no effect).

Answer 88

Tailoring treatment to patients depending on specific characteristics of their disease, to maximise the effect of their treatment and decrease the adverse effect of the medication.

Answer 89

1) Positive pregnancy test – no longer confirmed at GP 2) Book into antenatal care – see midwife 3) Nuchal scan – 10-14 weeks gestation. Different tests dependent upon NHS Trust (e.g. nuchal translucency, combined test, etc). 4) Mid-trimester anomaly scan 5) Ultrasound examination is the main method for prenatal diagnosis of fetal abnormalities. All pregnant women should be offered routine ultrasound scans at 11-14 weeks and again at 20-22 weeks.

Answer 90

1) To date the pregnancy accurately. 2) To diagnose multiple pregnancy. 3) To diagnose major fetal abnormalities. 4) To diagnose early miscarriage. 5) To assess the risks of Down Syndrome and other chromosomal abnormalities. 6) To assess blood flow through the fetal heart. 7) To assess nuchal translucency thickness.

Answer 91

This is a screening (not diagnostic) test taken at 10-14 weeks, that assesses the thickness of fluid at back of fetal neck. Increased nuchal translucency thickness (>3mm) can indicate: 1) Chromosome abnormalities: Downs, Edwards, Patau and Turners (NT + maternal age detects up to 75% of Down syndrome with 5% false positive rate). 2) Birth defects: Cardiac anomalies, pulmonary defects (e.g. diaphragmatic hernia), renal defects and abdominal wall defects. 3) Skeletal dysplasias

Answer 92

1) Following abnormal findings at nuchal scan or mid-trimester scan 2) Following results of combined test which give an increased risk of Down Syndrome. 3) If previous pregnancy affected with a condition (e.g. Down’s syndrome, cystic fibrosis). 4) If parent(s) are carriers of chromosome rearrangement or genetic conditions (e.g. t(13;14), Duchenne Muscular Dystrophy, Huntington’s Disease). 5) If there is family history of a genetic condition.

Answer 93

1) To inform and prepare parents for the birth of an affected baby 2) To allow in utero treatment 3) Manage the remainder of the pregnancy 4) To be prepared for complications at or after birth 5) To allow termination of an affected fetus

Answer 94

Cell-free DNA is short DNA fragments present in the maternal plasma during pregnancy. Most of this DNA comes from the mother, but 10%-20% of it is cell-free fetal DNA, which comes from the placenta, and is representative of the unborn baby. Cell-free fetal DNA is first detectable from about 4 -5 weeks’ gestation. In trisomy 21, the amount of cfDNA for chromosome 21 is higher than in normal pregnancies.

Answer 95

Non-invasive prenatal diagnosis (NIPD) works by analysing the cell-free DNA present in the maternal plasma during pregnancy. Although cell-free fetal DNA (cffDNA) is first detectable from about 4 -5 weeks’ gestation, it cannot accurately be detected on testing until around 9 weeks.

Answer 96

This is a maternal blood test at around 9 weeks of pregnancy: 1) If Achondroplasia is suspected in the fetus, then testing is free 2) If Thanatophoric dysplasia is suspected in the fetus, then testing is free 3) If Apert syndrome is suspected in the fetus, then testing is free

Answer 97

This is currently offered when there is a X-linked condition in the family (e.g. Duchenne Muscular Dystrophy). The test detects the SRY gene on the Y chromosome, enabling the sex of the fetus to be determined: – If male —> go on to prenatal test – If female —> no invasive test required

Answer 98

1) If the fetus is suspected of have an autosomal dominant single gene disorders inherited from the father or arise de novo (e.g neurofibromatosis type 1). 2) To alter management of pregnancies at risk of recessive conditions when the mother and father carry different altered genes: > The paternal alteration has been inherited by the fetus invasive prenatal testing can be offered. > Cystic fibrosis – haplotyping (RHDO) can test for both maternal and paternal mutation.

Answer 99

This is currently only offered by in the private sector, by companies such as Harmony, or via research studies. Harmony currently tests for T13, T18, T21 and this identifies: – 99% of fetuses with trisomy 21 – 97% of fetuses with trisomy 18 – 92% of fetuses with trisomy 13.

Answer 100

1) In the case of multiple pregnancies, it is not possible to tell which fetus the DNA is from when carrying twins/triplets, etc. 2) The relative proportion of cell-free fetal DNA is reduced in women with a high BMI as they have more of their own cell-free DNA. 3) Although it is just a blood test, it has the same implications as an invasive test. 4) Women may prepare themselves more for the implications of an invasive test result. 5) Women must consider the consequences of the results. Do they want this information? 6) An invasive test may still be required to confirm an abnormal result.

Answer 101

1) The number of invasive tests carried out is likely to reduce as a result. 2) There is no increased risk of miscarriage. 3) Less expertise is required to perform a blood test than an invasive test. 4) In many cases NIPD /NIPT can be offered earlier than traditional invasive testing, thereby getting a result much earlier.

Answer 102

These tests are only offered if there is a ‘known risk’. The tests can either be Chorionic villus sampling (CVS) or Amniocentesis. They include molecular, cytogenetic and biochemical tests, as well as ultrasound guidance. They vary on an outpatient basis.

Answer 103

This test is done after 11-14 weeks, and has a 1-2% risk of miscarriage. The test can either be transabdominal or transvaginal. It involves taking a sample of chorionic villi, which is part of the developing placenta, and is the same DNA as the fetus. It allows the patient to have an earlier result than amniocentesis, which is important for many patients.

Answer 104

This test is taken from 16 weeks and involves taking a sample of amniotic fluid which contains fetal cells. There are several associated risks including : an up to 1% chance of miscarriage, infection and Rhesus (Rh) sensitisation.

Answer 105

Tests are conducted for the suspected genetic disorder, but the timing for results are dependent upon the condition itself: 1) The fetal karyotype can be tested if there is a chromosomal abnormality in the family, and results take 2 weeks (dependent upon the cells growing). 2) QF-PCR for all genetic disorders, which looks for t13, 18 & 21 (plus sex chromosomes if sex chromosome disorder suspected). Results are returned within 24-48 hours.

Answer 106

If there are concerns on the 20 week scan, the gold standard is to offer CGH array. This test looks for small/large imbalances in chromosomes (picks up microdeletions and duplications). If something is found on the array, parents are then also tested to see if either is a carrier, which can help with interpretation.

Answer 107

1) Extract genomic DNA from a test and a reference sample and label one with a red fluorescent dye and the other with a green fluorescent dye. 2) Mix and hybridise to a microarray printed with thousands of oligonucleotide probes, then wash. 3) Detect red and green signals using a fluorescent scanner. 4) Compute and report gains or losses in the test DNA, using software.

Answer 108

This practice started with Deciphering Developmental Disorders (DDD) study. The exome is the coding region of the genome. DNA is taken from fetus and parents and where the fetus in a previous pregnancy had significant anomalies (e.g. heart, brain, skeletal) or where baby has been born with developmental delay, dysmorphic features (and array normal), is considered. Good pick up (40%+) where referrals are appropriate

Answer 109

Where there is a known reproductive risk, the options for family planning include: 1) Conceive naturally, no prenatal testing 2) Conceive naturally, have prenatal testing 3) Use of egg and/or sperm donors 4) Adoption 5) Choose not to have children 6) Pre-implantation genetic diagnosis (PGD)

Answer 110

This is no longer anonymous and children conceived have the right to contact donor when 18 years old. UK HFEA licensed fertility centres must conform to strict medical, ethical and legal standards. However, couples can privately find their own donor and some couples may consider going abroad.

Answer 111

1) Registration and checks > Registering interest with adoption agency > Medical and criminal background checks; three written references > Usually takes ~2 months 2) Assessment and approval > Home visits by social worker > Compilation of ‘prospective adopters report’, taken to adoption panel > Panel review information and make a decision whether a couple is suitable to adopt > Takes ~4 months

Answer 112

This uses IVF with an additional step to genetically test the embryo before implantation. It is particularly used by people who do not want TOP.

Answer 113

1) Stimulation of the ovaries 2) Egg collection: following hyperstimulation of the ovaries, many eggs are removed. 3) Insemination 4) Fertilisation: each egg is surrounded by sperm to allow fertilisation. 5) Embryo biopsy 6) Embryo testing 7) Embryo transfer 8) Pregnancy test

Answer 114

A single sperm injected into the centre of each egg. This type of injection is used for conditions caused by a single faulty gene to reduce the amount of non-embryo DNA (including sperm DNA) which could make the risk of a wrong diagnosis higher.

Answer 115

The cell count doubles each day from 1 cell a zygote on day 1, to a 64 cell blastocyst on day 5. It is at this point that a cell can be removed from the blastocyst and tested for the genetic condition in the family.

Answer 116

PGD is now nationally funded and is used for many genetic disorders, including: •Translocation carriers • Huntington’s disease •Duchenne Muscular Dystrophy – only implant female embryos (where mutation in family in unknown) •Cystic Fibrosis A licence is required from the HFEA for each genetic condition or indication.

Answer 117

These comprise the largest group of genetic disease and affect variety of pathways, including: •Carbohydrate •Fatty acid •Proteins • Lack enzyme Examples include Phenylketonuria (PKU), Medium-chain acyl-CoA dehydrogenase (MCAD) Deficiency, Maple Syrup Urine Disease and Homocystinuria.

Answer 118

This a major cognitive impairment that causes: behavioural difficulties fairer skin, hair and eyes than siblings, lack of melanin and recurrent vomiting.

Answer 119

Treated with a low protein diet – Tyrosine supplement. When first discovered, it was thought to be untreatable, but the PAH mutation was eventually identified. Before treatment, the cause needs to be identified. Possible before gene identified - biochemistry.

Answer 120

This a blood clotting disorder that has been known since ancient times. It is characterised by uncontrolled internal bleeding into joints and the brain, as well as excruciating. If untreated, it can potentially be fatal.

Answer 121

In the 1970s, sufferers of haemophilia were treated with Freeze-dried plasma-derived factor concentrates, containing the factor VIII clotting factor. In the 1980s, it was discovered that heat treated products kill viruses, and the Factor VIII gene was cloned. In the 1990s, Recombinant Factor VII treatment was introduced.

Answer 122

1) Growth hormone deficiency 2) Injection growth hormone now recombinant (cadaver derived cjd) 3) Lyosomal storage diseases – effect lysosomal breakdown 4) Fabry disease 5) Injection recombinant alpha galactosidase A 6) Pompe disease 7) Injection of alpha glucosidase

Answer 123

1) First stage discovery/preclinical 2) Longest part lab based: Testing in animals and clinical testing Clinical testing is generally split into 3 phases Phase I - first in man - safety – healthy volunteers <100 Phase II – check therapeutic effect few patients 100-300 Phase III- large scale therapeutic trials 200- 3000 Approved by European Medicines Agency (EMA) or Food and Drug Administration (FDA)

Answer 124

To be prescribed on NHS drugs need approval. In England and Wales, this is done National Institute for Health and Care Excellence (NICE), in Scotland it’s done by Healthcare Improvement Scotland. These organisations also set guidelines for treating conditions.

Answer 125

These treatments treat the condition rather that symptoms, but remain treatments and not cures. They attempt to normalise function of mutant protein.

Answer 126

Protein folding is complex process that involves molecular chaperones, but it sometimes fails. The system in the rough endoplasmic reticulum sometimes leads to misfolding proteins, which can lead to degradation by various pathways. Some mutations prevent proteins folding properly, so are subject the degradation pathway. If proteins are folded correctly, they would be active.

Answer 127

This is a deficiency of alpha-galactosidase A which causes the build up of globotriaosylceramide. Some mutations leading to Fabry disease are caused by misfolded proteins. Treatment of Fabry disease has been developed based on Migalastat, a small molecule chaperone, which binds to the misfolded protein and rescues the folding process. Stabilises the enzyme in correct shape and improves activity in the lysosome. NICE approved in Feb 2017. Mutation specific

Answer 128

These are commonly used drugs that act as receptor agonists/antagonist, as well as Ion channel activators/blockers. They can designed to have these effects on mutant receptor or channel, such as Bcl-abl Kinase inhibitors for the treatment of cancers caused by the Philadelphia chromosome.

Answer 129

Cystic fibrosis is caused by a defective chloride channel, as mutations in chromosome 33 cause channel not to open. They have design a drug which causes activation - Ivacaftor. However, this drug is mutation specific.

Answer 130

Cystic fibrosis is caused by a defective chloride channel, itself caused by mutation (f508del) which misfolds and inactives the channel. It is now treated with a combination of a chaperone and an activator. Orkambi (Ivacaftor/lumacaftor) – NICE approved I’m Oct 2019. Although this is not a cure, it does improve lung function.

Answer 131

Some diseases caused by non-sense mutation cause a premature stop codon. This leads to a much shorter protein, which actually prevents protein production. Aminoglycoside antibodies bind to the ribosome and cause mistranslation by causing the read through or stop codons in the bacteria. Drugs based on these actually cause the read through or nonsense mutations: if a mutant stop codon is introduced, release factors bind causing the release of the truncated peptide. Nonsense suppressive drugs, block this effect and allow the normal the normal tRNA to compete at this site, allowing a full length protein to form, sometimes with a point mutation.

Answer 132

Duchenne muscular dystrophy is caused by a premature stop codon which leads to truncated dystrophin. Becker muscular dystrophy is caused by a missing section. The theory is if reading through the premature stop codon in DMD, a phenotype more like BMD can be produced, which a much milder phenotype, allowing patients to live until old age. Ataluren has been approved in EU, but not in the US. It was NICE approved in June 2016. It is Non-sense mutation specific.

Answer 133

This is conceptually very easy. In the case of a recessive disease, the defective gene would simply be replaced. In the case of a dominant disease, the defective gene would simply be deleted. However, this is very difficult to achieve in practice as: specificity must be achieve, the therapy must be delivered to right place and gene expression must be maintained. This is much easier to accomplish in vitro/ex vivo (out of the living) than in vivo.

Answer 134

This is the only effective in vitro gene therapy and requires IVF. DNA is taken from the fertilised patient egg and transferred to a donor egg with normal mitochondria. Hence, these bakes are popularly known as three-parent babies. Although it is approved for use in UK, it is not without controversy.

Answer 135

This type of therapy can engineer a virus to carry the therapeutic gene. There are a wide variety of viruses used including: AAV, Adenovirus, Lentivirus – HIV and Vaccinia. The Virus chosen depends on the target tissue and the amount of DNA limited depends on the virus.

Answer 136

Severe Combined Immuno-Deficiency (used to be called Bubble baby disease) is characterised by a lack of both a B-cell and a T-cell mediated responses. It comes in several forms: X-linked (X-SCID 70%) and Adenosine deaminase deficiency (ADA-SCID 15%). It can be treated with bone marrow transplant, however this is not possible for all children as around 80% of them have no ADA-SCID no match. Bone marrow transplants also have their own risks.

Answer 137

Strimvelis is analogous to an autologous transplant. Bone marrow is taken from the patient and their Hemopoietic stem cells are isolated. The CD34+ are specially isolated and expanded, before being transfected with ADA – lentivirus. The transformed cells are then grown, whilst the patient is treated with busulfan, to kill their own Haemopoeitic stem cells. The transformed cells are then reinfused into the patient, allowing them to replace the HSCs which lack the adenosine deaminase.

Answer 138

This is useful when a patient lacks a copy of a functional gene. These supplements use a virus to carry in working copy. Some approaches also use a systemic injection, but the most successful approaches thus far are local injections in: the eye, spine and brain. Many treatments are still in development.

Answer 139

This is a recessive disease caused by mutation RPE65, which is involved in the generation of visual pigment. It leads to progressive blindness, due to a loss of retinal cells. Luxturna is used to treat this, and is based on the rAAV2 virus expressing RPE65. This is not a cure, but does greatly improve vision, however, patients do need a sufficient amount of remaining cells. This treatment was EMA approved in November 2018 and NICE approved in September 2019.

Answer 140

These are short modified nucleic acids, which are complementary to the target mRNA of the gene causing the disease. These are often modified nuclei acids, which allows them both entry into the target cells, and the prevention of degradation. They function by binding to the target and either blocking translation of the target mRNA or altering the splicing pattern of the mRNA. These are relatively cheap to make.

Answer 141

Anti-sense oligonucleotides are useful for diseases caused by gain of function and a number of these treatments have now been approved. Inotersen is such a drug. This is used in the treatment of the disease transthyretin-related hereditary amyloidosis, which is caused by a mutation in Transthyretin (TTH). These mutated TTH cannot form tetramers, meaning that the monomers aggregate and form amyloid desposits in various tissues, which damages the tissues. This treatment is mutation specific.

Answer 142

Anti-sense oligonucleotides can mediate the process of exon skipping. This targets the process of pre-mRNA maturation. Oligonucleotides bind to the acceptor site of an economic and block it from acting as an acceptor site, causing the exon to be skipped, causing the son to be excluded from the protein. This can be used to skip a disease causing exon, and allowing the reading-frame to go back in sync. This is only useful in limited circumstances and the exons skipped mustn't be vital. Hence, exons ate generally only skipped on large proteins.

Answer 143

The dystrophin gene is normally 2.6MB long and contains 97 exons. Duchenne muscular dystrophy is caused by a smaller deletion, which causes a change in the reading frame leading to a truncated dystrophin. However, Becker muscular dystrophy is caused by deletions of large sections of dystrophin, but the reading frame is left intact. Exon skipping in DMD would allow it to be inverted to BMD. Eteplirsen is an oligonucleotide which causes the skipping of exon 51. This results in the production of partially active dystrophin. It has been approved for use in USA after patient pressure, although it was originally not approved. It has not been approved in Europe as more data is required.

Answer 144

This stands for Clustered Regularly Interspaced Short Palindromic Repeats. It is based on a bacterial system that disables bacteriophages. CRISPR are sections of DNA derived from a previous bacteriophage in bacteria. These are associated with a protein called CAS (Crispr associated protein 9), which is an endonuclease, so cuts within DNA sequences. It recognises and cleaves DNA CRISPR hybrids.

Answer 145

Gene editing could correct relatively small errors, but cannot currently correct large changes (e.g. deletions, triplet expansion). It may also have off target effects. The system is not currently used in humans (1 exception). It also has the same problem as other methods, such as targeting and getting into cells.

Answer 146

A Chinese doctor called He Jiankui used CRISPR-Cas to alter genome of IVF embryos, which deleted CCR5 (involved in the entry of HIV) in a pair of twins. This was controversial as it is illegal in most of the world. It is possible that CRISPR-Cas9 could be used to prevent genetic disease, bit would need to be identified prior to conception. There are a ground of scientists in Russia looking to use CRISPR-Cas9 to prevent heritable deafness.

Answer 147

All cancers derive from single cells that have acquired the characteristics of continually dividing in an unrestrained manner and invading surrounding tissues. Cancer cells behave in this abnormal manner because of changes in the DNA sequence of key genes, which are known as cancer genes. Therefore all cancers are genetic diseases.

Answer 148

1) Chemicals (e.g. from smoking) and radiation can damage genes (environment) 2) Viruses can introduce their own genes into cells (exogenous factors) 3) Inheritance, alterations in genes that make a person more susceptible to cancer can be passed to the next generation (genetics – rare and common) Genes are altered, or "mutated," in various ways aspart of the mechanism by which cancer arises. All lead to abnormal cellular regulation.

Answer 149

1) A benign tumor is a mass of well-differentiated cells that grows slowly, is capsulated and lacks the ability to invade neighboring tissue or metastasize. 2) A malignant tumor is not self-limited in its growth (escapes apoptosis, is able to produce new blood vessels), cells are poorly differentiated and capable of invading into adjacent tissues, and may be capable of spreading to distant tissues (metastasis).

Answer 150

1) Large number of dividing cells 2) Large, variably shaped nuclei, cytoplasm may also display abnormality, such as invaginations. 3) Large nucleus to cytoplasm ratio 4) Variation in size and shape 5) Loss of normal cell features 6) Disorganised arrangement 7) Poorly defined tumour boundary

Answer 151

This is a particular class of proteins over-expressed in advanced cancers. These form the structural basis of the nucleapore. The increases number of nucleapores in the nuclear membrane, in advanced cancers, caused an abnormal ill influx of beta-cotinine into the nucleus, which is an important transcription faction found in colorectal cancer.

Answer 152

1) Carcinomas: the most common types of cancer arise from the cells that cover external and internal body surfaces. Lung, breast, and colon are the most frequent cancers of this type (epithelial) 2) Sarcomas: are cancers arising from cells found in the supporting tissues of the body such as bone, cartilage, fat, connective tissue and muscle 3) Lymphomas: are cancers that arise in the lymph nodes and tissues of the body’s immune system 4) Leukaemias: are cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream

Answer 153

1) Lung cancer: 21% 2) Bowel cancer: 10%, 3) Prostrate cancer: 7% 4) Breast cancer: 7%.

Answer 154

1) Melanoma 2) Hodgkin Lymphoma 3) Breast cancer 4) Prostate cancer 5) Testicular cancer 6) Cervical cancer 7) Thyroid cancer

Answer 155

Leukaemia (particularly acute lymphatic leukaemia and acute myelogenic leukaemia) is the most common childhood cancer, accounting for 30%. Other prominent cancers affect the germs cells, such as testicular cancer, and affect the brain, such as glioma and medulloblastoma. The cancers that mainly affect young people occur in the tissues undergoing a higher rate of proliferation. Conversely, major organs such as the liver, lung, and intestine are not as affected in children, indicating the major impact of the environment in causing these cancers in adulthood.

Answer 156

1) Self sufficiency in growth signals (e.g. activate H-Ras oncogene) 2) Insensitivity to anti-growth signals (e.g. lose retinoblastoma suppressor) 3) Evading apoptosis (e.g. producing IGF survival factors) 4) Limitless replicative potential (e.g. turn on telomerase) 5) Sustained angiogenesis (e.g. produce VEGF inducer) 6) Tissue invasion and metastasis (e.g. inactivate E-cadherin)

Answer 157

The life time risk of developing cancer in a particular tissue is correlated (r=o.8) with how often stem cells in that tissue divide.

Answer 158

Germ cells produce eggs and sperms (gametes), these are the only cells that can undergo meiosis and mitosis. Only germline mutation that occurs in gametes can be passed on to offspring. Consequently, every cell in the entire organism will contain that mutation, although the tissues would be affected at various levels.

Answer 159

Somatic cells form the building blocks of the body and only divide by mitosis. Usually, mutation in cancer genes accumulate in somatic cells over many years until a cell accumulates a sufficient number of errors to initiate the tumour. Most of the genetic events that cause cancer occur in somatic cells and only tissues derived from these mutated cells are affected. The frequency of the events can be altered my exposure to mutagens present in the environment, however these genetic events are not transmitted to future generations because they do not occur in gametes.

Answer 160

It is possible for a cancer predisposing mutation to occur in the germline. Positional cloning linkage studies can study the transition of cancer causing genes from one generation to the next, producing families that have a high incidence of specific cancer. Linkage analysis can be performed where all chromosomes are mapped with the use of polymorphic markers, until a specific region, likely containing the mutated gene, is preferentially segregated with the phenotype. Once the chromosome is identified, all the genes that are present are sequenced, and the sequences of the cancer families are compared to the normal population.

Answer 161

Mutations in the gene are some of the most well known cancer causing mutations. They lead to an increased risk of breast cancer as a part of a hereditary breast ovarian cancer syndrome. Undercover mutations in the BRCA1 are associated with an increased risk of cancer, females with an abnormal BRCA1 or BRCA2 gene have an up to 80% risk of developing breast cancer in their lifetime. Women with the BRCA1 mutation also have a 55% increase risk of developing ovarian cancer, while women with a BRCA mutation have a 25% increased risk.

Answer 162

1) Deletions 2) Insertion 3) Duplications: copy number increases from 2 in a haploid cell genome, to several hundred copies, known as gene amplification 4) Reductions: the complete absence of DNA sequence from the cancer genome compared to the fertilised egg. 5) Inversions 6) Translocations: rearrangements in which DNA has been broken and joint to DNA somewhere else in the genome 7) Single base substitutions (point mutations – silent, nonsense, missense)

Answer 163

1) Chromosome instability: refers to a higher than normal rate of mis-segregation or the chromosomes or part of the chromosomes, during mitosis. This is due to the defective cell cycle quality control mechanism, resulting in copy number alteration. 2) Aneuploidy: can be caused by chromosome instability. Occurs when a loss in the DNA repair system of cancer cells allows chromosomal rearrangements that generate loss amplification and/or the exchange of chromosome segments. Examples include ataxia telangiectasia which is a mutation in the DNA damage response, kinase ATM, NBRC1 or MRN complex mutations that play a role in responding to DNA damage. When these components are not functional, the cell can also lose the ability to induce cell cycle arrest or apoptosis. Therefore, the cell can replicate and segregate incorrect chromosomes.

Answer 164

Cancer may begin because of the accumulation of mutations involving oncogenes, tumor suppressor genes, and DNA repair genes. For example, colon cancer can begin with a defect in a tumor suppressor gene (APC) that allows excessive cell proliferation. The proliferating cells then tend to acquire additional mutations involving DNA repair genes, other tumor suppressor genes (p53), and many other growth-related genes (K-ras). Over time, the accumulated damage can yield a highly malignant, metastatic tumor.

Answer 165

About half of the variation in mutation frequency and be explained by the tissue type of origin. Paediatric cancers can show frequency as low as 0.1 mutation per megabase, approximately 1 change across the entire exome. At the opposite end of the spectrum, melanoma and lung cancer can exceed 100 mutations per megabase. The highest mutation frequency are, in some cases, attributable to extensive exposure to well known carcinogens, such as UV radiation (melanoma) and tobacco smoke (lung cancers).

Answer 166

A malignant melanoma genome can contain more than 33,000 somatic mutations. Many of these mutations are identical and bear the imprinting signature of the previous exposure to UV light. The DNA damage from UV radiation leads to the formation of covalent bonds between two adjacent pyridimines (C and T) in the DNA molecule. If the pyrimidine dimer is not repaired and becomes a substrate for DNA replication, then most DNA polymerase will follow the “A rule”, and insert two adenines opposite the dimer. Late repair, or another round of replication can then immortalise the original lesion as a C or T transition mutation. So the mutational signature of UV light is predominantly C to T transition in dipyrimidine context. If these DNA changes occur in critical genes such as BRAF, it can lead to inappropriate and sometimes aggressive cell growth therefore the development of malignant melanoma.

Answer 167

An excess of G to T transitions occurs in the P53 gene of smokers, with a 30% prevalence in lung cancers of smokers, compared to only 12% in the lung cancers of non-smokers.

Answer 168

1) Passenger mutation: many mutations can be tolerated by somatic cells (often in heterozygote state). These have no effect on the fitness of a clone, but may be associated with clonal expansion because they occur in the same genomes, carrying a driver mutation. 2) Driver mutation: few mutations can confer a selective advantage and are recurrently found (in homozygote state). They reside in the subset of cancer genes, oncogenes. These are cancer genes in which driver mutations activate or result in new functions. Driver mutations inactivate the function of tumour suppressors. These tend to cause clonal expansion.

Answer 169

Candidate driver genes are considered to be genes mutated in a greater proportion of cancer samples than would be expected from the background mutation rate. More frequent mutation than expected from the background mutation rate suggests that cell with a mutation of that gene are more likely to become cancerous than without the mutation of that gene. This, that gene is a candidate driver. However, accurately estimating background mutational frequency is difficult because of the variability in mutation rate between cancer types, thousand fold variation between samples of the same cancer type and up to five fold variation across the genome itself. Even if the correct average background frequency is used, underestimating variability between genes or between samples increases false positive results. Candidate driver mutations may also be distinguished from passenger mutation by their tendency to have a greater impact on protein function than passenger mutations do. Unlike frequency based approaches, function based approaches can identify candidate driver mutations using data from a single sample.

Answer 170

These are genes that have the potential to cause cancer. Most begin as proto-oncogenes, which are normal proteins involved in regulation of cell proliferation, differentiation and apoptosis. If these normal genes are upregulated through a mutation, which most often has the property of being dominant and/or gain of function, meaning increasing the activity of the protein that will predispose the cell to cancer are therefore called oncogenes. Most normal cells will undergo apoptosis when a critical function is altered or malfunctioning, but activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead. Sarcone was the first discovered oncogenes in 1970, and sarcoma was first discovered in a chicken retrovirus.

Answer 171

Most cancer-causing mutations involving oncogenes are acquired, not inherited. They generally activate oncogenes by simple mutations such as: base substitution, chromosome rearrangements, gene amplification (Myc), or mutation (Ras).

Answer 172

A chromosome rearrangement caused by the reciprocal translocation between chromosomes 9 and 22 creates an elongated chromosome 9 and a truncated chromosome 22. The resulting Philadelphia translocation fuses the genes BCR and ABL, the Philadelphia chromosome, which leads to chronic myeloid leukemia (CML). Chromosomal rearrangements are often detected in haematological malignancy as well as solid tumours and can result in the creation of fusion genes with oncogene cells potential.

Answer 173

The fracture of the normal BCR gene is not entirely clear, but the protein has serine threonine kinase activity and is a guanine nucleotide exchange factor for Rho family GTPase. The function of the mammalian ABL protein - a ubiquitously expressed no receptor tyrosine kinase - is in response to different types of signals such as cytokines, DNA damage, oxidative distress, when it is activated to stimulate cell proliferation or differentiation, retraction or migration and apoptosis. The product of this oncogene BCR/ABL as elevated ABL tyrosine kinase activity relocates to the cytoskeleton and phosphorylates in an uncontrolled manner multiple cellular substrate.

Answer 174

Gene amplification occurs through a redundant replication of a portion of the genomic DNA that can contain critical dosage, the dependent gene, such as Myc. Myc is a potential transcription factor, acting as a proto-oncogene and need this amplification signal. An increasing proto-oncogene expression can also occur by mutation that activates the promoter to transcribe more mRNA or through the de-expression of the entire genomic region.

Answer 175

Similarly to ABL, Ras protein controls the cellular signalling pathway responsible for growth, migration, adhesion, cytoskeleton integrity, survival and integration. Ras protein belongs to the large family of small GTPases, which are activated in response to various extracellular stimuli. Ras is a gene that acts as an on/off switch in cell signalling. When it functions normally, it controls cell proliferation, when it’s mutated, the feedback governing cellular proliferation is disrupted and the cell starts to divide in an uncontrolled manner. The specie oncogene is k-Ras, first identified as an oncogen in Kurstin Rat Sarcoma virus.

Answer 176

This is residue in which the most common mutations in Ras are found. The activity of Ras is governed by its business binding to GTP in its active state or to GDP in its inactive state. Ras is required to bind the protein GAP for its inactivation of GDP hydrolysis. Because Ras is a relatively poor catalyst on its own, as opposed to Gill domain containing containing proteins. The glycine to valine or cysteine substitution at residue 12 renders the GTPase domain of Ras insensitive to inactivation by GAP and thus, stick in the on state with dramatic consequence for the behaviour of the cell.

Answer 177

A few cancer syndromes are caused by inherited mutations of proto-oncogenes that cause oncogene to be turned on or activated: 1) Multiple Endocrine Neoplasia Type 2 (MEN2) is caused by an inherited mutation in the gene called RET, people affected by this syndrome often develop an uncommon thyroid cancer called medullary cancer of thyroid 2) Inherited mutations in the gene called KIT lead to hereditary gastrointestinal stromal tumors (GISTs). 3) Inherited mutations in the gene called MET lead to hereditary papillary renal cancer 4) Inherited mutations in the gene called CDK4 lead to malignant melanoma.

Answer 178

These are genes that regulate a cell during cell division and replication. When a tumour suppressor gene is mutated, it results in a loss or a reduction of its function. In combination with other genetic mutations, or with the loss of a second allele, this could allow the cells to grow abnormally. The loss of function of these genes is often recessive and may be even more significant in the development of human cancer compared to the activation of oncogenes.

Answer 179

These functions fall into several categories, including: 1) The repression of genes that are essential for the progression of the cycle 2) Coupling of the cell cycle to DNA damage, meaning that as long as there is DNA in the cells, they should not rise and if the DNA damage can be repaired, the cell can continue. 3) The control of apoptosis, if the DNA damage cannot he repaired, the cell should initiate apoptosis, to remove the threat it poses to the organism as a whole. 4) DNA repair, protein involved in this are usually classified as tumour suppressors, a mutation in their genes increase the risk of cancer. Increased mutation rate from decreased DNA repair leads to increased inactivation of other tumour suppressors and the activation of oncogenes.

Answer 180

This was a hypothesis proposed in 1971 by Dr. Alfred Knudsen, to explain the early onset at multiple sites in the body of an inherited form of cancer called hereditary retinoblastoma. Most loss-of-function mutations that occur in tumor suppressor genes are recessive in nature, thus in order for a particular cell to become cancerous, both of the cell’s tumor suppressor genes must be mutated. In the first event in the two-hit model is an inherited mutation, however inheriting one germline copy of a damaged gene present in every cell in the body is not sufficient to enable this cancer to develop. A second hit (or loss) to the good copy in the gene pair could occur somatically, producing cancer. This hypothesis predicts that the chances for a germline mutation carrier to get a second somatic mutation at any of multiple sites in his/her body cells is much greater than the chances for a non-carrier to get two hits in the same cell.

Answer 181

One function of regional asthma is to prevent the excessive growth by inhibiting cell cycle progression, until a cell has made all necessary checks in the G1 phase, and is ready to divide. When the cell is ready, the retinoblastoma is phosphorylated by cylin dependent kinase, leading to its inactivation, and allowing cells to enter into S phase. Retinoblastoma belongs to the pocket protein family, whose members have a pocket in their structure for the functional binding of other proteins. The partner of retinoblastoma is the important transcription E2F, essential for the activation of the transcriptional program of a cell moving onto S phase from G1, with the expression of proteins, such as cyclin E and cyclin A. Phosphorylated retinoblastoma binds E2F at a class D transcriptional program

Answer 182

p53 is also known as protein 53 or tumor protein 53, is a tumor suppressor protein that in humans is encoded by the TP53 gene. It is important to regulate the cell cycle and it functions as a tumor suppressor gene to prevent cancer. If the TP53 gene is damaged, tumor suppression function is severely reduced. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome.The TP53 gene can also be damaged in cells by mutagens (chemicals, radiation, or viruses), increasing the likelihood that the cell will begin decontrolled division. Loss of the TP53 gene (due to mutations or deletion) occurs in >50% of human cancers (almost100% of high grade serous ovarian cancers) These cancer cells are genetically unstable because they are unable to do the following: - Stop the cell cycling to allow time for DNA repair - Carry out efficient DNA repair - Undergo apoptosis

Answer 183

It has many different functions, including: 1) DNA repair 2) Inducing apoptosis and promoting ten senescence in response to shortening of the telomeres 3) Transcription 4) Regulating the cell cycle 5) Its main function is binding to DNA and regulating gene expression to prevent the accumulation of mutations in the genome, hence the name “the guardian of the genome”.

Answer 184

As it is such a potent protein, p53 must be kept at low levels in the cell, almost undetectable. This is achieve by constantly ubiquliated by the E3 ligases MDM2 and MDM4 and targeted by 26S proteosome for degradation. Only when p53 is required, like in the event of DNA damage, does it become phosphorylated by the ATM/ATR check one axis. Itss conformation is then changed, allowing it to detach from the MDM proteins and be stabilised in the nucleus, allowing it to exert its functions.

Answer 185

BRCA1 is phosphorylated by ATM and CHK2 in response to double – stranded DNA breaks (i.e. these could be produced due for example by ionizing radiation). BRCA1 binds to BRCA2, which interacts with RAD51 to form a complex which is involved in DNA repair

Answer 186

Several DNA and RNA viruses a have been linked to certain types of cancers in humans these occur when the viral DNA mixes with the host DNA, triggering changes in the cells to make it multiply and eventually interfere with its normal cellular program. One example is cancer of the cervix, linked to infection with the extremely common human papillomavirus (HPV), and is responsible for 99% of cervical cancers. However, not every viral infection leads to cancer and most HPV infections are low risk and produce localised tumours like warts. Some HPV proteins play an important role in viral genome replication, such as E1 and E2. Other proteins, such as E6 and E7, confer selective growth advantage to the host cells by interfering with the normal function of retinoblastomas and p53, respectively. E7 is a small protein, with no intrinsic enzyme activity, but has evolved a few amino acids that allow it to bind to retinoblastoma and promote its degradation. This way, the cell will divide faster and secure replication or the viral genome that it carries.

Genetics Flashcards

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