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YEAR 1 - Biochemistry and Medical Genetics (Anton) > 3. Molecular and Medical Genetics (TT) > Flashcards

3. Molecular and Medical Genetics (TT) Flashcards

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1
Q

Define phenotype.

A

The physical description of a character in an individual organism.

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2
Q

Define character and trait.

A
  • Character -> The structure, function or attribute determined by a gene or a group of genes.
    • e.g. The appearance of the seed coat in Mendel’s garden pea studies
  • Trait -> The alternate forms of the character
    • e.g. “Smooth” or “wrinkled” peas
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3
Q

Define genotype.

A
  • The genes an individual has at a particular site or locus
  • They are responsible for the observed phenotype
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4
Q

Define penetrance.

A
  • The chance that a given genotype will cause a given phenotype
  • It is usually used in reference to mutations (i.e. how likely a given mutation is to cause x)
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5
Q

Define locus.

A

A location within the genome of the individual.

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6
Q

Explain penetrance in relation to the BRCA1 gene.

A
  • Penetration in BRCA1 mutation carriers is about 80% (it is autosomal dominant)
  • This means that is a lifetime chance of 80% of developing breast cancer
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7
Q

What is pedigree drawing?

A

The drawing of genetic trees.

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8
Q

In pedigree drawing, what does this symbol mean?

A

Male, affected

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9
Q

In pedigree drawing, what does this symbol mean?

A

Female, unaffected

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10
Q

In pedigree drawing, what does this symbol mean?

A

Male, deceased

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11
Q

In pedigree drawing, what does this symbol mean?

A

Mating

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12
Q

In pedigree drawing, what does this symbol mean?

A

Consanguineous mating (inbreeding)

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13
Q

What is consanguineous mating?

A

Inbreeding.

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14
Q

In pedigree drawing, what does this symbol mean?

A

Pregnancy

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15
Q

In pedigree drawing, what does this symbol mean?

A

Female carrier

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16
Q

In pedigree drawing, what does this symbol mean?

A

Spontaneous abortion or still birth

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17
Q

In pedigree drawing, what does this symbol mean?

A

Dizygotic (non-identical) twins

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18
Q

In pedigree drawing, what does this symbol mean?

A

Monozygotic (identical) twins

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19
Q
A
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20
Q

In pedigree drawing, what does this symbol mean?

A

Person seeking advice

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21
Q

Draw the pedigree for this example:

  • A 35 year old lady is seeking genetic advice
  • She has 3 older sisters, two of whom have had breast cancer
  • Her mother also had breast cancer
  • She has two children, a son aged 6 and a daughter aged 4
A
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22
Q

Draw the pedigree for this example:

Jill is a 4 year old girl who has sickle cell anaemia. Her parents both have 2 sisters, and one of her father’s sisters also had a son with the condition, who has died.

A
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23
Q

Draw the pedigree for this example:

  • A couple, James and Emily, come to see you, as they are planning to have children.
  • They are first cousins, because their mothers are sisters.
  • James has a older brother, and Emily has an younger sister.
  • Emily’s sister has already had children, a pair of identical twin girls.
  • James’s older brother has achondroplasia
A
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24
Q

What is achondroplasia?

A

Short-limbed dwarfism.

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25
Q

What is a gene?

A
  • Genes are instructions for building proteins and to tell a cell how to behave.
  • Genes are composed of DNA
  • Genes are located on chromosomes
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26
Q

Based on what principle where the chromosomes numbered?

A

They were numbered based off size.

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27
Q

Are diseases based off of genetics or environmental?

A

They can be based off a combination of both.

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28
Q

Out of these, which diseases tend to have the highest population burden:

  • Genetically determined
  • Genetically and environmentally determined
  • Environmentally determined
A

Those which have both genetic and environmental factors.

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29
Q

Draw a diagram to show the spectrum of conditions from 100% environmental to 100% genetic.

A
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30
Q

What does autosomal mean?

A

That the gene is not on the sex chromosomes, but on one of the other ones (autosomes).

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31
Q

What is autosomal dominant inheritance?

A
  • Only one of the two copies of the gene needs to be mutated to get the disease
  • So heterozygotes are affected by the disease -> Subject to penetrance of the mutation
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32
Q

For an autosomal genetic condition, what are the chances of a heterozygous parent (and an unaffected parent) passing on the condition?

A

50%

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33
Q

What are some examples of autosomal dominant conditions?

A
  • Achondroplasia
  • Huntington’s disease
  • Marfan syndrome
  • Familial breast cancer
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34
Q

What is expressivity?

A
  • Expressivity is the degree to which a phenotype is expressed by individuals having a particular genotype.
  • Expressivity is related to the intensity of a given phenotype -> It differs from penetrance, which refers to the proportion of individuals with a particular genotype that actually express the phenotype
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35
Q

What is autosomal recessive inheritance?

A
  • When both copies of a gene need to be mutated to get the disease
  • Heterozygotes are unaffected ‘carriers’
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36
Q

For an autosomal dominant condition, what is the chance of two carriers having an affected child?

A

25%

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37
Q

Tay-Sachs disease is an autosomal recessive disease common in the Jewish population. It causes severe neurological degeneration. Affected individuals are unable to walk or communicate normally and are severely developmentally delayed. A Jewish couple, Rachel and Lev come to see you. Both are developmentally normal. They are planning to get married. Rachel’s brother has Tay-Sachs disease. What is the chance that Rachel is a carrier for this condition?

A

The likelihood is 2/3rd, because we know she is not affected.

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38
Q

What are some examples of autosomal recessive conditions?

A
  • Tay-Sachs
  • Cystic Fibrosis
  • Sickle Cell Anaemia
  • Albinism (mostly)
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39
Q

What is X-linked recessive inheritance?

A
  • Where the gene for the disease exists on the X chromosome
  • In males, if the X chromosome has the mutation, then they are affected
  • In females, if both X chromosomes have the mutation, then they are affected, but if only one has the X chromosome then they are carriers
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40
Q

For an X-linked recessive condition, what is the risk to the children of a carrier female?

A

Risk to female offspring:

  • 50% carrier, 50% normal

Risk to male offspring:

  • 50% affected, 50% normal
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41
Q

With female carriers of X-linked recessive conditions, are they usually affected or not?

A

Usually not, but X-inactivation is usally random. If it is skewed, then they may be affected.

[More flashcards on this later]

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42
Q

What are some examples of X-linked recessive conditions?

A
  • Haemophilia
  • Colour-Blindness
  • Duchenne Muscular Dystrophy
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43
Q

What is X-linked dominant inheritance?

A
  • Where the gene for the disease exists on the X chromosome
  • In males, if the X chromosome has the mutation, then they are affected
  • In females, if either of the X chromosomes have the mutation, then they are affected
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44
Q

Compare how being affected by X-linked dominant conditions is likely to manifest in males and females.

A
  • If a female has only one mutant X-chromosome, then she will be affected but is likely to survive/be less mildly affected due to X-inactivation
  • If a male has a mutant X-chromosome, then he wil be affected and is likely to die/be severely affected
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45
Q

For an X-linked dominant condition, what is the risk to the children of a heterozygous affected female and an unaffected male?

A
  • Risk to female offspring
    • 50% affected, 50% normal
  • Risk to male offspring
    • 50% very severely affected/dead, 50% normal
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46
Q

What are some examples of X-linked dominant conditions?

A
  • Rett syndrome
  • Hypophosphataemic rickets
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47
Q

What does hemizygous mean? Why is it relevant?

A
  • A condition in which only one copy of a gene or DNA sequence is present in diploid cells.
  • Males are hemizygous for most genes on sex chromosomes, having only one X and one Y chromosome -> This is relevant in X-linked conditions.
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48
Q

Are mitochondria inherited from the mother or father?

A

Mother

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49
Q

With mitochondrial diseases, is it easy to predict the risk to offspring?

A
  • No, because a cell has many mitochondria and not all of them will carry a mutation.
  • Therefore, it is hard to predict the mutation load on any given egg cell.
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50
Q

What is mutation load?

A
  • The total genetic burden in a population resulting from accumulated deleterious mutations
  • e.g. The total number of mutated mitochondria in a cell
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51
Q

What is mitochondrial heteroplasmy?

A
  • Heteroplasmy is the presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual.
  • It is an important factor in considering the severity of mitochondrial diseases.
  • Because most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mitochondrial DNA, it is common for mutations to affect only some mitochondria, leaving most unaffected.
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52
Q

When a mother passes on a mitochondrial disease, how will the offspring be affected?

A

The degree of severity will vary between individuals. This is because not all mitochondria in the mother are mutated, so the fraction of those passed on that are mutated is random in each offspring.

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53
Q

What are some examples of mitochondrial conditions?

A
  • MERRF (Myoclonic Epilepsy with Ragged Red Fibres)
  • MELAS (Mitochondrial encephalopathy, lactic acidosis, stroke)
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54
Q

What is uniparental disomy and why is it important?

A
  • The inheritance of 2 copies of one chromosome from one parent and no copies from the other parent (e.g. both copies of chromosome 19 coming from the father)
  • This is important because some genes are imprinted -> This means we only use the copy from one specific parent
  • If that copy is not inherited we get the condition
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55
Q

What is genomic imprinting?

A
  • An epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner.
  • In other words, it is when a for specific gene it is always the father or mother copy that is expressed.
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56
Q

What are some examples of inherited by uniparental disomy?

A

Prader-Willi syndrome:

  • Here you receive 2 copies of mum’s chromosome 15 -> No copies received from dad
  • The symptoms include being floppy as a baby and obesity as an adult

Angelman syndrome (once known as “happy puppet syndrome”):

  • Here you receive 2 copies of dad’s chromosome 15 -> No copies received from mum
  • The symptoms include severe mental development problems -> Often unable to string together more than a couple of words
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57
Q

Describe how medical genetics is involved in the NHS.

A
  • Clinical Genetics Consultant -> The patient-facing doctors that carry out clinical diagnoses, genetic counselling, risk assessment (in cancer genetic), prenatal & presympotmatic diagnoses
  • Molecular Genetics Lab -> Undertake mutation analysis
  • Cytogenetics Lab -> Do all the chromosome work
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58
Q

What do clinical geneticists do?

A

Work is split into 4 main categories:

  • Syndromes
  • Neurogenetics
  • Fetal/Reproductive Medicine
  • Cancer Genetics
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59
Q

Give an example of clinical geneticists dealing with syndromes.

A

Presentation:

  • A 5 year old boy is referred to Clinical Genetics
  • He started walking aged 2 years 9 months
  • He says the odd word but can’t talk in phrases
  • He looks nothing like his parents
  • His mum is worried because her brother was ‘delayed’ and had to go to a special school

Symptoms:

  • Large head
  • Large ears
  • Hyperactivity / Autism

Diagnosis:

  • Fragile X syndrome

Response:

  • Parents probably want to know what the likelihood of recurrence will be in their next child
  • If the next child is a boy:
    • 50% chance of him being affected
    • 50% chance of him being normal
  • If the next child is a girl:
    • 50% chance she will be a carrier
    • 50% chance she will be normal
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60
Q

What is fragile X syndrome?

A

X-Linked Recessive condition:

  • Most common cause of intellectual disability in boys after Down Syndrome Features
  • Hyperactivity/autism
  • Large head
  • Large ears
  • Post-pubertally - large testicles
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61
Q

Give an example of clinical geneticists dealing with neurogenetics.

A

Presentation:

  • A 30 year old lady comes to see you
  • Her father is in a nursing home
  • He has ‘Alzheimer’s’, but is only 52
  • She is worried that this might happen to her, and wants some advice.

Response:

  • First confirm the diagnosis in her father
  • It is CADASIL -> An early onset dementia syndrome
  • Genetic testing available
  • Autosomal dominant inheritance -> She has a 50% of inheriting the condition
  • There is no cure, so there must be a conversation with the patient about whether she wants to know if she has the condition
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62
Q

Give an example of a clinical geneticist dealing with fetal medicine.

A

Presentation:

  • A couple are referred to see you
  • They have had a miscarriage at 30 weeks, and the baby was known to be extremely abnormally developed
  • They want to know what the diagnosis was and the chance of it happening again

Diagnosis:

  • Thanatophoric Dwarfism (a form of dwarfism that is not compatible with life)
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63
Q

Give an example of a clinical geneticist dealing with cancer genetics.

A

Presentation:

  • Jennifer is referred to see you.
  • She is 26 and has just been diagnosed with breast cancer.
  • Her mother had breast cancer aged 41, and her maternal aunt died from it aged 45
  • She has a sister, Catherine, aged 24, who is panicking about getting cancer and wants to have her breasts removed immediately

Likely diagnosis = Familial breast cancer:

  • Caused by mutations in BRCA1/BRCA2
  • Autosomal dominant inheritance
  • BRCA1 mutation found in Jennifer and her mother
  • Implications for Catherine:
    • Likelihood of inheriting mutation 50%
    • Therefore, likelihood of breast cancer 40% (50% chance of inheriting x 80% chance if she is confirmed positive)
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64
Q

What are the two strands in a chromosome called?

A

Chromatids

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65
Q

What joins the two chromatids in a chromosome?

A

Centromere

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66
Q

What does the centromere divide each chromosome into?

A
  • p arm -> Short arm
  • q arm -> Long arm

(p for petit)

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67
Q

What are the different types of chromosome based on the position of the centromere?

A
  • Acrocentric -> Centromere near the end
  • Metacentric -> Centromere near the middle
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68
Q

What type of chromosome is this?

A

Metacentric

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69
Q

What type of chromosome is this?

A

Acrocentric

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70
Q

What type of chromosome is this?

A

Submetacentric

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71
Q

What is a telomere and what do they do?

A
  • The tip of each chromatid in a chromosome
  • Maintain the structural integrity of chromosomes
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72
Q

What do telomeres consist of?

A

Highly conserved tandem repeat sequences.

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73
Q

What is telomerase?

A
  • Enzyme that adds a species-dependent telomere repeat sequence to the 3’ end of telomeres -> This ensures that replication can continue.
  • Otherwise, the telomere becomes gradually shorter with each division until critical length is reached.
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74
Q

What happens when the critical length of the telomere is reached? Why is this clinically relevant?

A
  • Cell can no longer divide and becomes senescent
  • This occurs in normal cell aging
  • In tumours, this process goes wrong and the cell becomes immortal
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75
Q

How many chromosomes do humans have?

A

46 (23 pairs)

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76
Q

Describe the normal chromosome complement.

A

In humans the normal chromosome complement consists of 46 chromosomes, including the 2 sex chromosomes.

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77
Q

Draw the process of how chromosomes can be coloured to look like “stripey socks”.

A
  • Collect blood
  • Add phytohaemagglutinin and culture medium
  • Culture at 37*C for 3 days
  • Add colchicine and hypotonic saline
  • Fix the chromosomes on slides
  • Digest with trypsin and stain with Giemsa
  • Observe the metaphase spread of chromosomes
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78
Q

In which phase of the cell cycle are chromosomes frequently viewed?

A

Metaphase -> This shows them in their X-shape

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79
Q

What is G-banding and how is it done?

A

It is a staining technique used to give chromosomes a black and white band pattern:

  • Denature proteins with trypsin
  • Stain with Giemsa (a DNA-binding dye)
  • Gives each chromosome a characteristic pattern of dark and light bands
  • Active (transcribed) areas stain light
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80
Q

What enzyme is used to denature proteins in G-banding?

A

Trypsin

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81
Q

What stain is used in G-banding?

A

Giemsa (G-banding is short for Giemsa-banding)

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82
Q

In G-banding, which parts of the chromosomes stain light and which are dark?

A
  • Light = Transcribed (active)
  • Dark = Not transcribed (inactive)
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83
Q

Is G-banding the only type of banding?

A

No, there are also other types of banding, but G0banding is most common.

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84
Q

What is the resolution of G-banding?

A

6-8 megabases of DNA (i.e. each band is 6-8 megabases of DNA)

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85
Q

What is the problem with G-banding to view chromosomes?

A

The resolution of 6-8mb is relatively poor.

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86
Q

What is FISH?

A

Fluorescence In Situ Hybridization:

  • Uses the ability of a single-stranded piece of DNA (a probe) to anneal to its complementary target sequence wherever it is located
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87
Q

Where in the cell cycle can FISH (Fluorescence In Situ Hybridization) be used?

A
  • Metaphase
  • Interphase
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88
Q

What is the problem with FISH (Fluorescent In Situ Hybridisation)?

A

The resolution is too low to detect specific mutations.

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89
Q

What is chromosome painting and when is it used?

A
  • It is like FISH (fluorescent in situ hybridisation) except all of the chromosomes are painted different colours using a mixture of probes specific for each chromosome
  • This helps with the identification of an orphan piece of chromosome that we do not know the origin of
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90
Q

What is the standard tool for analysis of chromosome complement?

A

Array CGH

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91
Q

What does array CGH stand for?

A

Array comparative genome hybridisation

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92
Q

How does array CGH work?

A
  • Used to detect regions of gene amplification or gene loss by comparing the test subject to a ‘normal’ reference
  • This involves competitive fluorescence in situ hybridization
  • Test DNA is labelled with a green paint
  • Normal DNA is labelled with a red paint
  • Gene amplification in the test subject shows up as green
  • Gene loss in the test subject shows up red
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93
Q

What is array CGH used for?

A
  • In cancer genetics -> To detect unusual chromosome patterns in the cancer
  • Used to detect chromosome abnormalities in dysmorphic individuals (those with an abnormality in body structure)
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94
Q

In array CGH, what does green indicate?

A

Gene amplification (an increase in the number of copies of a gene without a proportional increase in other genes)

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95
Q

In array CGH, what does red indicate?

A

Gene loss (decrease in the number of copies of a gene without a proportional increase in other genes)

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96
Q

What is an array? Why is it used?

A
  • Array is shorthand for ‘Array Comparative Genome Hybridization’ or Array CGH
  • It involves the detection of dosage abnormalities on chromosomes that are not visible cytogenetically (not visible on a karyotype that is G-banded)
  • Some abnormalities are not phenotypically relevant
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97
Q

Draw the process of array CGH (comparative genome hybridisation).

A

The green colour shines through if there is gene loss from the patient DNA. The red colour shines through if there is gene amplification in the patient DNA.

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98
Q

What are the different categories of chromosome abnormalities?

A
  • Structural -> e.g. Translocation
  • Numerical -> e.g. Polyploidy
  • Different cell lines -> e.g. Mosaicism
  • Sex chromosome abnormalities
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99
Q

How is sex determined?

A
  • Presence of a Y chromosome leads to maleness regardless of number of X chromosomes present
  • SRY discovered as sex-determining region on Y chromosome
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100
Q

What is the evidence for the SRY region being the sex-determining region in males?

A
  • This region was present in a number of XX males
  • Deletion or mutation of this region was seen in a number of XY females
  • Transgenic XX mice where SRY had been inserted develop into males
  • Gene encodes a transcription regulator
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101
Q

How does SRY lead to sex determination in males?

A
  • Default option is female -> Female genitalia develop in embryos from Mullerian ducts
  • If SRY present, transcription of genes leading to testis production occurs from Wolffian ducts
  • Sertoli cells in the testis produce Mullerian Inhibitory Factor (MIF), which inhibits female genitalia production
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102
Q

Caster Semanya was an athlete at the Olympics who identified as a female and had female genitalia, but had muscles etc. like a man. What is a possible diagnosis for this?

A

Androgen insensitivity syndrome -> This results in in high levels of testosterone, but lack of differentiation of genitalia to male structures.

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103
Q

Is the amount of X-linked products the same in males and females? Why?

A
  • Yes, even though males have only 1 X chromosome, while females have two.
  • The explanation for this is the Lyon hypothesis.
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104
Q

What does the Lyon hypothesis describe?

A

The concept of X-inactivation.

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105
Q

Describe the concept of X-inactivation.

A
  • In somatic cells of a female, X-inactivation of one of the X chromosomes occurs early in embryonic life.
  • It is generally random whether it is the paternal or maternal X that is inactivated BUT not totally random
  • Inactivation does not include those with an analogue on the Y chromosome
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106
Q

Is X-inactivation random?

A

Generally, but a structurally abnormal X chromosome is preferentially inactivated.

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107
Q

Does X-inactivation affect the whole X chromosome?

A

No, some genes escape inactivation (i.e. the ones that are also present on the Y chromosome)

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108
Q

Is X-activation permanent?

A

Yes, except in reversed in development of germ cells (so it is not passed on to gametes).

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109
Q

Is X-inactivation propagated through mitosis?

A

Yes, the same X chromosome is inactivated in both the old and new cell.

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110
Q

What is a Barr body?

A

A Barr body is an inactive X chromosome in a cell with more than one X chromosome.

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111
Q

If you have, for example, 4 X chromosomes in a cell, how many of them are inactivated?

A

All of them except 1.

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112
Q

How many Barr bodies are present in a cell with 48 XXXX?

A

3

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113
Q

Explain tortoiseshell cats.

A
  • Tortoiseshell cat always female
  • They are heterozygous for black and orange hair: XBXO (XB=black) (XO=orange)
  • These are randomly inactivated during embryo development, so there are patches of black and patches on the cat
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114
Q

What are the main abnormalities of sex chromosomes?

A
  • Turner Syndrome
  • Klinefelter’s Syndrome
  • Triple XXX
  • XYY
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115
Q

What is the Turner syndrome karyotype and what are the symptoms?

A
  • 45X

Symptoms:

  • Webbed neck
  • Short stature
  • Widely-spaced nipples
  • Shield chest
  • Wide carrying angle
  • Primary amenorrhoea and infertility
  • Cardiac abnormalities
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116
Q

What is the Klinefelter’s syndrome karyotype and what are the symptoms?

A
  • 47 XXY

Symptoms:

  • Tall stature
  • Slightly feminised physique
  • Mildly impaired IQ
  • Tendency to lose chest hairs
  • Female-type pubic hair pattern
  • Testicular atrophy
  • Osteoporosis
  • Breast development
  • Poor beard growth
  • Frontal baldness absent
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117
Q

What is triple X syndrome and what are the symptoms?

A
  • When the karyotype is 47 XXX

Symptoms:

  • Tall, feminine
  • Slight intellectual impairment
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118
Q

What is XXY syndrome and what are the symptoms?

A
  • When the karyotype is 47XXY

Symptoms:

  • May be associated with aggression
  • May be associated with criminal tendencies

However, it is not reported as an abnormality is some countries.

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119
Q

What are the different types of numerical chromosomal abnormalities you need to know about?

A

Trisomies:

  • Down syndrome
  • Patau syndrome
  • Edwards syndrome

Deletions:

  • DiGeorge syndrome(22q11, CATCH-22)
  • WAGR
  • Williams syndrome
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120
Q

What causes Down syndrome?

A
  • Having an extra copy of chromosome 21
  • Can also result from a translocation (more on this later)
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121
Q

How common is Down syndrome?

A

1 in 700 births

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122
Q

What are some of the symptoms of Down syndrome?

A
  • Intellectual disability
  • Typical face
  • Cardiac problems
  • Increased risk of Alzheimer’s and leukaemias/lymphomas
  • Low muscle tone
  • Thyroid problems
  • Single palmar fold
  • Wide gap between toe and second finger
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123
Q

What type of chromosomal abnormality is Down syndrome?

A

Numerical

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124
Q

By what mechanism does Down syndrome occur?

A
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125
Q

What is Patau syndrome and what causes it?

A
  • Trisomy caused by an extra chromosome 13 (karyotype 47 XX+13)

Symptoms:

  • Clefting 
  • Finger and toe abnormalities 
  • Unlikely to survive 1st year
  • Severe intellectual disability
  • May have cyclopia
  • Heart defects
  • Scalp defects
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126
Q

What is Edwards syndrome and what causes it?

A
  • Trisomy caused by an extra chromosome 18 (karyotype 47 XX+18)

Symptoms:

  • Severe intellectual disability
  • Unlikely to survive first year
  • ‘Rocker-Bottom’ feet
  • Clenched fingers
  • Cardiac abnormalities
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127
Q

What are the different trisomies you need to know about?

A
  • Trisomies 13 (Patau), 18 (Edwards) and 21 (Down)
  • The others are not compatible with life
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128
Q

What is the main factor affecting the risk of trisomy?

A

The risk increases with the age of the mother.

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129
Q

What are the main chromosomal deletions you need to know about?

A
  • DiGeorge syndrome(22q11, CATCH-22)
  • WAGR
  • Williams syndrome
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130
Q

How are chromosomal deletions indicated in shorthand?

A

In the form 14Q11.

The 14 is the chromosome while Q is the arm on which the deletion is. Don’t know what the 11 is?

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131
Q

What is DiGeorge syndrome and what are the symptoms?

A
  • Deletion mutation on the Q arm of chromosome 22
  • 22Q11

Symptoms (very variable severity):

  • Cardiac abnormalities
  • Cleft palate
  • Short stature
  • Immunodeficiency
  • Association wth schizophrenia in adulthood
  • Long characteristic nose
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132
Q

What is WAGR and what are the symptoms?

A
  • Wilm’s tumour-Aniridia-Genital abnormalities-Retardation
  • Deletion mutation on the Q arm of chromosome 11
  • 22Q11

Symptoms:

  • Wilm’s tumour -> Renal tumour common in children under 5
  • Aniridia -> Absence of the iris
  • Genital abnormalities
  • Intellectual disabilities
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133
Q

Are all of the symptoms of WAGR always present together?

A

No, because there are many genes in the region, and not all of them are always deleted in the mutation.

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134
Q

What is Williams syndrome and what are the symptoms?

A
  • Deletion mutation on the P arm of chromosome 7
  • 7P11

Symptoms:

  • Intellectual disability
  • ‘Cocktail party chatter’
  • Hypercalcaemia
  • Cardiac abnormalities
  • Short stature
  • Full cheeks, full lips
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135
Q

What are the different types of structural chromosomal abnormalities?

A
  • Translocations
  • Deletions
  • Insertions
  • Inversions
  • Rings
  • Isochromosomes
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136
Q

What is a chromosomal translocation?

A

Transfer of genetic material from one chromosome to another.

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137
Q

What is the most common form of translocation mutation?

A
  • Reciprocal translocation
  • This is where there is a break in 2 chromosomes and the segments are exchanged to form 2 new derivative chromosomes
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138
Q

Do reciprocal translocations matter?

A
  • They don’t usually matter to the individual in which they occur, since the break is usually in the middle of a non-coding region, not a gene
  • However, they may matter to the future generations -> This depends on whether the meiotic segregation produces balanced genomes or not
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139
Q

What is a Robertsonian translocation?

A

A reciprocal translocation where the break-points are at or close to the centromeres of 2 acrocentric chromosomes.

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140
Q

How common are Robertsonian translocation abnormalities?

A
  • Most common structural chromosome abnormality in humans
  • Frequency = 1/1000 livebirths
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141
Q

What sort of chromosome does Robertsonian translocation involve?

A

Acrocentric (where the centromere is near the ends of the chromosomes)

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142
Q

What are the two types of Robertsonian translocation?

A
  • Involving homologous acrocentric chromosomes
    • Where the two chromosomes are of the same type
    • e.g. 14 & 14
    • The result is like a duplicate of the long arms of the chromosome, while the short ends are lost
  • Involving non-homologous acrocentric chromosomes
    • Where the two chromosomes are of different types
    • e.g. 14 & 21
    • The result is like a combination of the long arms of the chromosome, while the short ends are lost
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143
Q

How many chromosomes does a cell with a Robertsonian translocation have?

A

45 (since the two end bits that would form the 46th chromosome are lost)

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144
Q

Describe when a Robertsonian translocation is harmful to the offspring.

A
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145
Q

What type of chromosomal abnormality is this?

A

Balanced Robertsonian translocation -> The 21st chromosome has been taken and moved to the end of the 14th chromosome.

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146
Q

What type of chromosomal abnormality is this?

A

Unbalanced Robertsonian translocation -> There is a chromosome 21 attached to a chromosome 14, but there are also two 21st chromosomes. The result is trisomy (Down syndrome in this case)

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147
Q

Explain balanced and unbalanced translocations.

A

Balanced:

  • Even exchange of material between chromosomes with no genetic information extra or missing
  • Usually fully functional
  • Both adults and offspring can have this translocation

Unbalanced:

  • Where there are extra or missing genes
  • Not usually functional
  • Can only be inherited from adult with a balanced translocation -> This occurs when certain combinations of chromosomes are inherited
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148
Q

What is an isochromosome?

A
  • A structural chromosomal abnormality where one of the arms of a chromosome (either p or q) is lost and the other one is duplicated.
  • This produces a symmetrical chromosome.
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149
Q

In what specific case are isochromosomes clinically relevant?

A
  • Isochromosomes of chromosome 21 result in a 100% recurrence risk of Down syndrome
  • This is because chromosome 21 is an acrocentric chromosome, so the isochromosome is essentially two 21st chromosomes stuck together
  • This means that they are always passed on together to offspring, resulting in 100% chance of trisomy.
150
Q

What is a ring chromosome?

A
  • A chromosomal abnormality where both the ends of the p and q arm are broken and the remaining chromosome forms a ring.
  • The two ends are lost, which means this is essentially a double deletion.
151
Q

What chromosomal abnormality is this?

A

Ring chromosome

152
Q

What are some examples of conditions arising from a ring chromosome? Why do these occur?

A
  • Epilepsy, intellectual disability, craniofacial abnormalities
  • These occur because many important genes happen to be found at the ends of chromosomes
153
Q

What is a chromosomal inversion? What are the different types?

A

When there are two breaks in a chromosome and the fragment generated rotates 180*. This causes problems at meiosis.

154
Q

What are the main types of chromosomal inversion? Which is more severe?

A
  • Pericentric
    • Rotation around the centromere, involving both the p and q arms
    • More severe
  • Paracentric
    • Rotation within either the p or q arm
    • Less severe
155
Q

What is a insertion (relating to chromosomes)? When is it important?

A
  • When DNA is inserted into a chromosome, which can occur for many reasons
  • It is important when the DNA is inserted into a particular region of the chromosome
  • For example, inserting DNA into a regulatory element of certain genes can lead to uncontrolled growth and cancer
156
Q

What is duplication (in chromosomes) and what can it lead to?

A
  • It is the duplication of part of or an entire chromosome
  • Duplication can lead to trisomy of part of the chromsome
157
Q

What are mosaicism and chimerism?

A

The presence in an individual (or in a tissue) of 2 or more cell lines that differ in their genetic constitution:

  • Mosaicism -> Derived from a single zygote
  • Chimerism -> Derived from more than one zygote
158
Q

What is mosaicism and how can it occur?

A
  • The presence of two or more cell lines in an individual (or tissue) that are genetically different, but are derived from the same zygote.
  • It can occur when there is non-disjunction in one of the early mitotic divisions in the embryo
159
Q

What is chimerism and how can it occur?

A
  • The presence of two or more cell lines in an individual (or tissue) that are genetically different and are derived from different zygotes
  • It can occur when:
    • Dispermic chimeras -> When there are two sperm and two eggs that form one embryo
    • Blood chimeras -> When there is exchange of cells between non-identical twins via the placenta
160
Q

What condition can mosaicism lead to?

A

Down Syndrome -> However, this is usually less severe than normal Down Syndrome

161
Q

What are the two forms of chimerism?

A
  • Dispermic chimeras
    • 2 sperm, 2 eggs, one embryo
  • Blood chimeras
    • Exchange of cells between non-identical twins via placenta in utero
162
Q

What condition can cause true hermaphroditism?

A

Dispermic chimerism

163
Q

What is aneuploidy?

A

The presence of an abnormal number of chromosomes in a cell -> For example a human cell having 45 or 47 chromosomes instead of the usual 46.

164
Q

What are two important forms of aneuploidy you need to know about?

A
  • Monosomy
    • A form of aneuploidy with the presence of only one chromosome from a pair.
    • Partial monosomy occurs when a portion of one chromosome in a pair is missing.
  • Trisomy
    • A form of aneuploidy in which there are three instances of a particular chromosome, instead of the normal two.
165
Q

What is a mutation?

A
  • A heritable alteration or change in the genetic material.
  • These are usually pathogenic, but also drive evolution.
166
Q

What is a polymorphism?

A

A non-pathogenic alteration in DNA which may alter protein function but is not usually deleterious.

167
Q

Compare mutations and polymorphisms.

A

Mutations are usually pathogenic, while polymorphisms are usually not.

168
Q

How do mutations occur?

A
  • Mostly due to errors in DNA replication and repair
  • Exposure to exogenous mutagens (e.g. cigarette smoke)
169
Q

How common are dangerous mutations?

A

We all typically have around 6 lethal or semilethal mutations, but these are in recessive genes.

170
Q

Why is consanguinity dangerous?

A

The recessive lethal or semi-lethal mutations that the parents carry are more likely to be the same, so that the offspring have increased risk of inheriting genetic diseases.

171
Q

What are the different types of mutation?

A
  • Point mutations
  • Insertions
  • Deletions
  • Triplet repeat expansion
  • Splicing mutations
172
Q

What are point mutations and how do they arise?

A
  • Also known as substitution mutations -> Where a single base is replaced by another
  • This occurs due to spontaneous errors in DNA replication and repair, or errors induced by mutagens
173
Q

What are the two types of point mutation (based on what bases are involved)?

A
  • Transitions
    • Purine to purine (A↔G)
    • Pyrimidine to pyrimidine (T↔C)
  • Transversions
    • Purine to pyrimidine
174
Q

What is a transition point mutation?

A

Where a purine is replaced by another purine, or a pyrimidine is replaced by another pyrimidine.

A↔G or T↔C

175
Q

What is a transversion point mutation?

A

Where a purine is replaced by a pyrimidine, or a pyrimidine is replaced by a purine.

176
Q

What are the different types of point mutation in an exon (based on how the polypeptide is affected)?

A
  • Synonymous -> Does not change the amino acid sequence due to the redundancy of the genetic code
  • Non-synonymous -> Does change the amino acid sequence 
    • Missense -> Replacement of one amino acid by another
    • Nonsense -> The codon specifying an amino acid is replaced by a stop codon
177
Q

What is a synonymous point mutation?

A

Where a base is replaced by a base that does not change the amino acid at that point, so the polypeptide remains unchanged.

178
Q

What is a missense point mutation?

A

When a base is replaced by another base, causing the replacement of one amino acid by another.

179
Q

What is a nonsense point mutation?

A

When a base is replaced by another base, resulting in that codon being changed to a stop codon. This results in a premature termination of the polypeptide synthesis.

180
Q

What type of mutation is this?

A

Nonsense point mutation

181
Q

What type of mutation is this?

A

Synonymous point mutation

182
Q

What type of mutation is this?

A

Missense point mutation

183
Q

Give an example of a missense point mutation.

A

In sickle cell anemia, a GAG codon is turned into GTG, which changes the amino acid from glutamine to valine.

184
Q

How can you tell if a missense point mutation is important?

A

Consider the changes to the structure of the resulting polypeptide structure -> e.g. Whether the side chains are vastly different.

185
Q

What is the notation for point mutations?

A
  • Use either the letter or three letter code for amino acids
  • Write the original amino acid, the position it is at, and then the amino acid it is replaced by

e.g. The arginine at residue 117 is replaced by a histidine: R117H or Arg117His

186
Q

Write the notation for this mutation: “The glycine at residue 542 is replaced by a stop codon.”

A

G542X or Gly542Stop

187
Q

What are indels?

A

It is short for “insertions and deletions”.

188
Q

How long can insertion or deletion mutations be?

A

From 1bp to a megabase -> So they can disrupt either part of a gene or the entire gene

189
Q

Aside from the gene they are in, can indel mutations affect other parts of the genome?

A

Yes, if they are not a multiple of 3 bases, the insertions or deletions can cause frameshift and premature termination of proteins. They can also affect the normal regulation of genes.

190
Q

How can indel mutations lead to premature termination of proteins?

A

Insertion and deletion can cause frameshift and the creation of different codons. If the new codon created is a stop codon, it can lead to premature termination.

191
Q

What type of mutation is this?

A

Deletion mutation (leading to frameshift)

192
Q

What are some examples of a disease that is commonly caused by deletion mutations?

A

Duchenne muscular dystrophy:

  • It is an X-linked condition
  • It is a very large gene of over 79 exons, over 2 million base pairs
  • Most commonly, deletion mutations of one of more exons cause this
  • The symptoms include starting walking late, gradual deterioration and death from respiratory failure in the early 20s
193
Q

What does this image show?

A

The way in which children with muscular dystrophy stand up.

194
Q

What is a triplet repeat expansion mutation and why is it dangerous?

A
  • Triplet repeat sequences are common within the genome
  • During replication, the number in the sequence may be increased, leading to expansion
  • If this occurs within a gene or just upstream of a gene, this can lead to disruption of protein function
195
Q

What is anticipation with reference to triplet repeat expansion mutations?

A

Triplet repeats expand progressively over generations, leading to more early onset disease in offspring than their parents.

196
Q

What is the likely cause of triplet repeat expansion?

A

Strand slippage during replication:

  • The DNA strand being formed slips, folding in on itself
  • This leads to synthesis of extra triplets, means that the strand is longer than the original, resulting in a longer strand
197
Q

Are triplet repeat expansions always harmful?

A

No, usually only if they occur in the exons or the regulatory elements of a gene.

198
Q

Give examples of diseases caused by triplet repeat expansions:

  • In the exons
  • In the regulatory elements of a gene
A

In the exons:

  • Huntington disease

In the regulatory elements of a gene:

  • Myotonic dystrophy 1
  • Fragile X syndrome
199
Q

What causes Huntington’s disease and what is the pathology?

A
  • Expansion of a CAG repeat in exon 1 of the huntingtin gene
    • Chromosome 4Q16 
    • If there are >35 repeats, then it is pathological
  • Pathology -> Degeneration of neurons in the basal ganglia and cortical regions of the brain
200
Q

What triplet expansion underlies the development of Huntington’s disease?

A

CAG (on 4Q16)

201
Q

What indicates the age of onset of Huntington disease?

A

The number of CAG repeats -> If it is more than 60, then the onset is likely before age 25.

202
Q

What are the symptoms of Huntington disease?

A
  • In middle age -> Unsteady gait and jerky involuntary movements
  • Later symptoms -> Progressive dementia
203
Q

What causes myotonic dystrophy 1 and what are the symptoms? [EXTRA]

A

Cause:

  • Expansion of a CTG repeat in the 3’ untranslated region of the Dystrophia Myotonica Protein Kinase gene (i.e. upstream of the gene)
  • On chromosome 19q13 

Symptoms: 

  • Muscle pain
  • Myotonia (hyperexcitability of the muscle)
  • Cardiac arrhythmias (deviation from normal rhythm)
204
Q

At what two important sites can point mutations occur in non-coding regions?

A
  • Splice sites (for intron removal)
  • mRNA regulatory region
205
Q

What things can occur as a result of a point mutation in a splice site?

A
  • Intron retention -> The mRNA remains in the nucleus and is not translated
  • Exon skipping -> One of the exons is missed out from the final protein
206
Q

What occurs as a result of intron retention (due to splicing errors)?

A

The mRNA remains in the nucleus and is not translated.

207
Q

Draw a diagram to show exon skipping. Why does it occur?

A

It can occur due to a point mutation in splice sites.

208
Q

What are the effects of exon skipping (as a result of point mutations in splice sites)?

A
  • If frame maintained (i.e. number of nucleotides in skipped exon a multiple of 3), a truncated protein is formed
  • If frame not maintained (frameshift), a premature termination codon arises and RNA therefore degraded
209
Q

Describe how point mutations can affect mRNA regulatory elements.

A

An insertion can disrupt the regulatory element, so that transcription is not initiated properly. It is like the switch for a lightbulb being broken.

210
Q

What are the different categories of effects of mutations?

A
  • Loss of function
  • Alteration in function
  • Gain of function
211
Q

How can mutations cause loss of protein function?

A
  • By affecting the level of normal mRNA
    • Frameshift -> Causing premature termination codon
    • Nonsense mutations
    • Mutations in regulatory elements, promoters and enhancers
  • Or by a mutation in a critical domain of protein (i.e. ligand binding site of a receptor)
212
Q

Describe how mutations causing loss of function can be recessive or dominant.

A
  • Tend to be recessive
    • The cell can function normally with 50% of the product of the genes
  • Are sometimes dominant
    • The cell cannot function normally with only 50% of the product of the genes -> Haploinsufficiency
    • Alternatively, it is possible that the mutatant protein has lost its function and gained the ability to interfere with the function of the normal protein -> Dominant negative effect
213
Q

What is haploinsufficiency?

A
  • A situation in which the total level of a gene product (a particular protein) produced by the cell is about half of the normal level and that is not sufficient to permit the cell to function normally.
  • This is often the case with dominant mutations.
214
Q

What is the dominant negative effect?

A
  • In dominant mutations, the mutant allele may produce a protein that interferes with the function of the protein produced by the normal non-mutated allele.
  • This means that the cell does not function properly
215
Q

Draw diagrams to show recessive mutations and how they affect function.

A
  • The first diagram shows normal function
  • The second diagram shows normal function with one mutated allele
  • The third diagram shows the loss of function with two mutated alleles
216
Q

Draw a diagram to show haploinsufficiency.

A
217
Q

Give an example of a dominant loss of function disease. [EXTRA]

A
218
Q

What are three examples of diseases characterised by increased function due to mutations?

A
  • Huntington disease
  • Myotonic dystrophy
  • Achondroplasia
219
Q

What causes achondroplasia?

A

A mutation in the FGFR3 receptor:

  • Fibroblast growth factor receptor 3 -> Normally inhibits endochondral bone growth by inhibiting chondrocyte proliferation and differentiation
  • Mutation causes the receptor to signal even in absence of ligand
  • This causes short limbs
220
Q

What are some examples of diseases caused by failure of imprinted genes? What are imprinted genes?

A
  • Genes that, due to epigenetics, are expressed using just the maternal or just the paternal copy
  • Diseases include:
    • Prader-Willi Syndrome -> Failure of the paternal SNRPN gene
    • Angelman Syndrome -> Failure of the maternal UBE3A gene
221
Q

With imprinted genes, how does the body know whether to express the paternal or maternal copy?

A

If a gene is methylated at an upstream CpG sequence, it is switched off.

222
Q

Describe the 3 ways in which you can get Prader-Willi syndrome.

A
  • Uniparental disomy -> You get both copies of the gene from your mum
  • Mutation in the SNRPN gene inherited from dad
  • Methylation abnormality (dad’s SNRPN gene gets methylated and therefore switched off)
223
Q

Is cancer a hereditary disease?

A
  • Most cancer is not hereditary, but is instead caused by mutations in growth-controlling genes of somatic cells
  • Some families (rare) have inherited mutations (germline mutations) in those genes
224
Q

What are the three types of genes that can cause cancer when mutated?

A
  • Oncogenes
  • Tumour suppressor genes
  • DNA repair genes
225
Q

Draw a diagram to show the different functions of cancer genes (e.g. oncogenes, etc.) in the cell cycle.

A
226
Q

Compare when tumour suppressor genes and DNA repair genes act.

A

Tumour suppressor genes act before DNA replication to prevent any mutations, while DNA repair genes act after DNA replication, to correct any mutations.

227
Q

What are oncogenes and how can they lead to cancer?

A
  • Genes cause cells to grow and divide – essentially like ‘on’ switches
  • These ‘on’ switches are tightly controlled by other genes and by feedback control
  • If the control fails, the ‘on’ switch is permanently ‘on’ and the cell keeps dividing
228
Q

How many mutated copies of an oncogene are required for cancer to develop?

A

Only 1

229
Q

What are tumour suppressor genes?

A
  • They are the “off” switch for tumour formation
  • When they are mutated, they are less able to perform this function and a tumour may develop
230
Q

How many mutated copies of a tumour suppressor genes are required for tumour formation?

A

Both copies must be mutated, although having one inherited mutation increases your risk of cancer.

231
Q

What happens if you inherit one mutated tumour suppressor gene?

A

You are at increased risk of developing cancer (because only one tumour suppressor gene must mutate in order for you to develop a tumour).

232
Q

What is the ‘double hit’ hypothesis?

A
  • A cell can initiate a tumour only when it contains two mutant tumour suppressor alleles 
  • Individuals in the normal population therefore require two (somatic) mutations to initiate a tumour
  • Individuals who have inherited a germline mutation in a tumour suppressor gene only require one further somatic mutation to generate a tumour
  • These individuals therefore tend to develop tumours at younger ages and at multiple sites compared to the general population
233
Q

Who came up with the ‘double hit’ hypothesis?

A

Knudson

234
Q

Which genes does Knudson’s ‘double hit’ hypothesis refer to?

A

Tumour suppressor genes

235
Q

What is the importance of determining somatic mutations that underlie cancers?

A
  • May enable classification of tumours to aid prognosis and treatment -> Classification may mean less treatment for some patients
  • May enable targeted therapies
    • Glivec (targets BCR-ABL – see chromosome lecture)
    • BRAF inhibition (in melanoma)
236
Q

Why are cancers like fruit?

A

All cancers are cancers, but they are all different.

237
Q

What is the incidence of breast cancer in the UK?

A

About 1 in 8 women get it.

238
Q

What fraction of women with breast cancer are likely to get it because they are predisposed to it?

A

Around 1 in 10.

239
Q

At what age are women who are predisposed to breast cancer (by inheritance of one copy of a mutated tumour suppressor gene) likely to develop breast cancer?

A

She is likely to be a lot younger, because of Knudson’s double hit hypothesis, which means that they only need to have one mutation in their lifetime, while the general population need two.

240
Q

What are the main genes mutations predisposing to familial breast cancer?

A
  • BRCA1 and BRCA2
  • P53 (Li Fraumeni syndrome) [EXTRA]
241
Q

What is the lifetime risk of breast cancer for women with BRCA1/2 mutations?

A

85%

242
Q

What do BRCA1 and BRCA2 genes usually do?

A
  • Usually act to repair DNA
  • Reduces incidence of cancers
243
Q

What types of genes are BRCA1 and BRCA2?

A

DNA repair genes

244
Q

Describe the locus of BRCA1.

A

17q

245
Q

Describe the locus of BRCA2.

A

13q

246
Q

Are all BRCA mutations the same?

A

Most families with mutations have their own ‘private’ mutation.

247
Q

What is the inheritance form for BRCA genes?

A

Autosomal dominant

248
Q

Draw a graph to the show the cumulative risk (with age) of breast cancer in those with a BRCA1/BCR2 mutation.

A
249
Q

Draw a graph to the show the cumulative risk (with age) of ovarian cancer in those with a BRCA1/BCR2 mutation.

A
250
Q

When is genetic testing for BRCA mutations done and how is it done?

A
  • If a high-probability family is seen, genetic testing for mutations in the BRCA genes is done 
  • Simple blood test -> Results in 8 week
251
Q

What is the problem with screening this indiviudal for BRCA mutations?

A

Testing the woman automatically tests the mother (since the condition is autosomal dominant), which she has not given consent for.

252
Q

Mrs Jones is a 65 year old woman, recently diagnosed with unilateral breast cancer.
How does this history affect her daughter Jane’s risk of breast cancer?

A
  • It is important to consult the risk curves.
  • Jane has one 1st degree relative with breast cancer at age 65.
  • It is very unlikely (according to the curves) that the cause is genetic susceptibility therefore she is at the population risk for breast cancer (about 12%).
253
Q

(Following on from the last flashcard) Aside from Jane’s mother, there is no further family history of breast cancer on Mrs Jones’ side of the family, but Mr Jones informs you that he has a family history of breast cancer. How does this change Jane’s risk?

A

She has two 1st or 2nd degree relatives with breast cancer. However, this still puts her at population risk.

254
Q

(Following on from the last flashcard) It turns out that Jane has many more family members with breast cancer and ovarian cancer, as shown in the family tree. How does this change her risk?

A
  • She has 4 relatives with breast and/or ovarian cancer
  • Different generations on one side of the family
  • Some early onset and multiple primary cancers.
  • Therefore, this family has an autosomal dominant predisposition to breast/ovarian cancer and Jane is potentially at high risk.
255
Q

Assess Jane’s estimated risk of inheriting a high risk gene for breast cancer.

A
  • 1 in 4 chance of having inherited a high risk gene IF there is a gene fault running in the family.
  • This is because there is probably a germline mutation in susceptibility genes (BRCA1/BRCA2) or another cancer predisposition gene which is, as yet, unknown, that runs runs on her father’s side.
  • The gene is autosomal dominant, so Jane’s father has a 1 in 2 chance of inheriting it, and Jane has a 1 in 4 chance.
256
Q

(Following on from the previous flashcards) Jane thinks she wants to know if she carries a mutation in BRCA1/2. How can the risk for Jane be clarified?

A
  • If we test her and find no mutation, we don’t know if there is no mutation in the family, or if one exists but she hasn’t inherited it
  • Therefore, blood is taken from a living, affected family member where possible
  • If a causative mutation in BRCA1/2 can be identified, then can offer predictive testing to other family members (i.e. Jane)
257
Q

What are the two main ways of screening women for breast cancers?

A
  • Mammogram -> X-ray of the breasts
  • MRI
258
Q

Compare the advantages of using mammograms and MRIs to screen for breast cancer in women.

A
  • Mammograms -> Less sensitive and uses radiation, but cheaper
  • MRI -> More sensitive but expensive
259
Q

What form of breast screening works better in younger women and why?

A

MRI, because younger women have denser breasts, which show up white on a mammogram (since it is an x-ray) just like cancers do.

260
Q

Describe the different national breast screening programs for women.

A
  • If BRCA mutation found:
    • MRI + mammograms annually from age 30-50
    • Then mammograms annually to age 70
  • If no BRCA mutation found
    • Annual mammograms 40-60
261
Q

What is the main form of risk-reducing surgery for breast cancer? What does it reduce your risk to?

A
  • Breast removal (mastectomy) + reconstruction
  • Reduces risk of breast cancer to <10%
262
Q

What is the main form of risk-reducing surgery for ovarian cancer? What does it reduce your risk to?

A
  • Ovary removal (oophorectomy)
  • Reduces risk of ovarian cancer to <2%
263
Q

Dedscribe the main treatment for cancers in BRCA carriers and how this works.

A

PARP inhibitors:

  • The main pathways for repair of cancer cells with DNA damage is the BRCA pathway
  • In BRCA carrieris, this pathway is defective, so the secondary PARP (poly-ADP ribose polymerase) is an alternative pathways for repair
  • PARP inhibitors work by also inhibiting this this secondary pathways, so cancer cells have no choice but to apoptose
264
Q

What is the name for this diagram and what does it show?

A
  • Fried egg slide
  • It shows that only a small fraction of bowel cancers are caused by high inherited bowel cancer predisposition syndromes. A slightly larger fraction is due to bowel cancer with a family history.
265
Q

What are the two main types of genetic conditions associated with bowel cancer? What is their inheritance type?

A
  • Familial adenomatous polyposis (FAP)
  • Lynch syndrome (Heridetary non-polyposis colorectal cancer) (HNPCC)

They are both autosomal dominant.

266
Q

Mutations in what gene are responsible for FAP (familial adenomatous polyposis)? [IMPORTANT]

A

APC

267
Q

Mutations in what gene cause Lynch syndrome (hereditary non-polyposis colorectal cancer)?

A

MLH1, MSH2, MSH6, PMS2

268
Q

What is FAP bowel cancer, what causes it and how is it treated?

A

Familial adenomatous polyposis:

  • Caused by mutations in APC gene
  • This individual tends to develop hundreds of small polyps in the colon in early life
  • These are highly likely to develop into cancer, which usually occurs in the 20s
  • Prophylactic colectomy (removal of the colon) is standard treatment
269
Q

At what age does FAP usually result in cancer?

A

Early 20s

270
Q

What things might make you suspect that there is the presence of Lynch syndrome (hereditary non-polyposis colorectal cancer HNPCC) in the family?

A
  • Several members of the family with bowel cancer at young ages (before 60)
  • Individuals with bowel cancer between the ages of 30-45
  • People who develop bowel cancer twice -> Either two tumours at once, or at different times
  • Presence of other cancers in the family:
    • Endometrial (womb)
    • Ovary
    • Stomach/small bowel
271
Q

Compare the ages at which individuals are likely to get bowel cancer in familial adenomatous polyposis and Lynch syndrome.

A
  • FAP -> Early 20s
  • Lynch syndrome -> Between 30-60
272
Q

What are the different types of ovarian cancer and which gene mutation is each associated with?

A
  • Epithelial -> Associated with BRCA
  • Mucinous -> Lynch syndrome
273
Q

What condition does this family tree show?

A

Lynch syndrome

274
Q

How do you screen for bowel cancer? How often is this done in Lynch syndrome and FAP?

A
  • Colonoscopy -> Laxatives are taken the day before to clear out the bowel
  • In Lynch syndrome -> Every 2 years
  • In FAP -> Every year (until colectomy)
275
Q

What are we looking for during a colonoscopy as screening for bowel cancer?

A
  • The presence of polyps (even in Lynch syndrome, not just FAP).
  • In Lynch syndrome, a lasso-like tool at the end can be used to remove the polyps, although in FAP there are simply too many.
276
Q

Describe the forms of risk-reducing surgery for FAP and Lynch syndrome.

A
  • FAP -> Colectomy (removal of the bowel)
  • Lynch syndrome -> Women tend to have oophorectomy (removal of ovaries) or hysterectomy (removal of uterus)
277
Q

What are polygenic disorders?

A

Controlled by more than one gene.

278
Q

What are some polygenic congenital malformations?

A
  • Cleft lip/palate
  • Congenital dislocation of the hip
  • Congenital heart defects
  • Spina Bifida
  • Pyloric Stenosis
  • Clubfoot (talipes)
279
Q

What are some acquired polygenic diseases?

A
  • Asthma
  • Autism
  • Diabetes Mellitus
  • Epilepsy
  • Crohn’s disease
  • Ischaemic heart disease
  • Hypertension
  • Multiple sclerosis
  • Parkinson’s disease
  • Psoriasis
  • Osteoarthritis
  • Schizophrenia
280
Q

Draw diagrams to compare how single gene and polygenetic conditions produce a phenotype.

A
281
Q

Explain how common mutations causing single gene disorders and polygenic disorders are.

A
  • Mutations causing single gene diseases have a major impact on the function of the gene product, and are therefore rare.
  • Mutations causing polygenic disease have a more moderate effect, and are therefore relatively common.
282
Q

Are polygenic disorders determined only by genes?

A

No, they also often have an environemtnal component.

283
Q

Are the transmission patterns for polygenic conditions clear?

A

No, the transmission patterns are relatively unclear because there are many genes influencing the condition, so it is not obvious which is important in what way.

284
Q

Describe how different genes contribute to polygenic disorders.

A
  • Expression of a phenotype is determined by many genes at different loci
  • Each of these has a small additive effect (i.e. no gene is dominant or recessive to another, so their effects are cumulative)
  • This means that characteristics show a continuous distribution in the general population -> This resembles a normal distribution
  • The individuals at the ends of the distribution are those with the condition
285
Q

Polygenic traits are … traits.

A

Continuous

286
Q

Describe how a polygenic disorders generate a continuous normal distribtuion.

A
287
Q

What are some human traits that show a continuous distribution?

A
  • Blood pressure
  • Head circumference
  • Height
  • Intelligence
  • Waist size
288
Q

Polygenic traits involve a continuous distribution of characteristics (e.g. head size from small to large). However, polygenic disorders are binary (either you have the condition or not). How does this occur?

A

The disease manifests once a certain “threshold of susceptibility” has been surpassed.

289
Q

Explain the threshold model of susceptibility.

A
  • Polgenic traits show a normal distribution due to the influence of multiple genes that can have two alleles
  • There is a threshold above which an individual becomes affected by a polygenic disorder.
290
Q

What causes a person to cross the threshold of susceptibility for a polygenic disorder (meaning that they actually have the disorder)?

A
  • A combination of the genes one has inherited and the exposure one has had to environmental risk factors 
  • Lung cancer is good example:
    • Some people can smoke 20 a day for 30 years and never get lung cancer probably have protective genes 
    • Some will get lung cancer after only 510 years smoking
291
Q

Describe how the normal distribution for a polygenic condition is different for people with a sibling with that polygenic disorder compared to the general population.

A

The curve is shifted to the right, since the siblings are likely to inherit a large proportion of the genes that make you susceptible to that polgenic disorder.

292
Q

What is recurrence risk?

A
  • Risk that a disease will occur elsewhere in a pedigree, given that at least one member of the pedigree exhibits the disease
  • RR increases as the number of affected family members increase
293
Q

What is homozygosity mapping?

A

A technique in which the degree of similarity in the genes of two people is compared. [CHECK THIS]

294
Q

In cleft lip and palate (CL+P):

  • Proportion of 1st degree relatives affected is 6% if individual has bilateral CL+P
  • Proportion of 1st degree relatives affected is 2% if individual has only unilateral CL

What does this tell you?

A

Bilateral cleft lip and palate is more ‘genetic’ than unilateral cleft lip and palate.

295
Q

In spina bifida, how does the risk vary for an individual if they have a 1st degree, 2nd degree or 3rd degree relative with the condition? How does it vary if you have more than one close relative with it?

A
  • Risks to FDR 4%, to SDR 1%, to TDR 0.5%
  • If >1 close relative affected, risks increase
  • If 2 siblings affected, risk for next child~10%
296
Q

When it is difficult to assess an individual’s liability for a particular disorder, what is done?

A

Estimate what proportion of aetiology can be ascribed to genetic factors and environmental factors.

297
Q

What is heritability?

A
  • The proportion of the total phenotypic variance of a condition which is caused by additive genetic variance.
  • i.e. It is a measure of how ‘genetic’ a condition is as opposed to environmental
298
Q

How is heritability usually expressed?

A
  • Either as a percentage or a proportion of 1
  • Where the greater the number, the more genetic the condition
299
Q

Give some examples of the heritability for:

  • Schizophrenia
  • Asthma
  • Cleft lip and palate
  • Spina bifida
  • Coronary artery disease
A
  • Schizophrenia 85%
  • Asthma 80%
  • CL+P 76%
  • Spina Bifida 60%
  • Coronary artery disease 65%
300
Q

How can you assess whether a disease has a genetic component and how significant this genetic component is?

A
  • Twin studies
  • Relative risk studies
301
Q

What sort of twins are used in twin studies?

A

Both monozygotic (identical) and dizygotic twins (non-identical) are used.

302
Q

Describe thre principle of which twin stuides work.

A
  • The classical twin design compares the similarity of monozygotic (identical) and dizygotic (fraternal) twins.
  • If identical twins are considerably more similar than fraternal twins (which is found for most traits), this implicates that genes play an important role in these traits.
303
Q

What are some potential pitfalls of twin studies?

A
  • Monozygotic twins are always the same sex, while dizygotic are not always -> So always use same-sex dizygotic twins
  • Monozygotic twins are often treated differently than dizygotic twins are, which can influence behavioural traits -> So try to use wins that were separated at birth
  • Monozygotic twins share more intrauterine tissues than dizygotic twins during gestation, making it difficult to distinguish intrauterine environmental causes from genetic causes
  • Bias of ascertainment -> People often focus on twins who have strikingly similar behavioral traits but overlook those who don’t
304
Q

What type of study is used to identify genes that cause multifactorial disorders?

A

Genome-wide association studies (more on this later)

305
Q

Autism is a multifactorial disease. What are the symptoms?

A
  • Disorder of social interaction
  • Poor communication
  • Developmental delay
  • Repetitive behaviours
306
Q

Describe how autism is related to other conditions.

A
  • It is on a spectrum -> Asperger’s is a milder form
  • It is often seen as part of other syndromes -> Fragile X
307
Q

What did twin studies and other studies on autism find?

A
  • Twin studies
    • Monozygotic 80% concordance
    • Dizygotic 20% concordance
    • So it is very largely genetic
  • Familial recurrence risks 2-6% -> Much higher than general population risks 
  • Few candidate genes identified -> RELN (neuronal migration gene)
308
Q

What would be the advantages and disadvantages of genetic testing for autism?

A

Advantages:

  • Possibility of prenatal diagnosis and potential termination of pregnancy
  • Possibility of preimplantation diagnosis

Disadvantages:

  • Difficulty with predicting severity of condition
309
Q

What are some advantages and disadvantages of home genetic tests for predisposition to various conditions (e.g. Alzheimer’s)?

A

Home genetics tests could be useful, but their results cannot always be trusted:

  • Allow for prophylactic lifestyle choices -> But if erroneous then this would be counterproductive
  • Allow for increased surveillance -> But if erroneous then increased radiation exposure with no good grounds
  • Allow for risk-reducing surgery -> But there may be no need if the results are erroneous
  • Insurance implications
310
Q

What is a gene pool?

A

All of the alleles in a population.

311
Q

In Hardy Weinberg, for a gene with the alleles A and a, what is the notation for:

  • Chance of being AA
  • Chance of being aa
  • Chance of being Aa or aA
A
  • Chance of being AA = p2
  • Chance of being aa = q2
  • Chance of being Aa or aA = 2pq
312
Q

What are the two important relationships between p and q?

A
  • p + q = 1
  • p2 + 2pq + q2 = 1
313
Q

What is the usefulness of the Hardy Weinberg principle?

A

Enables one to predict the incidence of diseased individuals and unaffected carriers, if we know p & q.

314
Q

In Hardy Weinberg, what is the fraction of carriers equal to?

A

2pq

315
Q

What are some assumptions of the Hardy Weinberg principle and what are some factors that may disturb these?

A

Assumptions:

  • Large, random mating
  • No new mutations
  • No selection for or against particular genotype

Disruptions:

  • Non-random mating
  • Mutation
  • Selection
  • Small population size
  • Gene flow (migration)
316
Q

What are some multifactorial traits that feature non-random mating?

A
  • Intelligence
  • Waist size
  • Neurotic tendency
  • Height
  • Eye colour
317
Q

How does consanguinity affect the Hardy Weinberg principle?

A
  • Heterozygotes (for a recessive condition) more likely to mate than expected by chance random mating
  • More homozygotes (more disease) than predicted by Hardy-Weinberg
  • Hastens selective removal of “bad” recessive alleles and increase of “good” ones
318
Q

What is fitness?

A

A measure of the ability of an individual to survive and reproduce.

319
Q

How is fitness related to the existence of recessive diseases?

A
  • Some conditions have early and devastating onset -> These will reduce reproductive fitness (sometimes to zero)
  • Some have onset only later in life -> After reproduction has occurred
  • Generally, these will not reduce reproductive fitness -> Recessive allele therefore maintained

It is worth noting that diseases that affect cosmetic appearance are an exception to this.

320
Q

Describe the concept of positive selection with regards to sickle-cell anaemia.

A

Being heterozygous for sickle-cell anaemia makes you resistant to malaria without having the effects of the sickle-cell anaemia, which means that the condition has a high prevalence in many African countries.

321
Q

For each of these diseases, name the factor that causes them to be selectively favoured so that there is a high prevalence in certain parts of the world:

  • Sickle-cell anaemia
  • Thalassemia
  • Cystic fibrosis
A
  • Sickle-cell anaemia -> Malaria (Africa)
  • Thalassemia -> Malaria (SE Asia)
  • Cystic fibrosis -> Typhoid fever (UK)
322
Q

What is the source of variation?

A

Mutation

323
Q

Are new mutations likely to remain in a population?

A

No, unless there is a compensating advantage to the mutation.

324
Q

What is genetic drift?

A

Genetic drift is a mechanism of evolution in which allele frequencies of a population change over generations due to chance (sampling error).

325
Q

In what sort of populations is genetic drift most significant?

A

Small populations

326
Q

Give an example of genetic drift.

A
  • Ross is a carrier for a rare AR condition Z (carrier frequency in the general population = 1 in 10,000)
  • The condition causes death by age 5
  • He has increased reproductive opportunity since he is the best looking man in the population
  • Result: the children of this island will have an increased chance of being carriers for Z
  • Their children would be much more likely to suffer from Z than other people in the general population
  • Thus genetic drift has occurred in this population.
  • Eventually, the recessive allele may die out (especially since the affected die before they are 5) and drift will have occurred again
327
Q

What are the effects of genetic drift on alleles?

A
  • Given time, one allele will be fixed and the other eliminated
  • An allele’s probability of fixation is equal to its frequency
  • New alleles are at a great risk of elimination, especially in small populations
328
Q

What is genetic flow? When is it most significant?

A
  • The movement of alleles between populations.
  • It is most significant when the populations are small and if the allele frequency differences are large
329
Q

What is the founder effect?

A

Reduced genetic diversity in a population founded by a small number of individuals.

330
Q

What is a polymorphism?

A

The co-existence in a population of two or more alleles at a genetic locus.

331
Q

What is meant by a balanced polymorphism and why do these exist?

A
  • A balanced polymorphism is where two or more alleles for a gene exist in a population
  • This occurs due to:
    • Selection against each of the homozygous genotypes (i.e. the homozygous phenotype is disadvantageous)
    • Selection in favour of the heterozygous genotype (i.e. the heterozygous phenotype is advantageous, as is the case with sickle-cell anaemia and malaria)
332
Q

What are some conditions that have an especially high incidence in these populations:

  • Mediterranean and Africa
  • Maori
  • Finland
  • Amish
  • Ashkenazi
A
  • Mediterranean and Africa
    • Sickle-cell
    • Thalassaemia
  • Maori
    • Susceptibility to Crohns disease
  • Finland
    • Familial CJD
  • Amish 
    • Maple Syrup urine disease 
    • MCAD
  • Ashkenazi Jews 
    • Tay-Sachs disease
    • Riley-Day disease
    • Familial breast cancer
333
Q

What are the different factors that can account for ethnic differences in disease incidence?

A
  • Depends partly on open/closed populations
  • May depend on survival advantages (e.g. advantageous genes?)
  • May also depend on consanguinity
334
Q

What is the role of a genetic counsellor in helping a family regarding risk of genetic diseases? What are some difficulties of this?

A
  • Role is NOT to influence choice
  • Role IS to give information regarding reproductive choice legally available in the family circumstances, and to support decisions made by the family

Difficulties:

  • Religion
  • Language problems
  • Misinformation
335
Q

What are the various choices for a couple who want to have children but are at high risk for genetic disorders?

A
  • Do not have children (or adopt)
  • Cross your fingers
  • Use an egg or sperm donor
  • Use a surrogate
  • Have testing during pregnancy
336
Q

How many genes are there in the human genome and how many base pairs is this?

A

30,000 genes -> 3000Mb

337
Q

How much of the genome is genes (or gene-related) and how much is extragenic?

A
  • Genes = 30%
  • Extragenic DNA = 70%
338
Q

How much of the DNA that makes up genes is coding?

A

10%

339
Q

How much of extragenic DNA is repetitive DNA?

A

20%

340
Q

What is the Human Genome Project and what are its limitations?

A
  • A catalogue of genes as functional DNA units (Open reading frames, ORF’s)
  • Does not tell us anything about an unknown gene for a rare condition
    • Chromosomal location
    • DNA sequence
  • Usually, once these genes are identified they turn out to be previously known ORF’s (unknown function) or genes with another function
341
Q

What is an open reading frame (ORF)?

A
  • The part of a reading frame that has the ability to be translated.
  • It is a continuous stretch of codons that begins with a start codon and ends at a stop codon.
342
Q

Describe the different ways of identifying a gene for a given characteristic. [IMPORTANT]

A
  1. If the protein sequence is known, cDNA sequence can be worked out and a probe generated -> This probe is used to screen a cDNA library to isolate the gene
  2. If one member of a gene family has been shown to cause a certain disease, other members of the family are candidate genes for related diseases
  3. If a gene causes a phenotype in an animal, its human homologue is a candidate gene for similar human conditions
  4. If a gene product is part of a metabolic pathway, and that gene is mutated in some but not all people with a certain disease, other genes in the pathway are candidate genes for the remaining cases
  5. If a disease shows anticipation, it may well be caused by an unstable expanding DNA repeat
  6. Cytogenic clues
343
Q

Draw a diagram to show how a gene can be identified from a protein that we known the amino acid sequence of.

A
344
Q

What is genetic mapping?

A

The methods used to identify the locus of a gene and the distances between genes.

345
Q

What is recombination?

A

The exchange (crossing over) of DNA between members of a chromosomal pair, usually in meiosis.

346
Q

Describe the concept of genetic linkage. [EXTRA]

A

When recombination occurs in meiosis to produce gametes:

  • Genes with loci on different chromosomes will not be co-inherited
  • Loci on the same chromosome will be coinherited
  • The closer two loci are on the same chromosome the greater the probability that they will be co-inherited (i.e the likelihood of recombination is small)
347
Q

What is linkage analysis? [EXTRA]

A
  • The mapping of a trait on the basis of its tendency to be co-inherited with polymorphic markers
  • It is usually used in genetic mapping (identifying the locus of different genes)
348
Q

What are polymorphic markers?

A
  • Polymorphisms with a known location within the genome that have more than 1 form within the population
  • This helps to differentiate between the two copies of a gene that an individual inherits
  • They are not themselves pathological - they simply mark specific points in the genome -> Think of them like flags or landmarks in fog
349
Q

What are some different types of polymorphic markers used in gene analysis?

A
  • Variable number tandem repeats (VNTRs)
  • Microsatellites
  • Single nucleotide polymorphisms (SNPs)
  • Insertions and deletions (INDELS)
350
Q

What are VNTRs?

A
  • Variable number tandem repeats
  • These are repeating DNA sequences that can have varying number of repeats in different individuals
  • e.g. ACATGACATGACATG
351
Q

What are microsatellites?

A
  • They are like mini VNTRs
  • The repeat unit is between 1 and 6 base pairs long
  • e.g. ATGATGATGATGATG
352
Q

What is the most common microsatellite?

A

CAn microsatellites:

  • 6(CA) allele -> CACACACACACA
  • 8(CA) allele -> CACACACACACACACA
353
Q

What are some alternative names for microsatellites?

A
  • Short tandem repeats (STRs)
  • Simple sequence repeats (SSRs)
354
Q

What are single nucleotide polymorphisms and INDELS?

A
  • A single-nuclotide polymorphism is due to a base substitution
  • An INDEL is the insertion or deletion of a single base
  • Neither of these change the phenotype, which means they can be used as polymorphic markers
355
Q

Why does the substitution in an SNP not make any difference to the phenotype?

A

It is in a non-coding region.

356
Q

What is the genotype for this individual, regarding the mirosatellites?

A

(6 8)

357
Q

Describe how polymorphic markers can be used to identify the locus of a gene in this case. [IMPORTANT]

A
  • You can go along the length of the chromosome, comparing each polymorphic marker between individuals who are affected by the condition
  • If the markers are the same at a certain locus between all the individuals, then the gene causing the condition is likely to be very close to that marker
  • This is because the marker and gene are likely to be genetically linked and therefore inherited together
  • Example:
    • For example, at the top of the chromosome, far away from the gene, the genotypes for a marker in affected individuals might be (6 8), (4 7) and (5 9) -> This means that the gene is not at that locus
    • Near the actual gene, the genotypes for a marker in affected individuals might be (2 4), (2 6) and (2 3) -> The 2 indicates that the gene might be close to this locus
    • This locus can then be further investigated by comparing markers with more affected individuals
358
Q

After you have used a polymorphic marker to find the approximate locus of a gene that is causing a condition, what must you do next?

A
  • Define the maximal region of linkage around the marker -> The gene must be somewhere in this region
  • Use a database to look up which genes are in this region
  • Sequence all of the genes in that region to find the mutation responsible for the condition
359
Q

Describe how gene mapping is done in consangineous families.

A
  • These have more complex pedigrees
  • Autozygosity (homozygosity) mapping -> Detects regions of the genome common to affected individuals and obligate carriers within a consanguineous family
  • Markers identified within these regions
  • Candidate genes then identified close to markers and sequencing done

So this is quite similar to normal gene mapping.

360
Q

Describe the concept of exclusion testing for Huntington’s disease.

A
  • The father in the diagram doesn’t want to know whether he has Huntington’s, but wants to know whether the two foetuses are at high risk or not
  • This is done by looking at gene markers of the foetus
  • The (2-1) foetus:
    • Must have inherited the 1 from the father (since there are no other 1s in the parents).
    • In turn, this 1 must have come from the grandfather, since the 2 in the father must have come from the grandmother
    • Therefore, the foetus is at lower risk, since it has inherited genes from the unaffected grandfather
  • The (3-2) foetus:
    • Must have inherited the 2 from the father (since the 3 must have come from the mother).
    • In turn, this 2 must have come from the grandmother (since there are no other 2s in the grandparents)
    • Therefore, the foetus is at higher risk, since it has inherited genes from the grandmother with Huntington’s
361
Q

What is the GEL project and what are the main aims?

A
  • NHS 100,000 genome project
  • Main aims are:
    • Rare diseases -> Find the genes responsible
    • Cancer -> Try and find drug targets
362
Q

How is the 100,000 genome project used to try and understand cancer targets?

A

The genomes of normal cells and cancerous cells can be compared to try and find the differences that can be targetted.

363
Q

In projects such as the 100,000 genome project, what are some concerns surrounding incidental findings?

A
  • Whose information is it?
  • How do you consent patients for this analysis?
  • How much do patients want to know?
364
Q

In projects such as the 100,000 genome project, what are the 3 layers of consent that a patient can agree to?

A

The patient can agree to find out about:

  • Mutations in genes to do with my condition
  • Mutations in genes that I can do something about (e.g. genes predisposing to conditions)
  • Mutations in genes I can do nothing about
365
Q

What is the limiting factor in the projects such as the 100,000 genome project?

A

Analysis of the data that is produced, in order to find patterns.

366
Q

In this family tree:

  • No family history of cancer -> Both parents and all grandparents alive and well
  • Preliminary genetic analysis yielded no mutations
  • So the children are put forward for Whole Genome Sequencing
  • Samples collected from both affected children, unaffected sister and both parents.
  • Pathogenic mutation in FH gene found
  • FH mutations can lead to aggressive renal cancers, skin leiomyoma, uterine fibroids and sometimes cardiac abnormalities
  • But none of these symptoms where seen in the family

What conclusions can be drawn and what should be done?

A
  • We can conclude that it is possible that the FH gene mutation is responsible for the symtpoms of the children, which was not previously known
  • The family must be informed of the risks to the children of, for example, aggressive renal cancers
367
Q

Traditionally, how are polygenic disorders mapped (to find the genes that contribute to it)?

A
  • Look at pairs of siblings who are affected by the condition and use markers to look at the alleles that are inherited
  • For any given gene, there is a 25% likelihood that they have the same alleles, 50% chance that they have 1 in common and a 25% chance that they have none in common
  • Carry out these comparisons along the entire genome and with many sibling pairs
  • Eventually, you can identify the regions with maximum linkage
  • Within these regions, list the genes and identify the causal polymorphisms
368
Q

In modern times, what techniques do we use to identify the genes responsible for polygenic and monogenic disorders?

A
  • Polygenic -> Genome-wide association studies
  • Monogenic -> Whole genome sequencing
369
Q

What are genome-wide association studies and what are they used for?

A

Analyse a very large number of SNPs to try and identify candidate genes that may contribute to a polygenic condition.

370
Q

What are some conditions that have been studied using genome-wide association studies?

A
  • COPD
  • Parkinson’s disease
  • Pancreatic cancer
  • Narcolepsy
  • Type 2 diabetes
  • Alzheimer’s disease
  • ARDS
  • Systemic lupus
  • Cleft lip and palate
371
Q

What is the typical increase in relative risk found in a genome-wide association study?

A

1.3%

372
Q
A

YEAR 1 - Biochemistry and Medical Genetics (Anton) (8 decks)

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