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MBB329 - Genetics of Human Disease > Sudbery > Flashcards

Sudbery Flashcards

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Biology 101 flashcards
1
Q

How many live births have some kind of genetic disorder?

A
  • approx 8% (but estimates vary) have some sort recognisable before adulthood
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2
Q

Are genetic diseases rare?

A
  • individually rare but collectively common
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3
Q

What are most genetic disorders caused by?

A
  • single gene mutation (= single gene disorders = SGD)
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4
Q

What major birth defects are there?

A
  • chromosomal
  • mitochondrial
  • complex (multifactorial)
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5
Q

How common are complex diseases?

A
  • before we die 2/3 will suffer from one
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6
Q

What are complex diseases?

A
  • genetic component in etiology

- susceptibility caused by alleles at 100s-1000s lico and v heavily mod by env (interaction between genes and env)

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7
Q

Do freqs of SGDs vary, whats an eg.?

A
  • yes, vary in diff pops

- eg. CF v common (1 in 500) in N. Europe, but rare everywhere else

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8
Q

What are some eg.s of common complex disorders?

A
  • rheumatoid arthritis, epilepsy, MS, type I/II diabetes
  • psychiatric disorders –> alzheimer’s, schizophrenia, autism
  • congenital defects –> cleft lip and palate, pyloric stenosis
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9
Q

What is the missing heritability problem?

A
  • amount of genetic variability identified through GWAS etc. doesn’t account for variation of heritability disorders
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10
Q

Where are SGDs catalogued?

A
  • OMIM (online mendelian inheritance in man)
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11
Q

How many SGDs are there?

A
  • ≈5000 disorders affection ≈3400 genes (so mutations in some genes responsible for more than 1 disorder)
  • total no. documented = ≈7400
  • ≈20,000 human genes
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12
Q

How common are chromosomal disorders prenatally?

A
  • ≈8% clinically recognisable conceptions terminate due to chromosomal abnormalities
  • but may be 50% of all conceptions (but most terminate before know pregnant)
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13
Q

How common are chromosomal disorders in live births, and what types are there?

A
  • 0.1%
  • aneuploidies –> Down’s syndrome (trisomy 21), Edwards syndrome (trisomy 18)
  • translations
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14
Q

How significant is the mito genome?

A
  • 16kb, so much smaller than nuclear DNA, but sig amount by weight
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15
Q

What do mito disorders cause?

A
  • multi system failures –> basal ganglia (causing ataxia), heart, endocrine system, sight and hearing, skeletal muscle
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16
Q

When does maternal inheritance and what does this cause?

A
  • if mother heteroplasmic
  • variable phenotype in siblings
  • progressive onset
  • diff degrees of severity in diff organs
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17
Q

What might accum of mtDNA (and therefore O free radicals) be involved in?

A
  • ageing
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18
Q

Why bother identifying variants responsible for SGD?

A
  • stopping repeated medical tests which may be invasive and distressing –> not needed as know diagnosis
  • introd approp treatment and stop inapprop treatment (eg. for epilepsy usually have to try series of medication till find what works, but if know mutation, know treatment)
  • psychological benefits to affected and family
  • scientific knowledge
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19
Q

What are the difficulties w/ diagnosing rare diseases?

A
  • genetic heterogeneity in medically well characterised disorders (sometimes over 50 genes) –> so diseases can be caused by mutations in many genes
  • atypical disease presentation
  • novel variant in known gene
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20
Q

What are some eg.s of diseases that genetically heterogenous?

A
  • polydactyly
  • retinitis pigmentosa
  • lipid metabolism
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21
Q

What other problems is there w/ identifying alleles responsible or rare diseases (apart from w/ diagnosis)?

A
  • if novel disorder but suspected SGD

- or documented disorder w/ unknown genetic basis

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22
Q

How has identifying genes assoc w/ disorders progressed?

A
  • originally mapping
  • now WES/WGS
  • downward trend of genes identified in recent years
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23
Q

What are WES and WGS?

A
  • WES = whole exome sequencing

- WGS = whole genome sequencing

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24
Q

Why is WES used and not WGS?

A
  • SGD so far all in coding seq
  • cheaper
  • fewer variants to analyse (coding seq under selective pressure so less variation, unlike intergenic seq)
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25
Q

Where are complex disease variants usually found in genome?

A
  • nearly all outside coding seq, in intergenic seq

- prob affect expression of coding seq

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26
Q

If each individual shows approx 20,000 variants after WES, then how can we identify causative variant of a SGD?

A
  • predicted effect on protein function –> exclude any that don’t affect coding seq (ie. silent/replacement), look at whether AA changes are conservative (if not, bigger effect, eg. hydrophobic for hydrophilic)
  • disease allele will be rare, look at pop databases –> if recessive have to look for homozygous variant, doesn’t have to be same mutation as long as affects same gene
  • same allele in unrelated indivs w/ same disorder –> if unaffecteds too can rule out
  • expert appraisal of biological relevance to disorder phenotype –> recapitulation in model system/organism and look at seq conservation
  • databases of pathogenic variants (think genes not alleles)
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27
Q

What types of mutation can lead to loss of function, and how can loss of function be predicted/assessed?

A
  • likely to lead to loss of function –> by frameshift, protein terminating variant (PTV), splice sites, exon deletions
  • function prediction, eg. polar substitution in TM domain
  • seq conservation
    assessed by computer programmes, eg. SIFT, Polyphenz
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28
Q

When can usually loss of function mutations not be harmful and why?

A
  • frameshift and PTV if near end of ORF don’t have much effect
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29
Q

What was ExAC?

A
  • exome aggregation consortium
  • 60,000 exomes and identifies v rare alleles
  • looks at pop freq to identify which alleles are v rare and which pot harmful alleles occur freq in apparently healthy indivs
  • the size of the database is key
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30
Q

What has ExAC now been succeeded by?

A
  • gnomAD –> 123,000 WES an 15,000 WGS

- multiple other databases now exist

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31
Q

What is the problem with pop databases, such as ExAC?

A
  • most exome info from European originating pops, so not representative of other pops
  • ie. something could be rare in Europeans, but common in other pops and not diseases causing
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32
Q

Is it common to carry pot harmful mutations?

A
  • yes, we all carry 100s of them
  • mostly heterozygous missense mutations
  • 1 in 5 homozygous for a rare PTV
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33
Q

How can you match affected indivs who are geographically separate?

A
  • need precise phenotype description
  • controlled vocab –> human phenotype ontogeny (HGO)
  • allows computer matching, eg. GENEMATCHER
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34
Q

Why is it important to allow matching of affected indivs?

A
  • estimated 1000 genes w/ good candidate causal variant but not rep in unrelated cases
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35
Q

What is the major ethical problem with databases, eg. for phenotypic descriptions of diseases?

A
  • data sharing (need all data for gene matching)
  • fundamental right to indiv privacy of genetic info
  • but sharing of genetic data and phenotypic description vital
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36
Q

What is an eg. of how ExAC database has been used for a specific condition?

A
  • to identify relevant genes in cardiomyopathy

- can see if more mutations in healthy than affected indivs, then not relevant gene

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37
Q

How can you characterise a recessive pedigree?

A
  • may be compound heterozygote –> may not be exactly same bp change, but affecting same gene
  • will be heterozygous in each parent (assuming no non-paternity)
  • heterozygous siblings not affected
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38
Q

How can you characterise a consanguineous pedigree?

A
  • same allele in each gene

- only affected members of pedigree are homozygous

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39
Q

How can you characterise a de novo dominant pedigree?

A
  • new allele not present in either parent
  • heterozygous mutation not present in parents, but shared w/ other indep affecteds
  • an affected parent is less likely to have children, therefore de novo more likely
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40
Q

Why is standardisation needed?

A
  • to ensure compatibility between diff countries w/ diff medical organisations and diff labs
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41
Q

What is the simplest eg. of a consanguineous pedigree?

A
  • cousin marriage
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42
Q

What are the consequences of a consanguineous autosomal recessive pedigree?

A
  • allele in shared relative could be v rare, but sporadic occurrence could be freq in children and could be only cases of disease
  • homozygous variant in each affected
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43
Q

How does the distance of the relationship between affecteds affect the amount of rare homozygous variants, in a consanguineous autosomal recessive pedigree?

A
  • the more distant the relationship, the fewer homozygous regions to analyse
  • children of cousins have 15-20 homozygous rare variants
  • children of 3rd cousins have only 5-10 homozygous rare variants
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44
Q

What is the proband?

A
  • indiv in pedigree who 1st comes to medical attention
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45
Q

What is a case study of a consanguineous autosomal recessive condition?

A
  • proband was 16 y/o Saudi Arabian girl w/ complex symptoms shared w/ 8 consanguineous relatives
  • suggestive of complex neurotransmitter disorders
  • -> dopamine: parkinsonism, non-ambulation, global developmental delay, hypotonia
  • -> serotonin: sleep and mood disturbances
  • -> adrenaline: diaphoresis, temp instability
  • neurotransmitter levels normal, but dopamine breakdown products elevated in urine
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46
Q

What treatment was initially tried in this consanguineous case study, and what was the effect?

A
  • treatment to increase dopamine levels

- caused immediate worsening of condition

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47
Q

How was this case study of a consanguineous pedigree investigated further by mapping?

A
  • needed to map and look for regions of homozygosity
  • by looking at SNPs distrib over 3.2 mb region
  • calc LOD score as 4.1 –> means matching of alleles would occur by chance 1 in 10,000 (so v unlikely)
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48
Q

What is a LOD score?

A
  • stat test whether likely to occur by chance (threshold score)
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49
Q

What did mapping reveal about the consanguineous case study?

A
  • found 8 genes w/ neuronal function
  • identified p.pro387leu mutation in SLC18A2, encoding VMAT2 dopamine transporter
  • highly conserved residue –> transporter in ec loop that holds TM domain together
  • homozygous in all affected, but not in unaffected
  • not in >1000 patients in Parkinson’s study (affecting dopamine but not classic mutation involved in Parkinson’s, hence other symptoms
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50
Q

What does the nomenclature p.pro387leu mean?

A
  • p = protein

- leu sub for pro at position 387

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51
Q

What is the role of the VMAT2 dopamine transporter, and what is its importance in assoc w/ this case study?

A
  • transports serotonin and dopamine into presynaptic vesicles
  • w/in presynaptic vesicles dopamine converted to adrenaline
  • therefore providing a link between all 3 neurotransmitters assoc w/ disease)
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52
Q

What happened when they expressed WT and mutant VMAT2 in tissue culture?

A
  • reduction, but not complete loss of activity (makes sense as proband alive at 16)
  • so less dopamine going across synapse
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53
Q

After discovering the role of VMAT2 how was this targeted in the consanguineous case study?

A
  • need to target monamine receptor

- treatment w/ dopamine receptor agonist resulted in dramatic improvement w/in 7 days and maintained for 32 months

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54
Q

What does the SLC18A2/VMAT2 study show?

A
  • homozygosity mapping
  • choosing candidate genes by hypothetical function
  • mutation affecting functional part of protein
  • mutation in highly conserved seq
  • mutation present in affected but not unaffected
  • recapitulation of phenotype in in vitro model
  • diagnosis and treatment in rare and novel disorder (new gene, new disorder)
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55
Q

What are the characteristics of an autosomal dominant pedigree?

A
  • heterozygous variant in affected family members
  • not present in unaffected
  • generally difficult, as need mapping info (unlikely to have children so harder to look at pedigree)
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56
Q

What are the symptoms of Floating Harbor Syndrome?

A
  • dysmorphic syndrome –> triangular face, long narrow nose, short filtram
  • short stature
  • intellectual disability
  • language defects
  • 13 indep indivs
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57
Q

How was SRCAP identified as the mutation involved in Floating Harbor Syndrome?

A
  • by comparing indivs can narrow down mutations occurring in all 5 studied
  • SRCAP was gene affected in all 5 studied
  • SRCAP is a Snf2-related chromatin remodelling ATPase and cofactor for CREB BP
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58
Q

What is the role of chromatin remodelling complexes (CRMs), and how do they carry this out?

A
  • DNA assoc w/ nucleosomes can be inaccessible to DNA BPs
  • have DNA helicase activity that can push DNA into nucleosomes
  • causing them to “slide” along DNA
  • CRMs can bind to activation or repression domains of TFs
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59
Q

What are the majority of Diamond-Blackfan Anaemia caused by?

A
  • 50-70% cases due to autosomal dominant mutations in 10 genes encoding ribosomal proteins (ribosomopathy)
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60
Q

What kind of mutations are involved in Diamond-Blackfan Anaemia?

A
  • heterogenous –> caused by mutations in diff genes
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61
Q

What was discovered by studying 2 brothers w/o ribosomal gene mutation?

A
  • 31 mutations in both but only 1 on X-chromosome
  • affecting splicing of exon GATA1 TF, which controls dev of RBCs –> variable splicing, so affected inherit C and unaffected inherit G
  • prod less GATA1 protein
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62
Q

What is a summary of the pathway to finding a causative mutation?

A
  • disease causing mutations should be rare
  • v large databases of variants in healthy indivs
  • we all have multiple rare, apparently gene-inactivating mutations (not necessarily disease causing)
  • pedigree info
  • disease mutation database
  • some mutation in affected but not in unaffected
  • recapitulation in model system
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63
Q

What are the problems with identifying v rare diseases, where there is an unknown disease and unknown gene?

A
  • matching multiple indivs w/ same rare disease
  • data sharing vital for assigning mutations to genes –> but privacy issues when genetic info made widely available on web-based databases
  • accuracy of phenotypic descriptions –> need controlled vocab to standardise
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64
Q

Is CF found in non-caucasians?

A
  • yes, but if in non-Europeans can usually trace heritage back to Europeans at some point
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65
Q

How is the carrier frequency for CF calc w/ H-W?

A
  • q^2 = 1:2000 affected
  • q = √1/2000 = 1/44
  • carrier freq = 2pq = 2 x 43/44 ≈ 1/22
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66
Q

What are the pulmonary symptoms of CF?

A
  • thick dehydrated mucous (so cilia cant move it out of lungs
  • repeated bacterial infections (S. aureus, P. aeruginosa) –> get lodged in lungs and not removed (and fungal infections)
  • chronic inflam, overprod of elastase, irreversible lung damage
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67
Q

What are the non-pulmonary symptoms of CF?

A
  • pancreatic exocrine deficiency
  • diabetes congenital
  • bilateral absence of vas deferens (BAVD)
  • congenital bowel obstruction
  • salty sweat (diagnostic test)
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68
Q

What does autozygous mean?

A
  • genotype of homozygote where genes are copies of identical ancestral gene as result of consanguineous mating
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69
Q

What is the most common CF causing mutation, and how common is it?

A
  • 70% alleles = phe508del

- 90% cases have at least 1 phe508del allele (so useful for diagnosis)

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70
Q

How many other CF causing mutations are there?

A
  • approx 15 other mutations responsible for 1/2 remaining cases among Europeans
  • over 2000 private mutations catalogued (only identified in single families)
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71
Q

What is a similar protein to CFTR in bacteria, and what is its role?

A
  • ABC cassette transporter protein (membrane protein)

- pump antibodies out of cell

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72
Q

What is the phe508del mutation?

A
  • 3 base deletion so lose 1 AA (Phe) but maintain ORF
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73
Q

Why has the phe508del mutation remained in the gene poss when it is so deleterious?

A
  • poss heterozygote advantage –> protects from infantile cholera as less water lost in diarrhoea and point of entry of Salmonella
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74
Q

What is the result of the CF mutation?

A
  • CFTR (CF transmembrane regulatory protein) forms pore in membrane and pumps CL- out
  • have ASL (airway surface liquid) surrounding cell –> made up PCL (periciliary layer) which lubricates mucus (mainly water), then mucus and cilia beat in PCL to move mucus
  • on other side of cell is transporter to move Na+ out and Na+ diffuses round
  • get NaCl secreted on cell surface –> makes ASL more osmotically hypertonic, so suck water out of cell by osmosis, keeping ASL hydrated
  • CFTR also inhibits ENaC channel –> ENaC channel absorbs Na+ from surface, so inhibits inward flow if Na+
  • so in patients lacking CFTR no Cl- out, no inhibition of ENaC channel and PCL collapses, cilia can’t cope, so no mucus movement
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75
Q

What therapies are there for CF to treat the symptoms, and therefore prolong life expetancy?

A
  • physiotherapy = percussion therapy
  • DNAse to decrease mucus viscosity
  • antibiotics (decrease bacterial infections)
  • anti inflammatories, eg. steroids (as chronic inflam responsible for a lot of damage)
  • mannitol spray to increase osmolarity of mucus (increase hydration)
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76
Q

How could gene therapy be used to treat CF, and what are the problems?

A
  • viral vectors w/ tropism for airways –> but immune responses prevent repeated therapy
  • liposomes –> but poor delivery, research ongoing
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77
Q

How did Vertex pharmaceuticals use precision medicine according to the CF mutation?

A

POTENTIATORS = Ivacaftor, helps keep channel open

  • class III, reduced gating Gly551Asp, Phe508del
  • class IV, reduced conductance
  • class VI, high surface turnover, Phe508del
CORRECTORS = Lumacaftor, helps protein fold correctly so can get to surface, but still not as open as much as should be
- class II, misfolded and degraded Phe508del

PRODUCTION CORRECTORS = Alaluren

  • class I, no CFTR Gly542X
  • class V, v low CFTR levels 3849 and 10kb C–>T
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78
Q

Who decides if a drug works and if cost effective for NHS?

A
  • NICE (National Institute for Health and Excellence
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79
Q

What diff indicators do NICE look at?

A
  • Quality Adjusted Life Years (QALYs) = generic measure of disease burden inc quality and quantity of life, 1 QALY = 1 year in perfect health
  • Standard of Care (SoC) = how much longer would have good standard of life comp to no drug
  • incremental cost-effectiveness ratio = diff in cost between 2 intercalations (new and current)
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80
Q

Is Lumacaftor and Ivacaftor a cost effective treatment for CF cases w/ phe508del allele?

A
  • both drugs v expensive due to cost of dev

- plausible ICER of £30,000 per QALY gained, but was approx £220,000

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81
Q

Does Ivacaftor work and for how many CF cases is it effective?

A
  • Gly551Asp in ≈5% CF patients
  • yes, trials show 10% increase in forced expiratory vol (gets progressively lower w/ disease), decrease to half rate of exacerbations, normal sweat salt conc, reduced Pseudomonas infections and increased QoL
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82
Q

Was Ivacaftor justified as a drug on the NHS and why?

A
  • costs = £182,000
  • discounted ICER £285
  • NHS commissioning group agreed treatment for under 5s
  • justified as “ultra-orphan” drug (only drug for disease, no other option)
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83
Q

Why is a disorder affecting muscles v serious?

A
  • most abundant body tissue
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84
Q

How much of the body weight does muscle make up?

A
  • 23% in females

- 40% in males

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85
Q

What are the characteristics of skeletal muscle?

A
  • cells called fibres
  • single fibre runs length of muscle
  • striated appearance –> due to orderly arrangement of actin and myosin
86
Q

How many diff dystrophies are there?

A
  • around 40
87
Q

How do muscular dystrophies vary?

A
  • variety of clinical features
  • v heterogenous (mutations in many diff genes)
  • diff mol pathologies
88
Q

What are the assoc problems of muscular dystrophies?

A
  • progressive weakness and degen on skeletal muscle

- multi system disorder –> mental retardation, cardiomyopathy, peripheral nerves, smooth muscle

89
Q

What is the most common muscular dystrophy and what is the incidence of it?

A
  • Duchenne
  • 1:3500 male births necessary
  • can affect females but much more unlikely as would have to be homozygous
90
Q

How is DMD inherited?

A
  • X linked recessive
91
Q

What is the age of onset of DMD?

A
  • 3-5 y/o
92
Q

What is a major lifestyle impact of suffering from DMD?

A
  • wheelchair bound by 12 (non-ambulation)
93
Q

How does DMD affect lifespan, and why?

A
  • shorter, <30 years

- due to resp failures –> diaphragm stops working and suffocate

94
Q

In what way do the muscles degen in DMD?

A
  • muscle fibres fill up w/ fatty infiltrate –> can cause muscle to swell up
  • doesn’t have pink colour
95
Q

What are the characteristics of the DMD gene?

A
  • v large –> 2.4mb, 79 exons (so v complex splicing), 14kb mRNA transcribed from 7 diff promoters
  • v high intragenic recomb freq –> 2 hotspots
96
Q

Where are hotspots found in DMD gene, and what is the effect of them being present?

A
  • exons 1-20 and 44-50

- cause frameshifts when lost, so nonsense codons, resulting in truncated protein

97
Q

What protein does the DMD gene involve?

A
  • Dystrophin
98
Q

Are de novo mutations common in DMD, and why?

A
  • yes, 2/3 mutations are de novo deletions at 2 hotspots exons 3-8 and 44-50
  • often don’t have children so mutation dies out quickly
99
Q

What is Becker MD caused by?

A
  • caused by deletions that leave reading frame intact
  • lose some of repeated units that form rod like structure, so still maintains activity, as long as termini the same, so still maintains function
100
Q

Where is Dystrophin located?

A
  • under cell cortex (sarcolemma)
101
Q

What is the structure of Dystrophin?

A
  • v long rod like molecule
102
Q

What is the function of Dystrophin?

A
  • builds bridge between actin cytoskeleton w/in muscle cell, through dystroglycan complex (DGC) in sarcolemma, to Laminin 2 which interacts w/ ec matrix
103
Q

What is the structure of DGC (dystroglycan complex), and what do mutations cause)?

A
  • no. diff subunits

- mutations to these subunits cause forms of MD

104
Q

What is maintenance of the structure formed by Dystrophin important for?

A
  • for allowing muscles to regen after minor damage

- and therefore long term maintenance of muscle health

105
Q

How does exercise build muscle strength?

A
  • exercise causes lots of minor tears and repair of this damage builds up strength
  • w/o this complex tears cannot be repaired
106
Q

How can DMD mutation be identified and diagnosed by multiplex PCR?

A
  • if deletions don’t maintain ORF, get nonsense mutation and therefore premature protein truncation
  • test can be carried out in utero if know at risk (eg. if parents already have affected child)
107
Q

What is a morpholino?

A
  • chem mod antisense oligonucleotide (AON) that blocks access of proteins to mRNA by forming strong assoc
108
Q

How are antisense oligonucleotides used as a treatment for DMD?

A
  • DIAG*
  • when Δex49-50 then out of frame and get premature stop codon, so no dystrophin prod
  • treat w/ Eteplirsen to block access to splicing factors, so 51 deleted to and ORF restored, so shortened, functional dystrophin prod
109
Q

What is seen in patients after 24 weeks of treatment w/ Eteplirsen?

A
  • get dystrophin +ve fibres

- start to see protein prod, not as good as healthy patient, but big improvement

110
Q

Why might Eteplirsen not be a viable treatment after phase II trials?

A
  • only 14% DMD patients amenable to treatment

- v expensive ($300,000 /yr)

111
Q

What benefits did Eteplirsen show in phase II clinical trials?

A
  • in 12 boys some evidence of benefit
  • in walk test 150m less decline comp to controls after 36 months
  • less complete loss of ambulation
112
Q

What did a large scale investigation of dystrophin prod after Eteplirsen treatment show, and why did this cast doubt on the efficacy of Eteplirsen?

A
  • western blot varies in diff patients –> 0 - 2.8% of normal levels
  • % cells w/ dystrophin +ve fibres up to 10% of normal
  • immunofluorescence intensity up to 33%
  • but BMD patients have 40% normal dystrophin levels –> so is it working well enough to have clinical effect?
113
Q

How are complex diseases inherited and is this influenced by genetics or environment?

A
  • tend to run in families –> but share genes and env so hard to disentangle effects
114
Q

Do all complex diseases have a genetic component (ie. physical/psychological)?

A
  • not much dispute that physical disorders do (but don’t know how much)
  • but more dispute over whether psychological conditions do
115
Q

What is the difference between additive and dominance variation?

A
  • additive = phenotypic outcome is additive sum of alleles
  • dominance = dep on actual config of alleles, which cannot be same in parents as in their children
  • DIAG*
116
Q

What are the 2 types of twins and how much of their genotype and env do they share?

A
  • monozygotic (identical) = same genotype
  • dizygotic (non-identical) = 50% same genotype
  • share same env (and to same extent) –> but debate over this and some would argue they don’t
117
Q

What is correlation (r) or co-variance and how is calc in twin studies?

A
  • plot on graph and see to what extent does value of y vary when value of x varies
118
Q

What does ACE stand for in the ACE model, and what are the values for MZT and DZT?

A
  • A = additive variance, rMZ = 1, rDZ = 0.5
  • C = common env, rMZ = rDZ = 1
  • E = non-shared env
119
Q

What are the equations of the ACE model?

A
  • rMZ = A + C
  • rDZ = 0.5A + C
  • A = 2 (rMZ - rDZ)
  • C = rMZ - A or C = 2rDZ - rMZ
  • E = 1 - rMZ
120
Q

What did a paper about estimating h^2 for GCSE pass rate show?

A
  • study of 500 sets of twins
  • claimed biggest factor affecting performance at GCSE is genetic inheritance
  • focus on GCSE core subjects mean grade –> saw can mod up to 1/3, so can be affected by non-genetic factors too
  • therefore can’t say this isn’t much effect (as paper claims), esp as varies from 0.22 to 0.36
121
Q

Why can’t twins separated at birth be used for heritability estimates?

A
  • not many sets, so sample size would be too small
122
Q

How can correlation be measured for continuous traits, and why is this not that helpful?

A
  • can be directly measured

- but most things inherited not continuous (ie. whether disease inherited or not)

123
Q

How are discontinuous traits measured?

A
  • by concordance –> prop of twins that are both affected when 1 twin affected
  • concordance converted into correlation by mathematical transformation called tetrachoric correlation
124
Q

What is important to note when converting concordance to correlation?

A
  • that while large diff in concordance is indicative of high heritability we can’t simply double diff in concordance
125
Q

What percentage of DZTs and sibling pairs share alleles and genotypes, show this is a cross, and are dominance effects inherited/shared?

A
  • 25% have 100% identical genotype and 100% identical alleles
  • 50% have 0% same genotype, but 50% identical alleles
  • 25% have 0% same genotype and 0% same alleles
  • DIAG*
  • dominance effects in parents cannot be inherited by children
  • 25% of any dominance effects in siblings will be shared
126
Q

How can epistasis stop a function being performed?

A
  • DIAG*
  • if 2 alleles and have allele that blocks 1 pathway, function can still happen (in either pathway)
  • but if get allele affecting both pathways, then function doesn’t happen
127
Q

Is epistasis transmitted to children?

A
  • no
128
Q

What does broad sense heritability inc and which elements can’t be transmitted to children?

A
  • additive, dominance (D) and interaction (I) effects –> ie. all the ways genotype can affect phenotype
  • D and I not transmitted, as children can’t have same combo of alleles as either parent
129
Q

What does narrow sense heritability measure?

A
  • only measures additive effects which are transmitted to children
130
Q

Are twin studies closer to narrow or broad sense heritability?

A
  • nearer to broad sense
131
Q

What calculation can be performed if D or I are operating in a twin study?

A
  • 2rDZ - rMZ = C - 0.5D (+/or I)
132
Q

What does ACE assume when 2rDZ - rMZ is +ve or -ve?

A
  • +ve –> D = 0 (no dominance)

- -ve –> C = 0

133
Q

How much of familial resemblance is due to additive genetic variation, and how was this found?

A
  • 49% (= mean heritability across all traits)

- meta-analysis looking at lots of studies and combining data

134
Q

What did a meta analysis discover about evidence for dominance effects in physical and behavioural disorders?

A
  • no evidence for them in physical disorders

- cluster of behavioural disorders req either non-additive genetic effects or shared env influences to explain data

135
Q

What are the limitations of twin studies?

A
  • can twin data be extrapolated to general pop?
  • assumes MZT and DZT share same enz –> highly disputed, esp for behavioural traits, do parents treat MZT diff to DZT
  • in utero diffs –> whether share amniotic sac or whether diff ones
136
Q

What does heritability address, and what does it not?

A
  • addresses pop variance

- but NOT indiv genetic determination

137
Q

Why is there a bias in heritability studies?

A
  • generally carried out in Western world w/ people of European descendance
138
Q

What is the pattern of phenotypic variance for 1 locus and 2 alleles?

A
  • DIAG*
  • 2x as many heterozygotes
  • when add env variance DIAG
139
Q

WHat is the pattern of inheritance for polygenic inheritance (2 loci)?

A
  • DIAG*

- start to to see normal distribution (which would see w/ many loci = pseudoinfinite no.)

140
Q

What is the threshold model for multifactorial diseases, and what kind of traits is it used for?

A
  • DIAG*
  • liability is combo of genetic and env influences
  • used for discontinuous traits
  • or can look at relative risk to those increased no. risk alleles means curve shifted to right
141
Q

What may people with more predisposing alleles to eg. type II diabetes want to do?

A
  • take precaution and make lifestyle changes, eg. lose weight, improve diet etc.
142
Q

Why is this simple model of polygenic inheritance naive?

A
  • more than 2 alleles that all have effect

- assumes no interaction, that each allele has same freq, additive effect

143
Q

What is the relative contrib of each locus to overall pop risk dep on?

A
  • magnitude of effect of risk allele
  • allele freq
  • dominance
  • epistasis
144
Q

How can risk alleles appear in allele pop?

A
  • common, but effect small –> “common disease, common variant”
  • rare and large effect (know rare, as if common and large effect would be v easily identified, so if not easily identified, must be rare)
  • mixture of oligogenes mod by polygenes or modifiers
145
Q

How does effect size of risk alleles affect identification and mapping?

A
  • larger the effect, the easier to identify
146
Q

Why is susceptibility not pre-determination?

A
  • only small prop of indivs w/ at risk genotype may suffer from disease
  • indivs w/o risk allele may also still be affected
147
Q

What is the genotype relative risk (GRR)?

A
  • ratio of risk w/ allele comp to risk w/o allele
148
Q

What is the genotype odds ratio (OR) and how is it calc?

A
  • odds of getting disease w/ genotype comp to odds of w/ diff genotype
  • cases/non cases genotype 1 /
    cases/non cases genotype 2
149
Q

What are eg.s of small no. alleles being assoc w/ large risk of a complex disease?

A
  • HLA locus and T1D
  • ApoE e4 allele and Alzheimer’s Disease
  • CFH gene and wet macular degen
150
Q

How does a mutation at the HLA locus increase T1D risk?

A
  • DQB1 is high risk haplotype
  • mutation is asp57any
  • heterozygous OR = 5.6, homozygous OR = 18
  • 3% pop homozygous but only 0.3% have T1D –> genotype greatly increases risk, but doesn’t cause disease, only 1 in 10 do
151
Q

How does ApoE e4 allele increase Alzheimer’s risk?

A
  • allele freq in pop = 0.16

- homozygous OR = 13, heterozygous OR = 2.5

152
Q

What is the OR of the CFH gene?

A
  • 0.26
153
Q

How are SNPs used for seq comparison?

A
  • pairwise comparison 1bp every 1kb

- pop comparison 1bp diff every 300bp

154
Q

How many SNPs are used?

A
  • 15 mil common SNPs (>5%)
  • approx 15 mil <5%
  • don’t have to look at all 15 mil common –> LD
155
Q

What are eg.s of SNP databases?

A
  • ENCODE
  • 1000 genome projects
  • dbSNP database
156
Q

What commercial microarrays are there?

A
  • Illumina

- Perlegen

157
Q

How is GWAS used for identification of risk alleles for complex diseases?

A
  • collect dataset of cases and controls (1000s)
  • genotype each subject w/ genome wide panel of SNPs
  • calc OR for each allele in panel for each indiv in dataset
  • for each allele in genome wide panel across whole data set, is OR signif diff in cases comp to controls? –> such alleles said to be assoc w/ disease
158
Q

What are the 2 reasons why allele is assoc w/ disease?

A

1) allele causes risk
* DIAG*
- eg. changes AA seq in ORF
2) allele correlated w/ causative allele due to LD (more common reason)
* DIAG*

159
Q

How does LD occur?

A
  • DIAG*
  • endogenous process causes change in DNA
  • original haplotype remains assoc w/ risk allele, so don’t have to find variant, just look at haplotype assoc w/ disease
160
Q

What is LD?

A
  • non-random assoc of alleles at diff loci in given pop
161
Q

Why are haplotype blocks useful for looking at SNPs?

A
  • oligonucleotide arrays allow simultaneous genotyping of many alleles
  • tags are proxies for the other SNPs –> looking at small no. SNPs can predict others, as chromosomes organised into haplotype blocks
162
Q

How can you recognise haplotype blocks w/ tag SNPs?

A
  • DIAG*
  • in this eg. 496 combos poss, but only 3 actually exist
  • LD reduces haplotype diversity
  • genotype all 6 SNPs w/ just 2 tests
  • if knew, eg. that GA assoc w/ disease, then know all somewhere w/in this block
163
Q

What was the HapMap project, and what were there methods?

A
  • intl consortium
  • used commercial microarrays to map haplotype blocks in human genome
  • use map to select panel of SNPs that efficiently stand proxy for all other SNPs across genome (so panel is genome wide)
164
Q

What did detailed knowledge of LD relationships from HapMap and WGS allow?

A
  • seq 1 mil SNPs

- used to impute genotype of many more SNPs

165
Q

What diff types of errors does GWAS prod?

A
  • type 1 false +ves due to multiple testing

- type 2 false -ves

166
Q

How does GWAS prod type 1 false +ves, and what is the solution?

A
  • each SNP represents indep test
  • stat threshold of signif p ≤ 0.05 would mean result would occur < 1 in 20 times by chance
  • in 500,000 indep test expect 25,000 false +ves
  • it is no. SNPs tested that causes problem, not no. subjects
  • so use p value of p-trend statistic, p ≤ 10^-8 (for genome wide signif)
167
Q

How does GWAS prod type 2 false -ves?

A
  • set threshold too high and miss weak signals (as looking for small signal amongst lots of noise)
  • there are weak but genuine signals and this is reason why we can’t identify all disease causing alleles
168
Q

What diff type of Manhattan plots can be used for GWAS?

A
  • p value vs genome position

- or locus specific

169
Q

What was DIAGRAM looking for?

A
  • alleles contrib to TIID
170
Q

How do intl consortia collab for meta analysis?

A
  • standardise methods and data formats, and combine data

- allows v large no.s of cases/controls

171
Q

How much of TIID heritability has been explained, and what have diff studies shown?

A
  • no.s risk alleles large, but prop heritability explained is low
  • in 2012: 63 alleles explained 5.7% heritability, estimate 488 SNPs assoc but fell short of signif, 100,000 cases/controls would identify 37% more alleles and explain 10% liability
  • in 2014: research continues and 22,000 cases and 55,000 controls identified 7 more risk alleles
172
Q

How much heritability has been explained in TID, breast cancer and height?

A
  • TID –> 50 alleles identified explain 50-80% heritability
  • breast cancer –> 105 alleles explain 18% heritability
  • height –> 697 alleles explain 16% phenotypic variability
173
Q

Where is the missing heritability?

A
  • v large no. alleles w/ v small effects –> each allele has effect too small to be detected by GWAS
  • overestimation of additive heritability in twin studies –> twin studies inc non-additive dominant and epistatic effects, most alleles appear to be additive (eg. breast cancer), power decreases exponentially w/ no. interactions
  • moderately rare alleles (0.1 - 1%) w/ mod effect (OR = 2 - 4)
174
Q

How did the Intl Schizophrenia Consortium attempt to stop statistical rigour from preventing discovery?

A
  • looked at GWAS of few assoc alleles (<3% of variance)
  • identify alleles w/ diff signif thresholds (PT)
  • successively relaxed P values and looked if alleles more represented in 2nd group (target) comp to controls
  • saw effect gets larger w/ more liberal PT values
  • not consistent w/ 100 SNPs, but w/ many more w/ smaller effect
  • would explain 33% variance
175
Q

Why is it so easy to look at height?

A
  • v easy to measure and often measured while looking at other things too
  • so lots of data available
176
Q

What did a 2014 meta analysis of height involve?

A
  • looked at 79 studies w/ approx 250,000 indivs w/ European ancestry
  • 697 variants reached genome wide signif –> explains 16% phenotypic variance
  • relaxed p value and subdivided data sets to try and see if stringent threshold missed any genuine signals –> but also mre false +ves
  • SD score tested for GWAS alleles –> found most of genome has undergone selection for height, N. Europeans gen taller than S. Europeans
177
Q

What does pathway analysis involve?

A
  • looking to see if GWAS hits make biological sense
  • eg. may expect muscular-skeletal to be assoc w/ height
  • alleles w/ highest p-value often have link w/ disease or phenotype looking at –> often identify pathways unsuspected and gives important bio info about what underlies causation of disease
178
Q

What did pathway analysis and GWAS uncover about Crohn’s?

A
  • most signif alleles al involved in innate immunity

- so found caused by body reacting to normal micrological flora causing inflam of bowel

179
Q

How can genome-wide complex trait analysis (GCTA) be used to estimate prop of genetic variability?

A
  • instead of looking for particular alleles, can look for degree to which people share blocks of DNA (so how similar people are in terms of overall DNA)
  • use SNPs across genome to estimate instead of calculated relatedness
  • correl w/ height (more similar DNA = more similar height)
  • explains 45% heritability
  • prop to chromosome length
  • other factors such as incomplete LD increase prop further
  • but doesn’t identify indiv SNPs
180
Q

What 3 questions can be considered when deciding if GWAS has been useful, and what is a good eg. for each?

A

1) has it illuminated mechanisms of disease? eg. TID
2) can it be used to predict those at risk? eg. breast cancer
3) what does it tell us about genetic architecture of common disease and phenotypic traits? eg. omnigenic model

181
Q

What happens in TID?

A
  • autoimmune destruction of insulin prod β cells in Islets of Langerhan
182
Q

What is detectable in TID sufferers before onset?

A
  • autoantibodies
183
Q

When does TID onset occur, and what is it detectable?

A
  • mostly, not exclusively juvenile/teenage onset

- detectable in children before onset, so can screen for it

184
Q

What is the pop risk of TID, and the risk to a sibling of affected?

A
  • risk to sibling = 6% / recurrence risk = 15

- gen pop risk = 0.4%

185
Q

What is the concordance in MZTs for TID?

A
  • 50% lifetime
186
Q

What env factors may influence TID risk?

A
  • viral infections and vaccinations

- cows milk

187
Q

How do we know env factors are likely to play role in TID?

A
  • recent rapid increase in incidence
188
Q

How much of TID heritability has been identified?

A
  • 80% (50% by HLA allele)
  • 50 other genes –> inc other immune related genes for antigen presentation, insulin promoter
  • all other alleles OR < 1.1
189
Q

What establishes tolerance to insulin, and how does this occur?

A
  • neonatal apoptosis of cytotoxic T cells that recognise insulin
  • DIAG*
190
Q

What happens if there is a mutation to insulin promoter, so still working but less well?

A
  • less insulin prod
  • if DQβ1/IL2R mutated then all of pathway doesn’t occur
  • so cytotoxic T cell not sent down apoptotic pathway and can then attack Islets of Langerhan prod insulin
191
Q

How do TID risk alleles affect neonatal apoptosis of cytotoxic T cells that recognise insulin?

A
  • decreases it
192
Q

What is the lifetime risk of breast cancer in women?

A
  • 8-12%
193
Q

What % of healthy women have an affected 1st degree relative and how does this affect their risk?

A
  • 15%

- doubles risk

194
Q

How does having more than 1 affected relative affect risk of dev breast cancer?

A
  • increases risk sharply
195
Q

What can mod the BRCA risk in breast cancer?

A
  • the genetic background of other alleles
196
Q

What %s of the familial risk are caused by diff alleles?

A
  • 5% BRCA 1/2, OR = 10 - 50
  • 15% DNA repair pathways, OR = 2 - 4
  • 41% from common alleles –> 18% 105 confirmed alleles, OR = 1.05 - 1.2
197
Q

What shape is the curve for breast cancer risk alleles?

A
  • J-shaped
198
Q

When are UK women screened for breast cancer, and what is there risk at this point?

A
  • invited for mammography screening at 47

- 2.4% 10 year risk of breast cancer dev

199
Q

What is the polygenic risk score (PRS) based on and how is it calc for breast cancer?

A
  • based on 77 risk alleles
  • calc = βx1 + βx2 ….. βxn
    where β = per allele log OR for risk allele
    x = no. of alleles
200
Q

What kind of model is PRS for breast cancer?

A
  • multiplicative model
201
Q

What is the purpose of the PRS for breast cancer?

A
  • can identify women where need to screen earlier/later, dep on risk
202
Q

Why do epidemiological studies also need to be done for breast cancer?

A
  • also env risk, not all genetic
203
Q

What are some eg.s of mod and non-mod risk factors for breast cancer?

A
  • non-mod = PRS, fam history, age at merarate, age had 1st child
  • mod = alcohol consumption, BMI, HRT, smoking
204
Q

Is the profile of susceptibility loci useful for preventing breast cancer (figs)?

A
  • are modifiable risk factors
  • 28% fewer cancers if all women were in lowest risk decile (bottom 10%)
  • combine PRS and mod risk factors –> 16% have same risk at 40 as av 50 y/o and 32% have same risk as 50 as av 40 y/o
  • 20% preventable cancers would be avoided if top 10% at risk adopted healthy lifestyle –> women in top decile of non-mod risk factors would have same risk as av
205
Q

What were Jonathan Pritchards 2 big questions?

A

1) why do lead hits for heritability contrib so little to heritability, ie why are effect sizes so small?
2) why does so much of genome contrib to heritability (eg. for height virtually all genome has non 0 effect on height phenotype)?

206
Q

What do most risk alleles affect?

A
  • non-coding seqs and influence gene expression
207
Q

What are the 3 classes of genes in the omnigenic model of complex diseases and phenotypic traits?

A

1) biologically relevant genes –> core genes
2) peripheral genes –> broadly expressed in many tissues and active in relevant cells, enriched in GWAS hits
3) genes not expressed in relevant cells –> depleted in GWAS hits

208
Q

What genes have the largest effect size, and what explain more of the heritability?

A
  • indiv biologically relevant genes have largest effect size

- but collectively broadly expressed genes explain more of heritability

209
Q

What is the omnigenic model?

A
  • small no. core genes have direct effect on disease risk –> if have variants affecting coding seq, more likely to have major effect and be of SGD type rather than polygenic
  • “small world” property of networks
  • only a few core genes, so major effects on heritability comes from indirect effects of many broadly expressed genes
210
Q

What is the “small world” of networks, shown in the omnigenic model, and what does this mean as a result?

A
  • any node in network connected to any other node in small no. of connections
  • so most broadly expressed genes only few steps away from core genes and so can affect their expression

MBB329 - Genetics of Human Disease (2 decks)

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