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GEN > Discovery of Human Disease Genes > Flashcards

Discovery of Human Disease Genes Flashcards

1
Q

What causes most disease states and traits?

A

Combo of gen and env factors

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2
Q

Give e.g.s of diseases mainly driven by gen

A
  • achondroplasia

- CF

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3
Q

Give e.g. of diseases mainly driven by env

A
  • chicken pox
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4
Q

Give e.g.s of diseases caused by both gen + env

A
  • psoriasis

- Chron’s Disease

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5
Q

Why do we want to identify disease-causing genes?

A
  • molecular confirmation of clinical diagnosis
  • accurate carrier testing for indiv/couples
  • pre-symp testing for adult onset cond e.g. HD, familal breast cancer
  • prenatal diagnosis for pregnancies at high risk of sever disorder
  • provides insight into pathological mech underlying disease
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6
Q

What are the 3 steps of pos cloning?

A
  1. identify multigen affected pedigree - collect DNA of family members
  2. systematic evaluation of inheritance patterns across genome
  3. multinational search within genomic regions coseg with the disease
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7
Q

What are monogenic diseases caused by?

A

Mutation in a single gene

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8
Q

What things is nec and sufficient to produce clinical phenotype?

A

Mutations

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9
Q

What do monogenic disorders demonstrate in pedigrees?

A

Dom/rec inheritance patterns

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10
Q

Why is more known about mol basis of human phenotypes now than in the past?

A

Advances in DNA seq tech

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11
Q

What causes auto dom diseases?

A

Mutations in 1 copy of gene

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12
Q

How are auto dom cond inherited?

A

Vertical transmission - affected indiv must have 1 of 2 affected parents/de novo mutation

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13
Q

What are 2 key features of auto dom inheritance?

A
  1. equal no. of M + F affected

2. M to M transmission

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14
Q

What is the phenotype of unaffected indiv iffspring of auto dom cond?

A

Unaffected - but may arise as new mutation

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15
Q

How are auto rec cond inherited?

A

Mutations in both copies of gene nec to cause disease

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16
Q

What is phenotype of carries of auto rec cond?

A

Generally clincally normal

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17
Q

What are 2 key factors of auto rec inheritance?

A
  • equal no. of affected M + F

- consanguinity may be present

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18
Q

How are X-linked rec disorders inherited for M + F?

A

M - mutations in 1 copy of gene

F - mutations in both copies

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19
Q

What are 2 key features of X-linked rec inheritance?

A
  • incidence much higher in M than F

- no M to M transmission - as M passes on Y chr

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20
Q

During meiosis, what is role of precursor cells of sperm/ova?

A

must multiply and at same time dec no. of chr to 1 full set

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21
Q

What happens in process of recomb?

A

2 chr of homologous pair exchange segments

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22
Q

What does freq of recomb between 2 locations on chr depend on and why?

A

Distance - bc recomb can occur at location along chr

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23
Q

What is genomic linkage?

A

Genes close/DNA regions close together on the same chr more likely to be co- inherited than genes/DNA regions further apart

24
Q

How is genomic linkage observed experimentally?

A

By assessing genomic loci that vary within pop + evaluating their co-inheritance

25
Q

What can be said about distance of these 3 variants loci based on this info:

  • 11 informative meiosis
  • 11 recomb events observed
  • 8 recomb events between A + B
  • 3 recomb events between B + C
A

B is closer to C than A to B bc there are less recomb events between B + C so they must be closer together (linked)

26
Q

How can seg be used to map disease genes with linkage?

A
  • can reconstruct mutation genotype without actually knowing where mutation locus is
  • when discover new mutation, look for linkage to other genes to determine location of mutation on a chr + help identify mutated gene
  • can then consider series of variable loci across genome and see if they’re linked to mutation locus
27
Q

What can be said about the mutation locus based on coseg with variant locus A (use lecture diagram):

  • observe inheritance of the mutation twice with allele A1
  • twice with allele A2
A

Mutation locus not linked to locus A - should be consistency of same allele being inherited with disease and too many recomb events

28
Q

What can be said about the mutation locus based on coseg with variant locus B:
- inheritance of mutation 3x with B1 and 1x with B3

A

Mutation locus nearly linked to B as there’s little recomb events

29
Q

What can be said about the mutation locus based on coseg with variant locus C:
- inheritance of mutation everytime with C1 and never when disease not transmitted

A

Mutation locus linked to locus C and mutation located close to variant locus C

30
Q

What is linkage process typically used to assess, how and why?

A
  • Seg of genomic regions using aprrox 400 multiallelic loci aka microsatellite repeats/approx 5000 biallelic loci (usually SNPs).
  • approach enables systematic evaluation of coseg of genomic regions with disease locus
31
Q

What statistical is used to detect presence of linkage?

A
  • LOD score which estimates whether 2 genes/gene + a disease gene are likely to be located near each other on a chr + therefore likely to be inherited
  • Evaluate likelihood ratio that those genotypes occurred under hypothesis that there’s linkage between marker (look at seg of alleles from each marker) + trait (look at seg of trait within family)
32
Q

How is the LOD test score interpreted?

A
  • LOD score >3 consistent with linkage (2 genes located close to each other on chr)
  • odds are 1000:1 that 2 genes linked and therefore inherited together
  • LOD score
33
Q

What are the next steps once linkage to chr region has been identified?

A
  • identify genes located within linkage interval
  • assess genes as pot candidates based on their bio functions
  • seq genes in affected indiv to try to identify causative mutation
34
Q

What is result of establishing coseg of specific genomic regions with transmission of disease phenotypes in pedigrees?

A

Poss to locate genomic region where disease-causing gene resides

35
Q

Why is it nec to seq genes in linkage interval?

A

coseg region (linkage interval) likely to contain more than 1 gene so need to seq to identify causative mutation

36
Q

Why may genes in linkage interval be sequenced?

A

To attempt to identify causative mutation

37
Q

What 2 things can linkage analysis in single pedigree be confounded by?

A
  1. Non-penetrance

2. Phenocopies

38
Q

What is non-penetrance?

A

Indiv has mutation but won’t dev disease

39
Q

What are phenocopies?

A

Indiv has something that resembles disease but don’t have disease-causing mutation

40
Q

Where may linkage analysis also be performed and what issue can arise from results?

A

In multiple pedigrees and results combined has a confounding issue of gen heterogeneity

41
Q

What is gen heterogeneity?

A

Same/similar phenotypes caused by mutations in multiple genes

42
Q

Why have DNA seq costs dec?

A
  • Becoming more affordable to just seq protein coding regions of genome (exome seq)
43
Q

What are adv of exome seq?

A
  • ability to undertake affordable whole genome seq allow ‘ genome informed’ personalisation of care
  • also allows opportunity for identification of diseases causing genes
44
Q

What is size, no. variants and cost of human genome?

A

Size: approx 3 bn bp
No. of variants: approx 3m
Cost: approx £1000

45
Q

What is size, no. variants and cost of human exome (all protein coding regions)?

A

Size: 30-50m bp
No. of variants: approx 20 000
Cost: £300-£800

46
Q

Based on the figs, why is it more cost effective to seq exome for mongenic disease?

A
  • More cost effective and rep only approx 1%
  • whilst some exceptions, causative mutations in monogenic diseases consistently identified in ortein coding region of genome (exome)
47
Q

What can be found by seq the exome?

A
  • catalogue all protein altering variation in an indiv
  • if indiv has monogenic disease, can filter through this variation to identify which variant is causing disease
  • allows new e.g.s for disease gene identification
48
Q

How can exome seq help with identifying disease causing variants?

A
  • Seq 3 people’s exomes and identify pos in exomes to see where they varied
  • identify genes with hetero protein altering variants and therefore find allele passed on from 3 variants identified
49
Q

What has dramatic decrease in price of DNA seq provided?

A

New methods to identify disease causing genes

50
Q

What are the new methods of identifying disease causing genes?

A
  • filtering affected indiv variant profile to exclude variants unlikely to play role in disease
  • comparison between filtered variant profiles from unrelated affected indiv to identify genes that are site of candidate variation in multiple indiv
51
Q

What are the new methods of identifying disease causing genes not reliant on?

A

Ascertainment of large pedigrees

52
Q

What is the formula for the LOD score?

A

LOD = log10 [L(linkage)]/[L(no linkage)
LOD score = log10 x likelihood that genotype occurred under hypothesis that there’s linkage/likelihood that genotype occurred under hypothesis that there’s no linkage

53
Q

When are genes not linked?

A
  • genes on sep chr never linked

- genes far away on the same chr

54
Q

Explain how linkage works using an e.g. in genes that are not linked

A
  • gene 1 and 2 on same chr and far apart
  • each gene has 2 alleles (A+B) so have 1A + 2A on one pair and 1B + 2B on other
  • bc gene 1 + 2 far apart, more likely to be recomb evet between them so gametes end up with new allele combos not present in parent
  • gene 5 + 6 on sep chr but never linked
  • each gamete gets single copy at random of each chr + bc there’s nothing holding them together, alleles can pass to gametes in any combo
55
Q

Explain how linkage works using an e.g. in genes that are linked

A
  • gene 3 + 4 sit closer together on same chr
  • 3A + 4A on 1 pair + 3B + 4B on other
  • therefore less likely recomb event happen between them
  • most of the time, 3A + 4A stay together + therefore inherited together as well as 3B + 4B

GEN (6 decks)

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