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Unit 2 M2M > Unit 2 Day 5 > Flashcards

Unit 2 Day 5 Flashcards

1
Q

what is the reality of “simple Mendelian” disease characteristics?

A
  • variable disease progression depending on other factors common
  • different alleles in same gene associated with varying levels of severity
  • 1:1 relationship btw. variant and disease (e.g.: cystic fibrosis, huntingtons)
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2
Q

multifactorial inheritance

A
  • result of interactions between multiple variants and non-genetic factors
  • majority is a combo of genetic variation and non-genetic factors
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3
Q

complex traits of multifactorial inheritance

A
  • complex traits aggregate in families
  • don’t follow mendelian inheritance
  • need to distinguish between familial clustering and shared environmental factors
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4
Q

twin studies

A
  • monozygotic vs. dizygotic twins
  • if twins raised together-same degree of similar environment. differences=genetic
  • if twins raised separate-different environments. similarities=genetic
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5
Q

adoption studies

A
  • compare similarity btw. biological siblings raised apart and adopted siblings
  • if biological siblings are more concordant than adoptive=genetic as opposed to environment
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6
Q

risk of disease in relatives

A
  • compare frequency of disease in patients to see if higher than in general population
  • risk of disease in siblings of affected/risk of disease in gen. pop
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7
Q

heritability

A

proportion of variance in trait that is due to genetic variation
-eg: diabetes. 20% of pop has high risk haplotype, but disease incidence is 4%

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8
Q

incomplete penetrance

A

some with genotype will not get the trait (reality for complex traits)

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9
Q

penetrance

A

relationship btw. trait and genotype

probability that an individual develops trait if have genotype

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10
Q

complete penetrance

A

everyone with pre-disposing genotype will get trait

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11
Q

variable expressivity

A

individuals w/ same variant don’t show precisely the same disease or quantitative phenotype charachteristics

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12
Q

allelic heterogeneity

A
  • different alleles in same gene result in same trait (CF)
  • different alleles in same gene result in diff. traits (diff organ involvement w/in CF)
  • many alleles appear to have similar clinical progression
  • grouped into classes
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13
Q

CFTR genotype

A

2 copies=severe pancreatic insufficiency

1/0 copies=mild, mild sever insufficiency

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14
Q

locus heterogeneity

A
  • variants in different genes in very similar presentations

- eg: early onset AD (mutations in 3 genes: PS2, 1, APP; all result in early onset AD)

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15
Q

phenocopy

A
  • environmentally caused phenotype, mimics genetic version of trait
  • thalidomide induced limb malformation
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16
Q

why find disease genes?

A
  • genes/environment play role in all diseases
  • no systemic way to discover enviro risk factors, can find gene diseases
  • provides clues on pathogenesis (may allow new treatment)
  • enable genetic testing/screening/surveillance
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17
Q

personalized medicine program

A
  • discover risk genes common diseases
  • create DNA based predictive diagnostics
  • apply optimized treatments based on genetics
18
Q

problems w/ personalized medicine

A
  • genes and environment play role
  • genes for Mendelian (single gene) disorders=are deterministic
  • most genes for diseases are small risk
  • predictive genetic testing may be difficult/impossible
19
Q

odds ratio

A

risk of disease if carrying gene variant/risk of disease if not carrying gene variant

20
Q

DNA markers and mapping

A
  • too expensive to sequence genome

- “genotype” DNA “markers” (score able differences) at known positions

21
Q

surrogates for disease mutations

A

some polymorphisms cause disease. most don’t

22
Q

commonly used marker types

A

microsatellites
SNP
CNV

23
Q

microsatellites

A 
SSLPs, STRPs, SSRs
simple sequence repeats
multi-allelic
~1/30,000 bp
used for forensics
24
Q

SNP

A

single nucleotide polymorphism
bi-allelic
~1/50-300 bp
used for association
occurence/allele frequency differs based on pop./ethnic group
each occurs in local context/haplotype of surrounding SNP

25
Q

SNP Haplotype

A
  • recombinations breaks micro-patterns of polymorphic genes into haplotypes
  • recombination not random, cluster in ~10-50kb blocks
  • linkage disequilebrium blocks 2x smaller in african than caucasian
  • genotype enough SNPs, you can impute variation that wasn’t genotyped
26
Q

linkage diequelibrium

A

marker alleles within blocks tend to be co-inherited b/c recombination in blocks is uncommon

27
Q

CNVs

A 
copy number variants
bi allelic, multi allelic, unique
common genomic deletions
100s-1000s nt in size
detected by SNP patterns
most=not causal for human diseases
28
Q

Disease genes

A

medelian: 1 gene is sufficient to cause most of phenotype

polygenic/multifactorial: no one gene is sufficient for causing phenotype

29
Q

candidate gene DNA sequencing

A 
studies gene directly
depends on biological candidate gene/positional candidate gene
hit from GWAS or other mapping
sometimes successful Medelian disorders
most hypotheses=wrong!
30
Q

candidate gene association studies

A

markers used to test gene/causal variant indirectly
most common type of genetic study
depends on “a priori” biological hypothesis or positional hypothesis
powerful for common risk alleles
most a priori biological hypotheses are wrong
fatal flaws=false positive

31
Q

candidate gene association study

A
  • causal disease variation in candidate gene tagged by haplotype of polymorphic DNA markers
  • Depends on LD
  • genotype marker in candidate gene in cases and controls, compare allele frequencies in cases vs controls
32
Q

genetic association studies

A

done with reasonable sized # cases/controls (100’s)
simple statistics
if using multiple variants, apply multiple-testing correction
real association doesn’t imply causation, implies LD with causal mutation
almost always yields false positives

33
Q

why don’t gene association studies work?

A
  1. multiple testing correction must include all tests

2. must ethnically match cases and controls (impossible)

34
Q

how many confirmed genetic associations are false positives?

A

> 96%

35
Q

hypothesis free approaches to gene diseases

A
  • genetic linkage analysis
  • genome wide association studies (GWAS)
  • deep re-sequencing
  • exome/genome sequencing
36
Q

genetic linkage analysis

A
  • search genome for segments co-inherited in “multiplex families”
  • assumes affected relatives share susceptibility-identical by descent
  • best for mendelian traits
37
Q

unit of genetic distance/recombination

A

centimorgan

cM; 1cM=1% recombination btw 2 loci

38
Q

LOD

A

log of odds score
likelihood of date if loci linked at theta cM/likelihood of data if loci unlinked
significance is if >=3

39
Q

GWAS

A

case control association study
100’s thousands markers tested across whole genome
search for SNP w/ diff allele frequencies (case vs control)
match ethnically
can accurately measure/correct pop stratification
associations must be confirmed w/ independent replication

40
Q

deep re-sequencing

A

high throughput DNA sequencing
uses GWAS signals
full genome or exome sequencing
difficult to distinguish causal from non-pathological

41
Q

exome/genome sequencing

A

medelian diseases
costs 1-3000 dollars
data interpretation is difficult
can find principally single gene mendelian cause for disorder

Unit 2 M2M (8 decks)

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