Unit 2 Day 5

Question 1

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

Answer 1

• 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)

Question 2

multifactorial inheritance

Answer 2

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

Question 3

complex traits of multifactorial inheritance

Answer 3

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

Question 4

twin studies

Answer 4

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

Question 5

adoption studies

Answer 5

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

Question 6

risk of disease in relatives

Answer 6

• 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

Question 7

heritability

Answer 7

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%

Question 8

incomplete penetrance

Answer 8

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

Question 9

penetrance

Answer 9

relationship btw. trait and genotype

probability that an individual develops trait if have genotype

Question 10

complete penetrance

Answer 10

everyone with pre-disposing genotype will get trait

Question 11

variable expressivity

Answer 11

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

Question 12

allelic heterogeneity

Answer 12

• 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

Question 13

CFTR genotype

Answer 13

2 copies=severe pancreatic insufficiency

1/0 copies=mild, mild sever insufficiency

Question 14

locus heterogeneity

Answer 14

• 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)

Question 15

phenocopy

Answer 15

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

Question 16

why find disease genes?

Answer 16

• 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

Question 17

personalized medicine program

Answer 17

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

Question 18

problems w/ personalized medicine

Answer 18

• 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

Question 19

odds ratio

Answer 19

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

Question 20

DNA markers and mapping

Answer 20

• too expensive to sequence genome

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

Question 21

surrogates for disease mutations

Answer 21

some polymorphisms cause disease. most don’t

Question 22

commonly used marker types

Answer 22

microsatellites
SNP
CNV

Question 23

microsatellites

Answer 23

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

Question 24

SNP

Answer 24

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

Question 25

SNP Haplotype

Answer 25

- 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

Question 26

linkage diequelibrium

Answer 26

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

Question 27

CNVs

Answer 27

``` 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 ```

Question 28

Disease genes

Answer 28

medelian: 1 gene is sufficient to cause most of phenotype | polygenic/multifactorial: no one gene is sufficient for causing phenotype

Question 29

candidate gene DNA sequencing

Answer 29

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

Question 30

candidate gene association studies

Answer 30

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

Question 31

candidate gene association study

Answer 31

- 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

Question 32

genetic association studies

Answer 32

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

Question 33

why don't gene association studies work?

Answer 33

1. multiple testing correction must include all tests | 2. must ethnically match cases and controls (impossible)

Question 34

how many confirmed genetic associations are false positives?

Answer 34

>96%

Question 35

hypothesis free approaches to gene diseases

Answer 35

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

Question 36

genetic linkage analysis

Answer 36

- search genome for segments co-inherited in "multiplex families" - assumes affected relatives share susceptibility-identical by descent - best for mendelian traits

Question 37

unit of genetic distance/recombination

Answer 37

centimorgan | cM; 1cM=1% recombination btw 2 loci

Question 38

LOD

Answer 38

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

Question 39

GWAS

Answer 39

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

Question 40

deep re-sequencing

Answer 40

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

Question 41

exome/genome sequencing

Answer 41

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