Gene Identification

Question 1

General goal of linkage analysis

Answer 1

Identify marker alleles or haplotypes that are co-segregated with a disease phenotype

Question 2

How linkage is detected

Answer 2

Determining the amount of recombination between two markers

Rarer recombination between two loci are, the closer together they are on a chromosome

Question 3

Do linked loci segregate independently during meiosis?

Answer 3

No- they are inherited together

Question 4

Genetic markers definition

Answer 4

DNA variants in a given population or pedigree that are linked to a given disease or trait

Question 5

Do genetic markers associated with a trait generally cause that trait?

Answer 5

No- they generally are close to the causal genes, thus inherited together with them

Question 6

Two major types of genetic markers

Answer 6

Variable length polymorphisms and SNPs

Question 7

Variable length polymorphisms

Answer 7

Type of genetic marker
Characterized by long stretches of repeats
Different individuals have varying lengths of these repeats

Question 8

Single nucleotide polymorphisms (SNPs)

Answer 8

Type of genetic marker
Characterized by 1 base difference between individuals (2 different allele possibilities at a locus: some individuals carry one, some carry another)

Question 9

How SNP genotyping works

Answer 9

Used for already discovered SNPs
Different colored probes hybridize to different nucleotides (ex- homozygous A allele is one color, homozygous B allele is a second color, and heterozygous is a third color)
Hybridized DNA is shown on a plate: every SNP shows up as a dot on the plate
Can show up to several million SNPs on one plate
Each plate is one individual: can have multiple plates on a large plate

Question 10

Genetic distance

Answer 10

How often two markers are separated by recombinations

Question 11

Physical distance

Answer 11

Related to genetic distance

How many bases there are in between two markers

Question 12

What “1 centiMorgan” refers to

Answer 12

1% recombination per generation

Question 13

Is recombination uniformly distributed across the genome?

Answer 13

No- recombination resides primarily in “hot spots” (areas of higher recombination)

Question 14

Recombination fraction

Answer 14

Designated as Greek letter theta
Measures degree of linkage: fraction of times two markers are separated by recombination in a pedigree
Ranges from 0 to 0.5 (in meiosis, 2 chromosomes stay together half the time)

Question 15

What recombination fraction value (theta) is associated with linkage of two traits?

Answer 15

Two loci are said to be linked with theta is less than 0.5

Question 16

What does a recombination fraction value (theta) of 0.5 mean?

Answer 16

Loci are segregating independently- no linkage

Question 17

Log of the odds (LOD) score

Answer 17

Used to measure statistical significance of linkage

Higher score: linkage more likely

Question 18

What LOD score is considered to be significant?

Answer 18

Greater than or equal to 3

Question 19

Weaknesses of linkage analysis

Answer 19

Requires studying relatives (cannot use unrelated individuals)
Works best for rare, dominant traits (not useful for common traits)
Linkage regions are large and finding “the gene” is hard

Question 20

Do rare variants with large effects (as identified from pedigrees) underlie common genetic diseases?

Answer 20

No

Question 21

Common disease/common variant hypothesis

Answer 21

There are many variants with modest effects at higher frequency in the population that lead to common disease

Question 22

Significance- association analysis

Answer 22

Measures whether or not an association between a given SNP and disease is real

Question 23

Effect size- association analysis

Answer 23

Measures the strength of variant effect

Question 24

Power- association analysis

Answer 24

Measures the likelihood of finding a real association

Question 25

What are p values used to measure?

Answer 25

Statistical significance

Question 26

P value definition

Answer 26

Probability of observing a given association, if there is no real association (null hypothesis)

Question 27

What p value indicates that an association is statistically significant?

Answer 27

p < 0.05

Question 28

Genome-wide association studies (GWAS)

Answer 28

Testing millions of SNPs across the human genome to discover which genetic variations are associated with a given trait/disease

Question 29

Which populations GWAS tests

Answer 29

Population with given trait/disease | Population without given trait/disease

Question 30

Bonferroni correction: what it does and how it is calculated

Answer 30

Used to decrease number of false positives when testing a large number of samples Calculated by dividing 0.05 by number of tests

Question 31

2 ways to quantify effect size

Answer 31

Odds ratio | Relative risk

Question 32

When is odds ratio used?

Answer 32

Case-control designs

Question 33

When is relative risk used?

Answer 33

Cohorts and general population samples

Question 34

Odds ratio formula

Answer 34

``` a/b divided by c/d a- cases with allele b- controls with allele c- cases without allele d- controls without allele ```

Question 35

Relative risk formula

Answer 35

``` a/(a+b) divided by c/(c+d) a- cases with allele b- controls with allele c- cases without allele d- controls without allele ```

Question 36

Interpretation of odds ratio

Answer 36

Used to determine how likely an individual with the risk allele is to have the specific phenotype Bigger odds ratio: greater likelihood of having disease Odds ratio of 2 means that person who inherits risk allele is twice as likely to develop disease

Question 37

Interpretation of relative risk

Answer 37

Relative risk = 1: no difference in risk between experimental and control group Relative risk <1: event is less likely to occur in experimental group Relative risk >1: event is more likely to occur in experimental group

Question 38

How to calculate absolute risk

Answer 38

Multiply population risk by relative risk

Question 39

What is GWAS useful for finding?

Answer 39

Genetic variations contributing to common complex diseases where many common SNPs are associated with small effect sizes as well as large effect size from more rare SNPs for less common conditions

Question 40

How it is possible to see the effects of all the SNPs that were not directly genotyped in a GWAS

Answer 40

Not all theoretical haplotypes for a given combination of alleles on a chromosome exist- haplotype of a given individual can be inferred

Question 41

Linkage disequilibrium

Answer 41

Non-random association of two or more alleles (in GWAS, marker allele and disease-causing allele)

Question 42

How linkage disequilibrium is measured

Answer 42

Correlation coefficient (r^2 value): value ranges between 0 and 1 0: complete equilibrium (random segregation) of two alleles 1: complete linkage disequilibrium

Question 43

Do larger or smaller sample sizes yield higher power?

Answer 43

Larger sample sizes

Question 44

Do larger or smaller effects yield higher power?

Answer 44

Larger effects

Question 45

Is power higher for SNPs with higher or lower allele frequency?

Answer 45

Higher allele frequency

Question 46

3 outcomes of low powered studies (i.e. small sample size)

Answer 46

True effects can be missed Effect estimates can be less precise (even in the wrong direction) Some "detected" effects can be false positives