Genetic Analysis of Complex Traits

Question 1

genetically complex trait

Answer 1

any phenotypic trait that exhibits evidence for familial aggregation and genetic involvement but is not inherited in an easily determined manner

Question 2

diseases with genetic components

Answer 2

cancer

diabetes mellitus

polycystic ovary syndrome

atherosclerosis

cardiovascular disease

autoimmune disease

neurological disease

psychiatric disease

asthma

Question 3

Hardy Weinberg Equilibrium

Answer 3

describes the relationship between gene freqeuencies and genotype frequencies in random mating populations

A = p and a = q = (1-p)

1 = p^2 + 2pq + q^2

Question 4

Hardy-Weinberg Equilibrium Conditions

Answer 4

population is infinitely large

random mating (no population stratification, assortative mating, consanguinity or inbreeding)

no mutation, migration, and random drift

Question 5

Why does selection not remove deleterious mutations from the gene pool?

Answer 5

vast majority of the deleterious mutations are in the unaffected heterozygote

heterozygote selective advantage

new mutations introduced

lethal autosomal dominant traits have a high rate of de novo mutations

Question 6

linkage analysis

Answer 6

looking within a pedigree to see who is inheriting a disease and marker together, look for cosegregation

Question 7

parametric analysis

Answer 7

LOD scores, assume explicit mode of inheritance, Mendelian traits

Question 8

nonparametric analysis

Answer 8

affected sib pairs - no assumption about mode of inheritance, complex traits

Question 9

assortment of two alleles on the same chromosome

Answer 9

unlinked, completely linked, and partially linked

Question 10

genetic map

Answer 10

map of the relative locations of loci along a chromosome based on recombination frequencies, distance measured in centiMorgans

Question 11

map distance

Answer 11

number of units or centiMorgans between two loci

Question 12

map function

Answer 12

mathematical expression that describes the relationship between observed percent recombination and centiMorgans

Question 13

map unit

Answer 13

a measure of distance between two genetically linked loci, usually 1% recombination correpsonds to one map unit

Question 14

physical map

Answer 14

ordered set of genomic DNA clones demarcated with restriction endonuclease recognition or sequence tagged sites, the distance between sites is measured in base pairs

Question 15

LOD score

Answer 15

also known as Z score - logarithm of the ratio of the likelihood of linkage (H1) versus the likelihood of no linkage (H0)

LOD = Log10[L(H1)/L(H0)]

Question 16

LOD scores for linkage

Answer 16

linkage is assumed when the LOD score exceeds 3.6, and it can excluded when the score is less than -2.0

Question 17

recombination fraction

Answer 17

number of recombinant meiotic produces divided by the total number of meiotic products

Question 18

affected sip pair test

Answer 18

test for linkage by counting transmissions from heterozygous parents taht are shared by affected children

excess sharing of >50% indicates linkage, test significane by chi-squared

Question 19

association study

Answer 19

study based on the comparison of the frequency of a specific allele or haplotype in affected and unaffected individuals in a population

identify polymorphisms that may be linked with a specific disease trait

Question 20

haplotype

Answer 20

a unique combination of genetic markers present on a chromosome

Question 21

linkage equilibrium

Answer 21

when the frequency of each allele within a haplotype is the same as the frequency of that allele in the population as a whole (random assortment)

Question 22

linkage disequilibrium

Answer 22

a measure of the association of alleles on a chromosome, two loci are in linkage disequilibrium when their alleles are not randomly associated

Question 23

HapMap project

Answer 23

characterize common genetic variation across the genome in three major world populations

1 variant across every 5kb across the genome - phase I

Question 24

haplotypes between YRI, CEU, and CHB+JPT

Answer 24

most of the haplotypes are very similar, but the YRI group is a little older and therefore have slightly varying haplotypes

Question 25

proxy SNPs

Answer 25

20% of SNPs have >20 perfect proxies

60% have >5 perfect proxies

20% have no perfect proxies

varies by population

Question 26

htSNPs

Answer 26

haplotype tagged SNPs

a subset of SNPs which account for the majority of genetic variation in a given genomic fragment

Question 27

genome-wide association studies (GWAs)

Answer 27

260,000-474,000 SNPs capture all common SNPs in Phase I data set in caucasions