Genetic Analysis of Complex Traits Flashcards
genetically complex trait
any phenotypic trait that exhibits evidence for familial aggregation and genetic involvement but is not inherited in an easily determined manner
diseases with genetic components
cancer
diabetes mellitus
polycystic ovary syndrome
atherosclerosis
cardiovascular disease
autoimmune disease
neurological disease
psychiatric disease
asthma
Hardy Weinberg Equilibrium
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
Hardy-Weinberg Equilibrium Conditions
population is infinitely large
random mating (no population stratification, assortative mating, consanguinity or inbreeding)
no mutation, migration, and random drift
Why does selection not remove deleterious mutations from the gene pool?
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
linkage analysis
looking within a pedigree to see who is inheriting a disease and marker together, look for cosegregation
parametric analysis
LOD scores, assume explicit mode of inheritance, Mendelian traits
nonparametric analysis
affected sib pairs - no assumption about mode of inheritance, complex traits
assortment of two alleles on the same chromosome
unlinked, completely linked, and partially linked
genetic map
map of the relative locations of loci along a chromosome based on recombination frequencies, distance measured in centiMorgans
map distance
number of units or centiMorgans between two loci
map function
mathematical expression that describes the relationship between observed percent recombination and centiMorgans
map unit
a measure of distance between two genetically linked loci, usually 1% recombination correpsonds to one map unit
physical map
ordered set of genomic DNA clones demarcated with restriction endonuclease recognition or sequence tagged sites, the distance between sites is measured in base pairs
LOD score
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)]
LOD scores for linkage
linkage is assumed when the LOD score exceeds 3.6, and it can excluded when the score is less than -2.0
recombination fraction
number of recombinant meiotic produces divided by the total number of meiotic products
affected sip pair test
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
association study
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
haplotype
a unique combination of genetic markers present on a chromosome
linkage equilibrium
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)
linkage disequilibrium
a measure of the association of alleles on a chromosome, two loci are in linkage disequilibrium when their alleles are not randomly associated
HapMap project
characterize common genetic variation across the genome in three major world populations
1 variant across every 5kb across the genome - phase I
haplotypes between YRI, CEU, and CHB+JPT
most of the haplotypes are very similar, but the YRI group is a little older and therefore have slightly varying haplotypes
proxy SNPs
20% of SNPs have >20 perfect proxies
60% have >5 perfect proxies
20% have no perfect proxies
varies by population
htSNPs
haplotype tagged SNPs
a subset of SNPs which account for the majority of genetic variation in a given genomic fragment
genome-wide association studies (GWAs)
260,000-474,000 SNPs capture all common SNPs in Phase I data set in caucasions
