Lecture 50. Genome-Wide Association Mapping Flashcards
How do you find the causal gene of a genetic disorder?
- Define fine map interval: define locus with
flanking molecular markers to a region of <50 candidate genes - Identify candidate genes within the interval that are allelic (differing in mutations) between diseased and unaffected individuals
- Loss-of-function: mutational ‘knock-out’ analysis of genes within locus of an experimental organism
- Gain-of-function: genetic transformation of knock-out mutant with functional allele
What does likelihood that two loci are linked mean in terms of mapping?
Likelihood that a disease-related locus (D) is linked to
the locus of a molecular (SSR) marker
What does likelihood that two loci are unlinked mean in terms of mapping?
Likelihood that a disease-related locus (D) is not linked
the locus of a molecular (SSR) marker
What are the steps in calculating an LOD score for linkage to SSR2?
- Calculate the probability that the D locus is
not linked to SSR2 - Calculate the probability that the D locus is
linked to SSR2 - Plot LOD score using values of θ from 0 to 0.5
How do you calculate the probability that the D locus is not linked to SSR2 if the chance of getting parental alleles at both loci and recombined alleles at both loci = 0.5 and there a 6 observed non-recombinants and 1 recombinant?
(0.5)⁶ x (0.5)¹
How do you calculate the probability that the D locus is linked to SSR2 if 6 non-recombinants and 1 recombinant were observed?
If θ = recombination frequency from 0-0.5
1 - θ = chance of parental alleles at both loci
θ = chance of recombinant alleles at both loci
(1 - θ)⁶ x (θ)¹
How do you calculate the LOD score? (If 6 non-recombinants and 1 recombinant were observed)
LOD score = Log10( (1- θ)⁶ x (θ)¹ / (0.5)⁶ x (0.5)¹)
What is Zmax?
Highest LOD score
When is linkage shown?
When Zmax > 3
Why map human disease-related genes?
First step towards identifying the casual protein (and then more experiments)
Determining the nature of normal and abnormal
biochemical function involving the causal protein
What applications can be developed after identifying casual protein?
Diagnostic tests designed to detect the causal
mutations in clinical samples
Target specific drugs (e.g to inhibit an over-active protein)
Gene therapy (novel curative method to introduce a functional protein into a diseased individual)
What are the two ingredients for association mapping?
High resolution of genetic variation located on a physical map of a reference genome
Large set of phenotypic data
What are SNPs?
Single Nucleotide Polymorphisms
Molecular markers based on single base-pair substitutions
How do SNPs arise?
Mutagenesis or errors in replication
What is the mutation rate per locus per generation?
1x10⁻⁹
