Linkage mapping- determining the distance between & order of genes
Genetic maps are measured in bp, physical maps in cM
Linkage _ reflects gene proximity
Genes on different chromosomes link dependently
What are the two definitions of haplotype?
A set of genes on the same chromosome
The genes contained in two homologous chromosomes
A set of genetic determinants
What does this symbolise?
The recombination frequency
The location of the SNP marker
The first infected generation
Name two resons why large families are required for linkage studies in humans (for an accurate result)
Human families are small
Humans cannot be bred just to investigate phenotypes
Human genes are highly conserved
Human gene markers are rare
If 15% of meioses in a study show crossover, what is the recombination frequency?
Loci with a recombination factor of 50% have the same chance of being separated as loci on different chromosomes
Name the two steps required for functional mapping
Find what haplotype those with the mutations share
Find what markers those with the mutations share
Look for markers close to it
Look for genes close to it
What is the 'Critical Region'
There area containing the mutated gene
The area containing the related marker
A, B, C & D are all markers. B and C are found in homozygous form in people with autosomal recessive deafness. Where is the critical regions for genes causing this deafness?
Between B & C
Between A & D
Between B & D
Between A & C
Assuming a person is heterozygous, what do we need to know once markers for the alleles have been identified?
Which marker is segregated with which allele i.e A1D A2d, or A1d A2D
Which allele is diseased i.e. D or d
Which marker has bonded correctly
What is the difference between phase known and phase unknown?
In phase known, we know which allele contains the diease
In phase known, we have the genotype of the grandparents
In phase known, we don't know how many recombinants there are
Fewer recombinants mean the hypothesis is more likely
Assume 12% of people are recombinants - how many cM are the genes?
Name 3 things that can affect the recombination process
Crossovers are common near centromeres
Crossovers are rarer near centromeres
Oocytes crossover more frequently than sperm
Sperm crossover more frequently than oocytes
LOD - Log of the Odds Ratio
When using LOD, what are the two hypothesis?
There is a given (previously calculated) linkage frequency
There is null (50% or more) linkage frequency
Assuming 6 recombinants out of 10 children what is the equation for the statistical likelihood of 6 recombinents?
[(1-θ)^6] x θ
[(1+θ)/6] x θ
[6 x θ] x θ
The equation for NO linkage = [(1-θ)^no of children in study]
A = Liklihood of linkage
B = Liklihood of no linkage
What is the LOD full equation?
Log10 (A x B)
-2 is considered significant, 3 is considered no linkage
It is thought that 4 of 13 children are recombinants- calculate the LOD and see if this is significant
LOD scores are not additive
Linkage analysis in complex disorders is much more difficult
The first step of mapping complex disease genes is demonstrating how important the genes are on heritability
How do you gain estimates of heritability in complex disorders?
Look at mono/dizygotic twins
Look at siblings
Look at familial generations
Why is linkage analysis so much more difficult with complex disorders?
We don't know penetrance
We don't know how many genes are involved
We don't know the relative effect of each gene
Non-parametric linkage analysis typically uses what?
Affected sibling pairs
What is true of NPL?
No assumptions of no of loci/environmental role
Not concerned about penetrence
Assumed diseased individuals have alleles in common
This image shows two siblings that are...?
Identical by state
Identical by descent
The two siblings possess alleles that are...
What is used in Non-Parametric Linkage Analysis to indicate linkage?
Deviation from normal ratios of sibling inheritence
Deviation for normal ratio's of phenotype expression
Deviation from normal allelic ratios
Chron's disease occurs in 1-3/10,000 people