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L30 - Disease Mapping
Molecular Markers
Relies upon Single Nucleotide…
L30 - Disease Mapping
Molecular Markers
Relies upon Single Nucleotide Polymorphism (SNPs)
Variation of single base pair on genome
Mapping Using SNP Haplotypes
While individual markers may be used t map genes based on RF and Linkage, multiple markers may be used to determine haplotypes
Haplotype =
Segment of DNA, within which a specific combination of alleles are inherited together
Proximity of markers/alleles means that their sequences is not disrupted very frequently during recombination - inherited together
Haplotypes do not assort independently?
If one allele within the haplotype is in LD, then all alleles are in LD
Haplotypes
Mark recognizable chromosomal segments that can be tracked through pedigrees when not broken up by recombination
Haplotype Mapping
A diseased allele within a Haplotype s more easily tracked because it's attendant allele are inherited with it.
=> Whole chromosomal segment (haplo) is more easily identifiable than single allele
Haplotypes
- A haplotype is a chromosomal region defined by a specific array of marker alleles it carries
- Can be of any size, often between 10 and 50kb
- Inherited as blocks => break up due to recombination
Haplotype Block
Analysis of DNA suggests that some regions f DNA are composed of defined blocks with limited haplotype diversity
A Haplotype may be composed of 84kbp, amongst which only 8 SNPs exist.
2^8 = 256 Haplotypes are possible
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Genome Wide Association Studies
Sharing of Ancestral Chromosome Segments
AS=LD
Relies on basic premise that if a disease is common, than the variance causing that disease will also be common, vicer vercer
Limitaions of GWAS and issues of Missing Heritability
Relies on the premise that Common disease has common vairant, which is not as certain as we had originally thought
Many Variants = Increase Risk of Disease
Different combinations of variants, at multiple loci, actually aggregate in specific individuals to increase disease risk
Common variants are expected to be of ancient origin.
Instead of being causative, they are merely susceptibility factors and so individually, they generally have weakly deleterious effects *
Indeed, despite initial hopes, common disease variants identified by GWAS have very weak effects.
Even cumulative contributions of variants are small
GWAS data has Missing Heritability
Explains only a small proportion of variance causing complex diseases
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The more distant a common ancestor, the smaller each shared segment will, but number people sharing will be greater
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History
GWAS became increasingly common in 2000's, due to advances in technology
- Hap Map + 1000 genomes project
- Microarray technology => automated genotyping of SNPs
Process;
Case-control studies panels of affected individuals and matched controls are genotyped at hundreds of thousands of common SNPs
Analyse Whole Genome Chips
Certain snps will be more common in cases than in the non-cases. Those snps which are common amongst the cases may thereby be thought to be associated with the disease, especially if they are found more frequently in diseased dividuals than in non-ddiseased individuals*
Molecular Markers;
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Whole Genome Linkage Study
Whole Genome Linkage study : 6,000 Illumina SNPs and Affymetrix 10,000 SNPs
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Re-assessing our Approach
If variants themselves are rare yet the phenotype of disease which they cause is common, how do we reconcile these two somewhat contradictory findings?
Rare variants may be influencing the same biological pathways, in different ways, yet the end result is the same
E.g. Alzheimer's Disease
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