EHJ352H1 Lecture Notes - Balancing Selection, Hypotension, Missense Mutation

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Published on 26 Jan 2013
Lecture 21:
The genetic basis of phenotypic variation: the scale of the problem:
Human genome: 3.2 billion
Any 2 individuals are on average 99.9% identical (3.2 million differences)
The differences account for heritable phenotypic variation including disease
susceptibility variation
30, 000+ genes
Estimated 11 million common (>1%) SNPs plus many many rare variants
Which SNP affects which disease?
Variation of Phenotype = Variation (Genetic factors) + Variation (Environmental factors)
If variation in the phenotype is at least partly due to genetic variation, then there is
heritability for that trait
Heritability: the genetically determined proportion of trait variation in the population, the
percentage of variation in a trait that is due to genetic factors
The presence of heritability for the trait is a prerequisite for identifying genetic variants
underlying trait variation
Mendelian disease:
rare disorders
one single gene influences the phenotype very little environmental factors
Discrete phenotypes caused by alleles segregating at a single genetic locus
Highly heritable allelic variation at the single locus is sufficient to cause disease
Phenotype is an accurate predictor of genotype
Polygenic disease: common disorders
Variation in phenotype in the population is caused by alleles segregating at multiple
genetic loci
The more loci affecting the trait, the greater the number of possible multi-locus
genotypes. Different combinations of loci affect the same phenotype
E.g. for n loci with 2 alleles at each locus, there are 3 possible genotypes at each locus thus
3^n possible multi-locus genotypes
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Polygenic traits: the effects at different loci add together to result in the phenotype, the more
loci affecting the trait the more genotypes there are with the same phenotype
More and more number of alleles = more possible genotypes = more possible quantitative risk,
100 genes affecting heart disease = a lot of risk strategies
Mapping and Identifying disease-causing variation:
Family history is a strong risk factor for nearly all diseases, suggesting that inherited
genetic variation matters (i.e. there is a non-zero heritability) for genesis of disease
The goal of genetic mapping is to establish that variation at a genomic locus is correlated
with the trait phenotype
The hope is that identification of the genes and alleles will 1) predict disease susceptibility
(do you have the disease allele) and 2) lead to treatment options through a better
understanding of the disease biology (molecular pathways that lead to the disease)
Disease Mapping Methods:
1. Linkage mapping: marker trait correlation assessed in pedigrees/families, Mendelian
2. Genome wide association mapping: marker trait correlation assessed in the population.
What markers are correlated with disease risks?
Linkage approaches are successful for Mendelian traits, despite the limited recombination
events in the pedigree
Linkage-mapping and polygenic traits have mixed results
No clear genotype-phenotype relationship.
The genetic basis of the phenotype is heterogenous and our ability to look at large
amounts of progeny is low: A bunch of alleles that are increasing and decreasing risk of
heart disease. Linkage studies typically find large genomic regions that significantly affect
the trait, but the results are usually not replicated.
Different genomic regions are mapped in different samples of pedigrees
Correlation between genetic variant and trait on a population level
E.g. human height. Are the individuals with g allele taller than individuals with t allele?
Kind of like a t-test. The blue dots indicate regions with a significant effect
Problems: (3)
False negative: many biological associations do not reach stringent significance threshold
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