Download Quantitative genetics

Quantitative genetics
[email protected]
www.imbm.sk
Basics
• Genotype affects phenotype
• Hardy-Weinberg equilibrium
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• Mendelian genetics is easy
• ...but it works only rarely
• Selection, mutation, drift...
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• Happiness
• Always...do literature search
• Environmental factors
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• Genetic factors???
Issues 
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Who is happy?
Is it binary or continuous?
How to measure it?
How to analyze genetic effects?
How to find the the genetic factors?
Quantitative genetics
• Non-Mendelian inheritance
• Polygenic traits
– Many genes
– Continuous variability
• Categorical, treshold parameters
• Multifactorial traits
– Polygenic
– Environmental factors
Gauss curve
Genetic basis for the Gauss curve
Panmixia vs inbreeding
• Selective vs non-selective mating
• Inbreeding disturbs normal distribution
– Median=mean=modus
– Symmetric histogram
• Decrease of heterozygosity
• Reduced fitness
Heritability
• P = G + E + GxE
• G=A+D+I
• E=C+E
• G - Genetic factors, E - environmental factors, GxE interactions, A - additive effects, D – dominance (alleles
at one locus), E – epistasis (alles at different loci), C common and E - non-shared environment (children in
one family are different)
• EEE...
Heritability
• Variability
• 1 = a2 + d2 + i2 + c2 + e2 + interactions
• Heritability
– h2=genetic variability/phenotypic variability
– narrow
2
VA
h 
VP
• h2 = a 2
– broad
• H 2 = a 2 + d2 + i 2
VG VA  VD  VI
H  
VP
VP
2
Heritability
• Proportion of phenotypic variability attributable
to genetic variability
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Examples
A statistical parameter – population measure
Do not use for individuals
Not a constant (place, time, population)
Not specific
Itself highly affected by environment
Low reproducibility
Heritability
• Does not mean familial occurence
– Genetic factors
– Cultural factors
– Socioeconomic variables
– Chance!!!
• Does not mean unmodifiable
– Diabetes
• Does not mean inherited!
– Down syndrome, autism
Heritability
• Correlations
– cor(P1,P2) = raa2 + rdd2 + rii2 + rcc2
• Interactions
– Passive (born into), active (extroversion), reactive –
evocative (attractive)
– Phenylketonuria
– Effect of age
– Effect of socioeconomical status
• Heritability and selection
– Low heritability – inefficient selection
IQ variability
Bouchard & McGue, 2003
IQ variability
Turkheimer et al, 2003.
Happiness 
Scientific approaches
• Twin studies
• Adoption studies
• Linkage analysis
• Case-control studies
– Candidate gene approach
– Genome-wide association studies
Twin studies
• Twins
– Monozygotic MZ (100% genetic relatedness)
– Dizygotic DZ (50% genetic relatedness)
– Concordance of traits
– rMZ > rDZ
– rMZ = rDZ
– rMZ < 1
Twin studies
• Heritability
– rmz = A + C
– rdz = ½A + C
– A = 2 (rmz – rdz)
– C = rmz – A = 2 rdz – rmz
– E = 1 – rmz
Twin studies
Twin studies
Twin studies
– Environmental relatedness?
• Monochorionic (2/3 MZ), dichorionic (1/3 MZ, all DZ)
Twin studies
Adoption studies
• Genes vs environment
• Biological parents vs adoptive parents
• Cave:
– prenatal development
– selective placement
– questionable representativness
QTL
• Quantitive trait locus/loci
• Search for specific genetic factors
• Locations at chromosomes, not genes
• SNP or CNV marker in linkage
McCarthy et al, 2008
GWAS
• Cases and controls – binarization
• Frequent genotypes with small effects
• Large numbers
– Study power – sample size
• Bias – false positive results – why?
• Quality control (samples and SNP calling)
• Replication
• Validation
GWAS results presentation
• Quantile – quantile plots
• Manhattan plots
Happiness 
• Twin and adoption studies
– Estimates of heritability
• Linkage analysis and GWAS
– Search for genetic factors
• Experiments
– Mechanism of action
– Interpretation of animal experiments
– Ethics
Test
Psychometry 
• Well being questionnaire
• http://www.who-5.org/
• Valid? Precise? Specific? Sensitive?
• Reproducible?
Statistics
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Tests
Correlation
Regression
Confidence intervals