human genetics multifactorial traits. genes and the environment
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Human Genetics
Multifactorial Traits
Genes and the Environment
Genes and the environment interact to mold many of our traits.
Mendelian trait due to a single gene
Polygenic trait due to multiple genes
Multifactorial trait results from action of genes and the environment
Discontinuous Variation
Phenotypes fall into two or more distinct non-overlapping classes Example - short and tall phenotypes in
pea plants no in betweens
Continuous Variation
Phenotypes distribute from one extreme to another in an overlapping (continuous) fashion.
Examples - height, skin color, eye color, intelligence
Height is Continuous
Except when it is Discontinuous
Seven heights produced through the interaction of 3 genes
Polygenic Traits
Polygenic Traits are produced by the action of multiple genes.
Variation is continuous, not discrete Effect of genes is additive or synergistic Also called quantitative trait loci (QTL) Genes can have major or minor
impacts
QTL takes time and lots of chromosomal Markers.
Nature Genetics 31, 235 - 236 (2002) doi:10.1038/ng0702-235
QTL is the First Step
Diseases can be Polygenic
Congenital malformations
Cleft palate Congenital dislocation of
the hip Congenital heart defects Neural tube defects
(spina bifida etc.) Pyloric stenosis Club Foot (Talipes)
Adult onset diseases Osteoporosis Diabetes Mellitus Cancer Epilepsy Glaucoma Hypertension Ischaemic heart disease Manic depression Schizophrenia
Osteoporosis
Osteoporosis is defined as low bone mineral density (BMD) and associated fractures.
Osteoporosis causes morbidity and mortality in the elderly.
It has a significant genetic components that are largely unknown.
In Iceland, a linkage analysis in a large number of extended osteoporosis families in Iceland, (using a phenotype that combines osteoporotic fractures and BMD measurements) showed linkage to Chromosome 20p12.3.
QTL on Chromosome 20 for Osteoporosis
Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, et al. (2003) Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol 1(3): e69
Other QTLs for Osteoporosis in Humans
Osteoporosis QTL Gene Identification
Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients.
Eye color: A polygenic trait?
Five eye colors can be produced by the interaction of just two genes.
Number of dominant alleles at two genes produces five phenotypes
Polygenic Inheritance
Each allele for all the genes involved contributes to the expression of the trait
Not necessarily the same for each geneSome alleles will make no contributionExpressed trait is the sum of all the small
contributions.
Polygenic Inheritance Challenge
Phenotypic expression can vary over a wide range
Traits are often quantified by measurement rather than by counting. Height- relatively easy Eye Color- need instrumentation Skin Color- Environmental component like
tanning- use unexposed skin Needs to analyzed populations rather
than individuals.
Multifactorial Traits
Traits produced through gene-gene interactions and gene interactions with environment factors.
What are “environmental factors”?
Non-genetic factors physical – pregnancy, obesity, diet chemical - diet, smoking, alcohol , medicine
social - illness, stress Age
How much of a given phenotype is genetic (inherited) and how much is environment?
Multifactorial Traits
- are influenced by genes and by the environment
Many genes +
Trait environment
fingerprints prenatal touch
height nutrition
skin color sun exposure
Fingerprints -Multifactorial Traits
Height is influenced by genes and environment during growth
1997Maximum 6’5”
Improved nutrition can impact height.
Empiric Risk
Based on incidence in a specific population.
Empiric Risk is a StatisticIncidence is the rate a trait occurs- like
number of new diagnosesPrevalence is how common the trait is in
the population a a particular time.If a trait is inherited, the closer the
relationship, the greater the risk.
Empiric Risk
Empiric risk for an individual increases with severity of the disorder number of affected family members relatedness of the individual to the affected
individual
We have to use the frequency of occurrence of the trait in a specific population to predict its reoccurrence.
Genes are shared “on the average”
Degree of Relationship
% of Genes in Common
Example
First Degree 50% Parent, Child
Siblings
Second Degree 25% Aunts, Uncles Niece Nephew Grandparents
Third Degree 12.5% First Cousins
Empiric Risk of Cleft Lip
Relationship
Identical Twin Sibling Child Niece/Nephew First Cousin General Population (no
affected relatives)
Empiric Risk
40% 4.1% 3.5% 0.8% 0.3% 0.1%
Heritability: H
Portion of the phenotypic differences due to genetic inheritance at any particular point in time.
Highly related trait, in a large group of siblings, 50% will share the trait.
Heritability =1 when a trait is completely genetic
Heritability= 0 (0%) when a trait is completely envoronmental
Multifactorial Polygenic Trait
Genetic VariationEnvironmental
Variation
Additive Effects ofRecessive Alleles(small)
Dominant Alleles (few)
Epistasis
Check out Reading 7.1 in the Text
Each direct degree of relationship shares 50% of genes (1/2)
You and first cousin once removed You to mom 1/2 Your mom to her mom (grandmother) 1/2 Your grandmother to her brother 1/2 Your great uncle to his daughter (your first cousin)
1/2
½ X ½ X ½ X ½ = 1/16
How do we advised people on relative risks with poorly understood
inheritance patterns? We need to understand the components of
phenotypic variation
genetic variance number of different genotypes within the
population
environmental variance number of different environments in which all
the genotypes have been expressed
Calculating Heritabilty
Useful to study
- Relatives in pedigrees
- Adopted children
- Twins
- Twins raised apart
Heritability CalculationEstimated from the proportion of people sharing a trait
compared to the proportion predicted to share the trait.
Concordance - % of pairs of individuals that share the trait (both affected or both unaffected)
Language skills (measured by vocabulary at age 2)
Relation %concordance % expected MZ twins 0.81 1.00 DZ twins 0.42 0.5
How do we isolate environmental and genetic components to
determine heritability?
Adopted individuals- Share environment, but not genes
Dizygotic twins- Share environment and 50% of genes
Monozygotic twins- Identical genotype, shared
environment- Twins raised apart
- Share genotype, but not environment
Correlations between relatives for total ridge count (TRC).
Heritability of Human TraitsTrait Heritability
Clubfoot 0.8
Height 0.8
Blood Pressure 0.6
Body Mass Index 0.5
Verbal Aptitude 0.7
Mathematical Aptitude 0.3
Spelling Aptitude 0.5
Total fingerprint Ridge Count 0.9
Intelligence 0.5-0.8
Total Serum Cholesterol 0.6
Adoption Studies
Danish Adoption Register 1924-1947One study looked at causes of death
If a biological parent died of infection before age 50, then the Adoptive child was 5 times more likely to die of infection at a young age relative to the general population.
Suggests a strong genetic component
Adoption Studies
Danish Adoption Register 1924-1947Regarding cardiovascular disease
Adoptive parents who died of cardiovascular disease before age 50, their adoptive children were 3 times more likely to die of cardiovascular disease than a person in the general population.
suggests a strong environmental component
Twin Studies
Powerful genetic toolIdentical twins (experiment)
Genotype is identical Same environment at the same age
Fraternal twins (controls) Different Genotypes (50%) Same environment at the same age
Bottom line: concordance values A trait observed to be present more often in both members of a MZ twin pair than in both members of a DZ twin pair is presumed to have a significant inherited component.
What do we measure in twin studies?
Concordance
- the expression of a trait in both twins
- measured as a percentage of pairs in which both twins express the trait.
- if both twins don’t share the trait - discordant
Concordance values in monozygotic (MZ) and dizygotic (DZ) twins.
SNP (single nucleotide polymorphism)
On average between two random individuals, there is one SNP every 1000 bases => 3 million differences!
Nucleotide site with more than one allele is a polymorphism.