Transcript Human Genetics

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 gene
Some alleles will make no contribution
Expressed 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
1997
Maximum 6’5”
Improved nutrition can impact height.
Empiric Risk
Based on incidence in a specific
population.
Empiric Risk is a Statistic
Incidence is the rate a trait occurs- like
number of new diagnoses
Prevalence 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%
Third Degree
12.5%
Aunts, Uncles
Niece Nephew
Grandparents
First Cousins
Empiric Risk of Cleft Lip
 Relationship
 Empiric Risk
 Identical Twin
 Sibling
 Child
 Niece/Nephew
 First Cousin
 General Population (no
affected relatives)
 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
Environmental
Variation
Genetic Variation
Additive Effects of
Recessive 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
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You to mom
Your mom to her mom (grandmother)
Your grandmother to her brother
Your great uncle to his daughter (your first cousin)
 ½ X ½ X ½ X ½ = 1/16
1/2
1/2
1/2
1/2
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 Calculation
Estimated 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 trai
(both affected or both unaffected)
Language skills (measured by vocabulary at age 2)
Relation
MZ twins
DZ twins
%concordance
0.81
0.42
% expected
1.00
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 Traits
Trait
Clubfoot
Height
Blood Pressure
Body Mass Index
Verbal Aptitude
Mathematical Aptitude
Spelling Aptitude
Total fingerprint Ridge Count
Intelligence
Total Serum Cholesterol
Heritability
0.8
0.8
0.6
0.5
0.7
0.3
0.5
0.9
0.5-0.8
0.6
Adoption Studies
Danish Adoption Register 1924-1947
One 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 1924-1947
Regarding 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 tool
Identical twins (experiment)
 Genotype is identical
 Same environment at the same age
 Fraternal twins (controls)
 Different Genotypes (50%)
 Same environment at the same age
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
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.
Concordance values in monozygotic
(MZ) and dizygotic (DZ) twins.
SNP (single nucleotide polymorphism)
Nucleotide site with more than one allele is a
polymorphism.
On average between two random individuals, there
is one SNP every 1000 bases => 3 million
differences!