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 Adult onset diseases
malformations Osteoporosis
Cleft palate Diabetes Mellitus
Congenital dislocation of Cancer
the hip Epilepsy
Congenital heart defects Glaucoma
Neural tube defects Hypertension
(spina bifida etc.)
Ischaemic heart disease
Pyloric stenosis
Manic depression
Club Foot (Talipes)
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 % of Genes in Example
Relationship Common
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 Empiric Risk
Identical Twin 40%
Sibling 4.1%
Child 3.5%
Niece/Nephew 0.8%
First Cousin 0.3%
General Population (no 0.1%
affected relatives)
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
Genetic Variation
Variation
Additive Effects of Dominant Alleles Epistasis
Recessive Alleles (few)
(small)
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 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 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 Traits
Trait 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 1924-1947
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!