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.