1. Multifactorial Traits
Human Genetics
Multifactorial Traits 1

2. Genes and the Environment2

3. 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

4. Discontinuous Variation
Phenotypes fall into two or more distinct non-overlapping classes
Example - short and tall phenotypes in pea plants
no in betweens

5. Continuous Variation
Phenotypes distribute from one extreme to another in an overlapping (continuous) fashion.
Examples - height, skin color, eye color, intelligence

7. Height is Continuous
Why do we need to understand how genes form continuous traits?
1) The genes underlying continuous traits are following Mendelian principles of segregation and independent assortment.
2) Many human traits and genetic disorders show continuous variation.
Mechanism:
- traits are being determined by more than one gene. - it is the sum of the genes that produces the trait.

8. Except when it is Discontinuous

9. As the number of loci involved in a trait increase, the number of resulting phenotype classes increase.
Look at 3 loci use height as a model trait
- assume we have only 3 loci each with only 2 alleles
A,a, B,b and C,c
- each dominant trait makes an equal contribution to phenotype
- each recessive trait contribute nothing
- effect of each dominant trait is small, but additive
- genes are not linked – (they sort independently)
assume a base height of 5 ft
- each dominant allele adds 3 inches to the base height

10. Seven heights produced through the interaction of 3 genes

13. 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

14. QTL takes time and lots of chromosomal Markers.
Nature Genetics  31, (2002) doi: /ng

15. QTL is the First Step

16. 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

17. 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.

18. 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
Example of a Scan for Quantitative Trait Loci (QTL) on a single chromosome; this study was performed on patients with osteoporosis; 1,100 microsatellite markers were used for a Genome-wide Scan, and the main finding was a major QTL on chromosome 20 which is shown here with the detailed QTL data; see also this image for the complete results of all chromosomes Source 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

19. Other QTLs for Osteoporosis in Humans
Example of a Genome-wide Scan for Quantitative Trait Loci (QTL); this study was performed on patients with osteoporosis; 1,100 microsatellite markers were used, and the main finding is a major QTL on chromosome 20; see also this image for a more detailed map of chromosome 20SourceStyrkarsdottir 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

20. 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.

21. Eye color: A polygenic trait?
Five eye colors can be produced by the interaction of just two genes.

22. Number of dominant alleles at two genes produces five phenotypes

24. 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.

25. 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.

26. 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?

27. Multifactorial Traits
- are influenced by genes and by the environment
Many genes +
Trait environment
fingerprints prenatal touch
height nutrition
skin color sun exposure

28. Fingerprints -Multifactorial Traits

29. Height is influenced by genes and environment during growth
1997
Maximum 6’5”
Improved nutrition can impact height.

31. 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.

32. 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.

33. 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

34. 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%

35. 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

36. Multifactorial Polygenic Trait Environmental Genetic Variation
Additive Effects of
Recessive Alleles
(small)
Dominant Alleles
(few)
Epistasis

37. 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 /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

38. 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

39. Calculating Heritabilty
Useful to study
- Relatives in pedigrees
- Adopted children
- Twins
- Twins raised apart

40. 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
DZ twins

41. 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

42. Correlations between relatives for total ridge count (TRC).

43. Heritability of Human Traits
Clubfoot
0.8
Height
Blood Pressure
0.6
Body Mass Index
0.5
Verbal Aptitude
0.7
Mathematical Aptitude
0.3
Spelling Aptitude
Total fingerprint Ridge Count
0.9
Intelligence
Total Serum Cholesterol

45. 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

46. 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

48. Twin Studies Powerful genetic tool Identical twins (experiment)
Genotype is identical
Same environment at the same age
Fraternal twins (controls)
Different Genotypes (50%)

49. Bottom line: concordance values
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.

50. Concordance values in monozygotic (MZ) and dizygotic (DZ) twins.

52. 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!