1. The Inheritance of Complex Traits
Chapter 5

2. 5.1 All The King’s Men
1713 – new King of Prussia began largest military buildup
King Frederick William I, enlarged his army from 38,000 men to around 100,000 in 20 years.
Potsdam Grenadier Guards – his personal troops
Composed of the tallest men he could find
He was obsessed with having giants in his guard – his recruiters used bribery, kidnapping, and smuggling to fill the ranks
Minimum height requirement was 5 feet 11 inches but some soldiers close to 7 feet (average height at the time 5 feet 4 inches)
To save money he ordered tall men to breed with tall women
Most children born were actually shorter than their parents
King reverted back to kidnapping and bounties

3. Differences Among Siblings
Is due to both Genetic and Environmental Factors

4. VIDEO: Designer Babies

5. 5.2 Traits Controlled by Two or More Genes
Many phenotypes are influenced by many gene pairs as well as the environment
Height is a complex trait determined by several gene pairs and environmental interactions.
Phenotypes can be discontinuous or continuous

6. 5.2 Traits Controlled by Two or More Genes (contd.)
Discontinuous variation
Phenotypes that fall into two or more distinct, nonoverlapping classes
Mendel’s tall and short pea plant phenotypes
If Mendel had chosen to study height in tobacco plants, he would have encountered continuous variation
Continuous variation
Phenotypic characters that are distributed from one extreme to another in an overlapping fashion
Human height

7. Comparison of Discontinuous and Continuous Phenotypes
100 50
% of individuals
Dwarf
Tall
P1 parental generation
100
% of individuals 50
Dwarf
Tall
F1 generation
(a) Pea plants
100 50
% of individuals
Dwarf
Tall
F2 generation

8. Comparison of Discontinuous and Continuous Phenotypes
100 50
% of individuals
Dwarf
Tall
P1 parental generation
100
% of individuals 50
Intermediate
F1 generation
(b) Tobacco plants
100
% of individuals 50
Dwarf
Intermediate
Tall
F2 generation

9. Example of a Continuous phentoype

10. Genetics – Fall 2014

11. What are Complex Traits?
These are determined by the cumulative effects of genes and the influence of environment
Polygenic traits
Traits controlled by two or more genes
Patterns of inheritance that can be measured quantitatively
Multifactorial traits
Polygenic traits resulting from interactions of two or more genes and one or more environmental factors
Underlies many human traits and diseases – environmental components can be hard to identify and measure

12. 5.3 Polygenic Traits
Assessing interactions of genes, environment, and phenotype can be difficult
In some cases, only a specific gene and a specific environmental factor causes an effect
Polygenic: when several genes (each makes a small contribution) control a phenotype the result is continuous phenotypic variation

13. Polygenic Inheritance
Traits are usually quantified by measurement rather than counting
Two or more genes contribute to the phenotype
Phenotypic expression varies across a wide range
Best expressed in populations rather than individuals
Interactions with the environment often participate in creating the phenotype
Traits such as height, weight, skin color, eye color, and intelligence are under polygenic control
Congenital malformations such as neural tube defects, cleft palate, and clubfoot, as well as genetic disorders, such as diabetes, hypertension and behavioral diseases are polygenic and/or multifactorial.

14. Polygenic Inheritance
The distribution of polygenic traits through the population follows a bell-shaped (normal) curve 18 16 14 12 10
Percentage of men 08 06 04 02 50 55 60 65 70 75 80 85
Phenotype (height in inches)

15. A Multifactorial Polygenic Trait: Skin Color
Skin color is controlled by 3 or 4 genes and environmental factors leading to a wide range of phenotypes
Exposure to the sun can alter skin color and obscure genotypic differences.

16. The Additive Model of Polygenic Inheritance
As the number of genes involved increase, the number of phenotypic classes increases
Example (controlled by these conditions):
The traits is controlled by 3 genes, each has 2 alleles (A,a,B,b,C,c)
Each dominant allele makes an equal contribution to the phenotype and recessive alleles make no contribution.
Effect of each active (dominant) allele is small and additive
Genes controlling height are not linked – sort independently
Environment acts equally on all genotypes

17. The Additive Model of Polygenic Inheritance
Example – King Frederick William’s army
Assume all women were at least 5’9”
All dominant alleles A,B,C add 3 inches above base height of 5’9” and recessive alleles add no base height
aabbcc individual = 5’9”; AABBCC individual = 7’3”
Suppose 6’9” (AaBbCc) member of the guard mates with a 6’3” woman (AaBbcc).
Results in diagram
Most children were shorter
were shorter than their fathers

18. The Additive Model of Polygenic Inheritance

19. The Additive Model of Polygenic Inheritance
Gametes
ABC
AbC
aBC
abC
Gametes
AABBCc 7 ft.
AABbCc
6 ft. 9 in.
AaBBCc
6 ft. 9 in.
AaBbCc
6 ft. 6 in.
ABc
Abc
AABbCc
6 ft. 9 in.
AAbbCc 6 ft. 6 in.
AaBbCc 6 ft. 6 in.
AabbCc 6 ft. 3 in.
AaBBCc 6 ft. 9 in.
AaBbCc 6 ft. 6 in.
aaBBCc 6 ft. 6 in.
aaBbCc 6 ft. 3 in.
aBc
AaBbCc
6 ft. 6 in.
AabbCc
6 ft. 3 in.
aaBbCc
6 ft. 3 in.
aabbCc 6 ft.
abc
(b)

20. The Additive Model of Polygenic Inheritance
Full expression of the height genotype depends on the environment
Poor nutrition during childhood can prevent people from reaching their potential heights
Optimal nutrition from birth to adulthood cannot make someone taller than genotype dictates

21. The Additive Model of Polygenic Inheritance
2 genes
F2 ratio: 1:4:6:4:1
% of individuals
Classes

22. A Polygenic Trait: Eye Color
Five basic eye colors fit a model with two genes, each with two alleles

23. The Additive Model of Polygenic Inheritance
3 genes
F2 ratio: 1:6:15:20:15:6:1
% of individuals
Classes

24. The Additive Model of Polygenic Inheritance
4 genes
F2 ratio: 1:8:28:56:70:56:28:8:1
% of individuals
Classes

25. Averaging out the phenotype
Regression to the Mean
Averaging out the phenotype
In a polygenic system, parents with extreme differences in phenotype, tend to have offspring that exhibit a phenotype that is the average of the two parental phenotypes
Called Regression to the Mean

26. 5.5 Multifactorial Traits
Variations in expression of polygenic traits often are due to the action of environmental factors
Multifactorial or complex traits are polygenic traits with a strong environmental component
Epigenetics – a new field helps us to understand and to explain how our cells can selectively turn on or off different gene sets in response to environmental factors.
Characteristics
Traits are polygenic
Each gene controlling the trait contributes a small amount to the phenotype
Environmental factors interact with the genotype to produce the phenotype

27. The Genetic Revolution: Dissecting Genes and Environment in Spina Bifida
Spina Bifida is a common birth defect involving the nervous system
1-2 per 1,000 births in US
Neural tube defect – neural tube forms earl in embryonic development and gives rise to brain and spinal cord.
Neural tube defects occur during days 17 to 30 of development –embryo size of rice
Diagnosis by ultrasound during week of development
Twin studies show a significant genetic component – multifactorial with significant environmental components
Nutrition (especially folate) has a significant impact on the frequency of occurrence
Gene, VANGL1, normally controls movement of cells during development
Mutations in this gene cause abnormalities in neural tube formation
A diet rich in folate reduces SB by 70% - green, leafy vegetables, peas and beans

28. The Threshold Model
Explains the discontinuous distribution of some multifactorial traits.
Liability for a genetic disorder distributed in a normal curve.
Caused by a number of genes, each acting additively
Only individuals with genetic liability above certain threshold are affected if exposed to certain environmental conditions
Environmental conditions are most likely to have the greatest impact on those individuals who have the highest level of genetic predisposition.
Threshold effect in families – as degree of relatedness decreases, so does the probability that individuals will have the same combination of alleles for the genes that control the trait

29. The Threshold Model
In multifactorial disorders, the risk of recurrence depends on several factors:
Consanguinity – first-cousin parents have about a twofold higher risk than unrelated parents of having a child with a multifactorial disease because of the shared genes they carry.
Previous affected child – If parents have 2 affected children, it means their genotypes are probably close to threshold, increasing the risk of recurrence
Severity of defect – A severely affected phenotype means that the affected child’s genotype is well over the threshold and that the parental genotypes confer a higher recurrence risk in children
Higher frequency in one sex – if disease is expressed more often in one sex than the other, the threshold in the less frequently affected sex is shifted to the right, and the rate for that sex is lower

30. Familial Risks for Multifactorial Traits

31. 5.6 Heritability
Heritability – An expression of how much of the observed variation in a phenotype is due to differences in genotype
Uses single number 0 to 1 to express the fraction of phenotypic variation among individuals in a population that is due to their genotypes.
If heritability is high (100% when H = 1), observed variation in phenotypes is genetic, with little or no environmental contribution
If heritability is low (zero when H = 0), there is little or no genetic contribution and the environmental contribution is high
Phenotypic variation is derived from two sources:
Genetic variance
The phenotypic variance of a trait in a population that is attributed to genotypic differences
Environmental variance
The phenotypic variance of a trait in a population that is attributed to differences in the environment

32. Heritability Estimates
Heritability is estimated
By observing the amount of variation among relatives who have a known fraction of genes in common (known as genetic relatedness)
Only for the population under study and the environmental condition in effect at the time of the study

33. Correlation
Correlation coefficient – measures the degree of interdependence of two or more variables.
The fraction of genes shared by two relatives
A child receives half of his or her genes from each parent – half set of genes corresponds to a correlation coefficient of 0.5
Identical twins have 100% of their genes in common (correlation coefficient = 1.0)
When raised in separate environments identical twins provide an estimate of the degree of environmental influence on gene expression
A heritability value can be calculated for a specific phenotype in a population
If value is 0.72, this means 72% of the phenotypic variability seen in the population is caused by genetic differences in the population

34. 5.7 Twin Studies and Multifactorial Traits
Using correlation coefficients has one problem: the closer the genetic relationship, the more likely it is that relatives will also share a common environment.
To solve this problem, geneticists study identical twins separated at birth and raised in different environments.
To reverse the situation, geneticists also compare traits in unrelated adopted children with those of natural children in the same family
Similar environment and maximum genotypic differences
Monozygotic (MZ)
Genetically identical twins derived from a single fertilization involving one egg and one sperm
Dizygotic (DZ)
Twins derived from two separate and nearly simultaneous fertilizations, each involving one egg and one sperm
DZ twins share about 50% of their genes

35. Monozygotic and Dizygotic Twins
Monozygotic (MZ) twins
Single fertilization event
Mitosis
Two genetically identical embryos
(a)

36. Monozygotic (identical) Twins Share a Single Genotype

37. Monozygotic and Dizygotic Twins
Dizygotic (DZ) twins
Two independent fertilization events
Mitosis
Two embryos sharing about half their genes
(b)

38. Concordance
The study of heritability in twins assumes that MZ twins share all of their genes; DZ twins share half of their genes
Concordance - Agreement between traits exhibited by both twins
Twins show concordance if both have a trait and are discordant if only one twin has the trait.
In twin studies, the degree of concordance for a trait is compared in MZ and DZ twins reared together or apart
If trait is completely controlled by genes, concordance should be 1.0 in MZ twins and close to 0.5 in DZ twins
The greater the difference, the greater the heritability
Concordance for cleft lip in MZ twins is higher than DZ twins (42% vs. 5%)
Although this suggests a genetic component, the value is so far below 100% that environmental factors are obviously important in the majority of cases

39. Concordance in MZ and DZ Twins

40. Exploring Genetics Twins, Quintuplets, and Armadillos
Some armadillos produce litters of two to six genetically identical, same-sex offspring by embryo splitting, the same way identical multiple births can occur in humans

41. Concordance, Heritability, and Obesity
Concordance can be converted to heritability by statistical methods
Twin studies of obesity show a strong heritability component (about 70%)

42. VIDEO: Obesity Genes

43. Obesity: Now a National Health Problem
Almost 70% of all adults in the US are overweight and more than 35% are obese.

44. Genetic Clues to Obesity: The ob Gene
The ob (obese) gene encodes the weight-controlling hormone leptin in mice;
Mice homozygous for the genes obese (ob) or diabetes (db) are both obese
file:///D:/Media/PowerPoint_Lectures/chapter5/videos_animations/leptin_research.html

45. Leptin and Fat Storage The ob gene encodes the hormone Leptin
Produced by fat cells that signals the brain and ovary
Hunger is inhibited by Leptin when the amount of fat store reaches a certain level
As fat levels become depleted, secretion of leptin slows and eventually stops

46. Human Obesity Genes
In humans, mutations in the gene for Leptin (LP) of the Leptin receptor (LEPR) account for about 5% of all cases of obesity
Other factors cause the recent explosive increase in obesity
Obesity is a complex disorder involving the action and interaction of multiple genes and environmental factors.
More than 70 genes associated with obesity have been identified through genome scans

47. 5.8 Genetics of Height
New technologies allow researchers to survey the genome to detect associations with phenotypes such as height.
The use of single nucleotide polymorphisms (SNPs) allows the association between haplotypes and phenotypes.
Haplotype: specific combinations of SNPs located close together on a chromosome that are likely inherited as a group.
The human genome contains more than 10 million SNPs and couples the use of a subset of 300,000 to 500,000 of these markers with technology that allows thousands of genomes to be analyzed in a single experiment

48. Haplotypes DNA source SNP SNP SNP SNP Reference standard
Original haplotype
10,000 nucleotides
Person 1
Haplotype 1
Person 2
Haplotype 2
Person 3
Haplotype 3
Person 4
Haplotype 4

49. 5.9 Skin Color and IQ
Genetics of skin color – between 1910 and 1914 – studied black-white marriages in Bermuda and in the Caribbean
F1 had skin colors intermediate to those of their parents
F2 – a small number of children were as white as one grandparent, a small number were as black as the other grandparent, most had a skin color between those two extremes
Five phenotypic classes – investigators hypothesized that two gene pairs control skin color
Later work showed that skin color is actually controlled by more than two gene pairs

50. 5.9 Skin Color and IQ

51. Multifactorial Traits: Skin Color
Skin color is controlled by 3 or 4 genes, plus environmental factors
KEY
1 gene
2 genes
F1 × F1 (F2)
3 genes
4 genes
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
Skin reflectance at 685 nm.

52. Are Intelligence and IQ Related?
Early studies believed that physical dimensions of regions of the brain were a measure of intelligence

53. Are Intelligence and IQ Related?
Can intelligence be measured quantitatively?
Psychological measurements and the ability to perform specific tasks as a function of age led to the development of the intelligent quotient (IQ) test
If a 7-year old was able to perform tasks for a 7-year old but could not do tasks for an 8-year-old, a mental age of 7 would be assigned
There is no evidence that intelligence can be measured objectively (like height or weight)
Intelligence is often thought of as abilities in abstract reasoning, mathematical skills, verbal expression, problem solving, and creativity
There is no evidence that any of these properties are measures directly by an IQ test

54. Are Intelligence and IQ Related?
Interestingly, IQ measurements do have a significant heritable components.
If we take IQ as a trait, heritability estimates range from 0.6 to 0.8.
High correlation observed for MZ twins raised together indicates genetics plays a significant role in determining IQ.

55. IQ Correlation Coefficients
Expected value
Pairs studied
(5)
Nonbiological sibling pairs (adopted/natural pairings)
0.0
Nonbiological sibling pairs (adopted/adopted pairings)
(6)
0.0
Foster-parent child
(12)
0.0
Single-parent offspring reared together
(32)
0.5
Single-parent offspring reared apart
(4)
0.5
Siblings reared apart
(2)
0.5
Siblings reared together
(69)
0.5
Dizygotic twins, opposite sex
(18)
0.5
Dizygotic twins, same sex
(29)
0.5
Monozygotic twins reared apart
(3)
1.0
Monozygotic twins reared together
(34)
1.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Correlation coefficient

56. Controversy About IQ and Race
IQ test scores can’t be equated with intelligence
Relative contributions of genetics, environment, social and cultural influences can’t be measured
Heritability can’t be used to estimate genetic variation between populations
Heritability measures only variation within a population at the time of measurement
Genetic variability within a population is greater than the variability between any two populations
Both genetic and environmental factors make important contributions to intelligence

57. Intelligence: meaningful measures and the search for genes
General cognitive ability
An expanded definition of intelligence
e.g. verbal and spatial abilities, memory and speed of perception, and reasoning
Genes associated with reading disability (dyslexia) and cognitive ability have been discovered by comparing haplotypes
As more human genomes are sequenced, it will become easier to define the number and actions of genes involved in higher mental processes and provide insight into the genetics of intelligence