The Inheritance of Complex Traits Chapter 5. All The King’s Men  1713 – new King of Prussia began largest military buildup  King Frederick William I,

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1 The Inheritance of Complex Traits Chapter 5

2 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 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 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 0 DwarfTall P 1 parental generation 100 50 % of individuals 0 Dwarf Tall F 1 generation 100 50 % of individuals 0 DwarfTall F 2 generation (a) Pea plants

8 Comparison of Discontinuous and Continuous Phenotypes 100 50 % of individuals 0 DwarfTall P 1 parental generation 100 50 % of individuals 0 Intermediate F 1 generation 100 50 % of individuals 0 DwarfIntermediateTall F 2 generation (b) Tobacco plants

9 Example of a Continuous phentoype

10 Genetics – Fall 2014

11 Genetics – Spring 2015

12 Genetics – Fall 2015

13 Genetics – Spring 2016

14 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

15 Polygenic Inheritance  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.

16 Polygenic Inheritance  The distribution of polygenic traits through the population follows a bell-shaped (normal) curve 18 16 14 12 10 08 Percentage of men 04 06 02 0 5055606570758085 Phenotype (height in inches)

17 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.

18 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 trait 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

19 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

20 The Additive Model of Polygenic Inheritance

21 Gametes AbCaBCabC Gametes ABc AABBCc 7 ft. AABbCc 6 ft. 9 in. AaBBCc 6 ft. 9 in. AaBbCc 6 ft. 6 in. Abc AABbCc 6 ft. 9 in. AAbbCc 6 ft. 6 in. AaBbCc 6 ft. 6 in. AabbCc 6 ft. 3 in. aBc 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. (b) ABC

22 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

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

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25 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 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 early 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 15-17 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 Heritability  Heritability – An expression of how much of the observed variation in a phenotype is due to differences in genotype.  Is the variation within a population caused by genetics or the environment?  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

29 Twin Studies and Multifactorial Traits  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  http://learn.genetics.utah.edu/content/epigenetics/twins/ http://learn.genetics.utah.edu/content/epigenetics/twins/  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

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31 Monozygotic (identical) Twins Share a Single Genotype

32 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 they both have a trait and are discordant if only one twin has the trait.  http://www.dailymail.co.uk/news/article-2974869/The-twins-tell-apart- Striking-sisters-couldn-t-different-quirk-mixed-raced-parentage.html http://www.dailymail.co.uk/news/article-2974869/The-twins-tell-apart- Striking-sisters-couldn-t-different-quirk-mixed-raced-parentage.html  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  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  http://wnep.com/2014/11/13/twins-separated-at-birth-reunited-by- facebook/ http://wnep.com/2014/11/13/twins-separated-at-birth-reunited-by- facebook/

33 Concordance in MZ and DZ Twins

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

35 VIDEO: Obesity Genes

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

37 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/vid eos_animations/leptin_research.html file:///D:/Media/PowerPoint_Lectures/chapter5/vid eos_animations/leptin_research.html

38 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

39 Human Obesity Genes  In humans, mutations in the gene for Leptin (LP) 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

40 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

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

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

43 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 measured directly by an IQ test

44 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.

45 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  Both genetic and environmental factors make important contributions to intelligence  http://www.telegraph.co.uk/science/science- news/9755929/IQ-tests-do-not-reflect-intelligence.html http://www.telegraph.co.uk/science/science- news/9755929/IQ-tests-do-not-reflect-intelligence.html

46 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

47 1. What is continuous variation? 2. What is the difference between polygenic traits and multifactorial traits? 3. How does the additive model of polygenic inheritance work? 4. What is the range of heritability and what two factors affect it? 5. Difference between monozygotic and dizygotic. 6. What is concordance? 7. What is a haplotype? 8. Can intelligence be measured with an IQ test? 9. What is General Cognitive Ability?