The Inheritance of Complex Traits Chapter 5

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

Differences Among Siblings Is due to both Genetic and Environmental Factors

VIDEO: Designer Babies

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

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

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

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

Example of a Continuous phentoype

Genetics – Fall 2014

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

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

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.

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)

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.

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

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

The Additive Model of Polygenic Inheritance

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)

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

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

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

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

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

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

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

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 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

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

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

Familial Risks for Multifactorial Traits

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

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

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

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

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

Monozygotic (identical) Twins Share a Single Genotype

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

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

Concordance in MZ and DZ Twins

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

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

VIDEO: Obesity Genes

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

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

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

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

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

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

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

5.9 Skin Color and IQ

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.

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

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

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.

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

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

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