The Inheritance of Complex Traits Chapter 5. 5.1 All The King’s Men 1713 – new King of Prussia...

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

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Comparison of Discontinuous and Continuous Phenotypes

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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

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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


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


Gametes

AbC aBC abCGametes

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.

abcAaBbCc 6 ft. 6 in.

AabbCc 6 ft. 3 in.

aaBbCc 6 ft. 3 in.

aabbCc 6 ft.

(b)

ABC


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


2 genes

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A Polygenic Trait: Eye Color

Five basic eye colors fit a model with two genes, each with two alleles


3 genes

F2 ratio: 1:6:15:20:15:6:1

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4 genes

F2 ratio: 1:8:28:56:70:56:28:8:1

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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

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

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/vid

eos_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




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 gene2 genes F1 × F1 (F2)3 genes4 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


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


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

Pairs studiedExpected

value

Nonbiological sibling pairs (adopted/natural pairings) (5) 0.0Nonbiological sibling pairs (adopted/adopted pairings) (6) 0.0Foster-parent child (12) 0.0Single-parent offspring reared together (32) 0.5

Single-parent offspring reared apart (4) 0.5Siblings reared apart (2) 0.5

Siblings reared together (69) 0.5

Dizygotic twins, opposite sex (18) 0.5

Dizygotic twins, same sex (29) 0.5Monozygotic twins reared apart (3) 1.0Monozygotic twins reared together (34) 1.0

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0Correlation 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

The Inheritance of Complex Traits Chapter 5. 5.1 All The King’s Men 1713 – new King of Prussia...

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