Human GeneticsConcepts and Applications

Tenth Edition

RICKI LEWIS

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PowerPoint® Lecture Outlines Prepared by Johnny El-Rady, University of South Florida

7 MultifactorialTraits

Biol 4355 - Genética Humana

Capítulo 7 – Rasgos Multifactoriales UPR – Aguadilla

JA Cardé, PhD

2

Objetives

• To consider characteristics that represent input from many genes (multifactorial)

• To review the tools used to study multifactorial traits

3

Genes, Environment and Traits

Few, if any, genes act alone

Environmental factors and other genes may modify expression

Traits can be described as

- Mendelian = Caused by a single gene

- Polygenic = Caused by multiple genes

Both can be multifactorial or complex due to an interaction between genes and the environment (epigenesis)

4

Genes, Environment and Traits

Single-gene traits are discrete or qualitative

- Often produce an “all-or-none” effect

Polygenic traits produce a continuously varying phenotype

- Also called quantitative traits

- DNA sequences involved are termed quantitative trait loci (QTLs)

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Genes, Environment and Traits

Figure 7.1

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Polygenic Traits

Are influenced by interaction of genes and by the environment

Examples:

- Height

- Skin color

- Body weight

- Fingerprint patterns

- Behavioral traits

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Polygenic Traits

Individual genes follow Mendel’s laws, but their expression is hard to predict

Effect of genes is additive or synergistic

- However, input of genes is not necessarily identical

The frequency of distribution of phenotypes forms a bell-shaped curve!

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Fingerprint Patterns

Dermatoglyphics is the study of fingerprints

The number of ridges is largely determined by genes and prenatal contact with the amniotic sac

The average total ridge count is 145 in a male and 126 in a female

Abnormal numbers in Down Syndrome

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Fingerprint Patterns

Figure 7.2

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HeightThe difference in height between the two sets of

students is attributed to improved diet and better overall health

- 1920 height max = 5’9”

- 1997 height max = 6’5”

Genome-wide association studies have identified dozens of genes that affect height

- Also, certain SNPs patterns are seen in individuals with periods of rapid height increase

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Height

Figure 7.3

1920 height max = 5’9” 1920 height max = 6’5”

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Skin Color• Melanin protects against DNA damage

from UV radiation• Exposure to the sun increases melanin

synthesis

• All have same number of melanocytes per unit area of skin

- However, we differ in melanosome number, size and density distribution

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Skin Color

Figure 7.4 – Modelo de 3 genes con dos alelos cada uno, para color de piel . Se sortean de multiples formas dando mutiples tonos de color. (Gemelas, padre aleman madre jamaiquina)

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Skin Color

The definition of race based largely on skin color is a social construct more than a biological concept

Skin color is NOT a reliable indicator of ancestry

- Overall, 93% of varying inherited traits are no more common in people of one skin color than any other

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SummaryPolygenic Traits

- Determined by more than one gen and vary continuously in expression

Multifactorial Traits

- Determined by a combination of a gene, or genes and the environment

- A bell curve describes the distribution of phenotypic classes of a polygenic trait.

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Investigating Multifactorial Traits

Empiric risk - measures or predict the likelihood that a trait will recur based on incidence in specific population

- ethnic group, community, families with CF

Incidence- the rate at which a certain new event occurs in a population during some period of time

Prevalence - number of individuals who have a particular trait at a specific time (ie. during a year)

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Empiric Risk

• Is not a calculation• It is a population statistic based in observations

• It will increase with:- the severity of the disorder- the number of affected individuals in a family- how close (consanguinity) is the individual to

the affected individual

• Ex: cleft lip

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Investigating Multifactorial Traits

• Cleft lip is more likely in a person who has a relative with the condition

• The closer the relationship between two individuals, one of them having the condition, the greater the probability that the second individual has the trait. They share more genes.

Figure 7.5

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Investigating Multifactorial Traits

Table 7.2

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Heritability (H)Estimates the proportion of the phenotypic variation in a

population due to genetic differences

What factors contribute to the observed variation in a trait?

Figure 7.6

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Heritability (H)H=1:variability completely due to gene action (lab rats)

-No environmental variability: genetic differences alone determine expression of a trait-H changes as environment changes.-Winter months vs Summer months

(μg) 250 375 500 1000 C+

Effects of Plasticizers on Vtg Synthtesis

Vtg

169 153

116

Alb

1 2 3 4 5 6

BPA

Anti S1 (Vtg)

University of Puerto Rico Intercampus Doctoral Program in Biology

Effect of Methoxychlor on Vtg SynthesisEffect of Methoxychlor on Vtg Synthesis

Mtx 70 μg C- C+

Vtg

169 153 116

Alb

1 2 3 4 5 6 7 8 9 Anti S1 (Vtg)

University of Puerto Rico Intercampus Doctoral Program in Biology

Endocrine Disrupting Chemicals

Metoxychlor(Mtx)

Bisphenyl A(BPA)

Diethylstilbestrol(DES)

Dose (µg)

Vtg +

Vtg -

Dose (µg)

Vtg +

Vtg -

Dose (µg)

Vtg +

Vtg -

70 4 3 375 2 5 0.3a 6 0

140 5 2 500 1 6 3.0 7 0

280 5 2 1000a 1 3 30a 5 1

Dose Response Experiments

(a) Dead animals.

University of Puerto Rico Intercampus Doctoral Program in Biology

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Heritability (H)

Researchers use several statistical methods to estimate heritability

One way is to compare the proportion of people sharing a trait to the proportion predicted to share the trait

The expected proportion is derived by knowing the blood relationships of the individuals and using the C of R

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Coefficients of RelatednessThe proportion of genes shared between two

people related in a certain way

Table 7.4

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Adopted Individuals

Similarities between adopted people and adopted parents reflect mostly environmental influences

Similarities between adoptees and their biological parents reflect mostly genetic influences

Therefore, information on both sets of parents can reveal how heredity and the environment both contribute to a trait

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Twins

Twin studies have largely replaced adoption methods

Concordance measures the frequency of expression of a trait in both members of monozygotic (MZ) or dizygotic (DZ) twins

- Twins who differ in a trait are said to be discordant for it

For a trait largely determined by genes, concordance is higher for MZ than DZ twins

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TwinsTable 7.4

Tuberculosis?? Vs Susceptibilidad

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Separating Genetic and Environmental Influences

Dizygotic twins = Shared environment and 50% of genes

Monozygotic twins = Identical genotype and shared environment

Twins raised apart = Shared genotype but not environment

Adopted individuals = Shared environment but not genes

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Twins

Figure 7.8

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Genome-Wide Association Studies

Older techniques search for known gene variants, typically in only a few people

Sequencing of the human genome and the HapMap project (which identifies SNPs) have led to a new tool

Genome-wide association studies seek correlations between SNP patterns and phenotypes in large groups of individuals

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Genome-wide Association Studies (GWAS)

Studies to identify common variants behind a particular phenotype

Study to identify genetic associations with observables traits (Blood pressure/weight)

Genetic markers: used to follow variations, across the genome, form patterns compared between groups with a disease

34Table 7.5

underexpressed

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SNPs

SNPs (single nucleotide polymorphisms) are sites in a genome where the DNA base varies in at least 1% of the population

In these studies, SNPs span the genome, rather than define a single gene

- A SNP can be anywhere among our roughly 3.2 billion base pairs

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SNPs

Figure 7.9

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Genome-wide association studies seek SNPs that are shared with much greater frequency among individuals with the same trait than among others

Figure 7.10

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A Step-wise Approach to Gene Discovery

Figure 7.11

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Study Designs

In a cohort study, researchers follow a large group of individuals over time and measure many aspects of their health

In a case-control study, pairs of individuals from different groups are matched so that they share as many demographics characteristics as possible

- SNP differences are then associated with the presence or absence of the disorder

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Study Designs

The “affected sibling pair” strategy scans genomes of siblings for SNPs shared by those with the condition, but not by those who don’t have it

Homozygosity mapping is performed on families that are consaguineous

- The children in this case are more likely to inherit two copies of the mutation

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Limitations of Genome-Wide Association Studies

1) They include so many data points and so are prone to error

2) They reveal associations between two types of information, not causes

3) Bias can be introduced in the way the patient population is selected

4) Their accuracy is affected by complicating factors, such as phenocopy and epistasis

5) They may miss extremely rare SNPs

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Table 7.6

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Asignado: Body Weight

Body weight is a multifactorial trait that reflects energy balance

About 30% of all adults in the US are obese, and another 35% are overweight

Scientific studies use a measurement called body mass index (BMI)

= weight (kg)/height2 (m2)

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Body Mass Index (BMI)

Figure 7.12

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Body Weight

Studies on adopted individuals and twins indicate a heritability of 75% for obesity

Lifestyle, including diet and exercise, are environmental components impacting weight

Genes influence hunger and metabolism

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Leptin and Associated Proteins

Leptin is a protein hormone produced by fat cells

- Acts on the brain to decrease appetite

Ghrelin is a peptide hormone produced in the stomach

- Responds to hunger by increasing appetite

These and other hormones are important for general weight regulation

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Leptin and Associated ProteinsTable 7.8