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Pedigree Analysis

For researchers, families are tools; the bigger the family, the easier it is to discern modes of inheritance

Pedigrees are symbolic representations of family relationships and the transmission of inherited traits

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Pedigree AnalysisFigure 4.15

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An Unusual Pedigree

A partial pedigree of Egypt’s Ptolemy Dynasty showing:

- Genealogy not traits

- Extensive inbreeding

Figure 4.16a

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Autosomal Dominant Trait

Polydactyly = Extra fingers and/or toes

Figure 4.16b

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Autosomal Recessive Trait

Albinism = Deficiency in melanin production

Figure 4.17

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An Inconclusive Pedigree

This pedigree can account for either an autosomal dominant or an autosomal recessive trait

Figure 4.18

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Victor McKusick: father of human genetics

The new emerging area of genetics is multifactorial in nature and includes common diseases such as: type 2 diabetes, macular degeneration, hypertension, heart disease, cancer, stroke, bipolar, ADHD, autism…all are genetic diseases.

These complex genetic traits are multifactorial, common but complex

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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

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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 multifactorial 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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multifactorial traits

Lung cancer caused by smoking illustrates the compexity of multifactorial traits.

Migraines are also multifactorial:

chromosome 1 contributes to sensitivity to sound

chromosome 5 produces the pulsating headache and sensitivity to light

chromosome 8 is asssociated with nausea and vomiting

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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

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

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Fingerprint Patterns

Figure 7.2

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Height

Figure 7.3

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Height

The difference in height between the two sets of students is attributed to improved diet and better overall health

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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Skin Color

Melanin protects against DNA damage from UV radiation, and exposure to the sun increases melanin synthesis

We 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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Testing DNA indicates that biologically speaking, it makes more sense to classify people by ancestry rather than by the color of their skin.

Offering medical treatments based on skin color may make sense on a population level, but on the individual level it may lead to errors.

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A white person might be denied a drug that would work, or a black person given one that doesn’t if treatment is based on a superficial trait not related to how the body responds t a particular drug.

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Skin Color

Figure 7.4

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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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Investigating Multifactorial Traits

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

Figure 7.5

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Investigating Multifactorial Traits

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Heritability (H)

Estimates the proportion of the phenotypic variation in a population due to genetic differences

Figure 7.6

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Heritability (H)

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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

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Coefficients of Relatedness

The proportion of genes shared between two people related in a certain way

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Tracing Relatives

Figure 7.7

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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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Twins

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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 seek SNPs that are shared with much greater frequency among individuals with the same trait than among others

Figure 7.9

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If SNP always occurs in individuals who share a specific trait, then it may do so because it lies in or near a gene that does cause the trait.

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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 7.10

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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 are matched so that they share as many 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 ( inbreed)

- 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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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

48Figure 2.3

BMI Animation

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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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Multiple Alleles

An individual carries two alleles for each autosomal gene

However, a gene can have multiple alleles because its sequence can deviate in many ways

Different allele combinations can produce variations in the phenotype- PKU gene has hundreds of alleles resulting in four basic phenotypes- CF gene has over 1500 alleles

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Incomplete Dominance

The heterozygous phenotype is between those of the two homozygotes

Example: Familial hypercholesterolemia (FH)

- A heterozygote has approximately half the normal number of receptors in the liver for LDL cholesterol

- A homozygous for the mutant allele totally lacks the receptor, and so their serum cholesterol level is very high

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Incomplete Dominance

Figure 5.2

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Blood problems

1900 Karl Landsteiner’s Observations lead to the ABO blood typing due to antigen-antibody reactions

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Agglutinins Aggutinogens (antibodies) (anti-antibodies) A may be A/A or A/O B A B may be B/B or B/O A B AB is A/B none AB (universal donar) O is O/O A, B none( universal donar)

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Codominance

The heterozygous phenotype results from the expression of both alleles

The ABO gene encodes a cell surface protein

- IA allele produces A antigen

- IB allele produces B antigen

- i (IO) allele does not produce antigens

Alleles IA and IB are codominant, and both are completely dominant to i

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Figure 5.3

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Offspring from Parents with Blood Type A and Blood Type B

Figure 5.4

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Bombay phenotype.

In 1952 a very unusual situation provided information concerning the genetic basis of H substance.

A woman in Bombay displayed a unique genetic history that was inconsistent with her blood type. In need of a transfusion, she was found to lack both the A and B antigens and was thus typed as O.

However, it was shown that one of her parents was type AB, and she had donated a B allele to two of offsprings…thus, she was genetically type B, but functionally type O.

The Bombay woman was shown to be homozygous for a rare recessive mutation, h which prevented her from synthesizing the complete H substance…thus was functionally type O

People with this condition are thus to distinguished as having Bombay phenotype.

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EpistasisThe phenomenon where one gene affects the

expression of a second geneExample: Bombay phenotype

- The H gene is epistatic to the I gene - H protein places a molecule at the cell surface

to which the A or B antigens are attached- hh genotype = no H protein

- Without H protein the A or B antigens can not be attached to the surface of the RBC

- All hh genotypes have the phenotype of type O, although the ABO blood group can be anything (A, B, AB, or O)

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MN blood groups

Genotype to Phenotype

Individuals who inherit two N alleles have blood group N.

Individuals who are homozygous for the M allele have blood group M.

Heterozygous individuals produce both proteins and have blood group MN.

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Rh Antigen:

In 1939 Levine and Stetson, and in 1940 Landsteiner and Weiner made observations which laid the foundations of our knowledge about the remaining major blood group - the Rhesus system. Once reliable tests for Rhesus grouping had been established, transfusion reactions became rare

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Rh Antigens

Another set of antigens that was discovered by about 1940 Can cause the disorder erythroblastosis fetalis also referred to as hemolytic disease of newborns, it is a form of anemia.

This condition occurs if an Rh- positive fetus whose mother is Rh-negative and whose father is Rh-positive, contributing that allele to the fetus.

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Blood types

Consequently, we each belong to one of 8 different blood groups Within the ABO system people can be one of four types - 0, A, B or AB, whilst in the Rh system they can be either Rh positive or Rh

85% population is Rh positive

15% population is Rh negative

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PROBLEM:

A man is suing his wife for divorce on the grounds of infidelity. Their first child and second child, whom they both claim, are blood groups O and AB, respectively. The third child, whom the man disclaims, is blood type B.

Can this information be used to support the man’s case? Another test was made in the M-N blood group system. The third child was

group M, the man was group N.Can this information be used to support the man’s case?

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Rabbit coat color

In rabbits the ordinary ( wild type) color is called agouti ( banded hairs with gray at base then yellow then black tip)

Albino lack pigment Then there is chinchilla ( black gray color) and himalayan

( white with black extremities)

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Rabbit coat color

Phenotype: Genotype

Agouti c+c+, c+cch, c+ch, c+c

Chinchilla cchcch ,cchch, cchc

Himalayan chch , chc

Albino cc

DO SOME BOARD PROBLEMS

ch

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S antigens and Sectetors

Closely related to MN antigensS = SS or SsS = ss

Ex MS/Ns x NS/NSF1 ½ MS/NS ½ Ns/NS

Secretors release antigens in body secretions ex eyes, noses ect. 78% population are secretors

Secretor: HH or HhNon secretor: hh

Secretors