Pedigree Analysis in Human Genetics

Chapter 4

Abraham Lincoln

1960s – child diagnosed with genetic disorder called Marfan Syndrome – had ancestor common with Abraham Lincoln Marfan syndrome – affects body’s connective tissue, causes

visual problems, blood vessel defects, and loose joints. Know from photographs – Lincoln had long arms and legs, was

loose-jointed, and wore glasses – led to speculation that Lincoln had Marfan syndrome.

Evidence against claim – Farsighted (People with Marfan are nearsighted), no outward signs of problems with blood vessels, and his son Robert showed no signs

Soon after gene was isolated, scientists proposed extracting DNA from Lincoln’s skull

Was not performed

4.2 Pedigree Analysis and Construction

Analysis of pedigrees allows us to determine:

Whether the trait has a dominant or recessive pattern of inheritance

Whether the gene in question is located on an X or Y chromosome or on an autosome

This kind of information can be used to predict risk

Human Pedigrees

The use of pedigrees is an important method for analyzing the inheritance of traits in human populations

Patterns of Inheritance

Six basic patterns

1. Autosomal dominant

2. Autosomal recessive

3. X-linked dominant

4. X-linked recessive

5. Y-linked

6. Mitochondrial inheritance

Pedigree Analysis

Proceeds in several steps: Rule out patterns of inheritance that are

inconsistent with the pedigree If only one pattern of inheritance is consistent with

the pedigree, it is accepted as the pattern for that trait – Ex. Autosomal dominant or X-linked Dominant

If more than one pattern in consistent with the pedigree, which one is expected to be more likely?

If due to small sample size, it is impossible to choose among pattern of inheritance, the inclusion of more family members may be necessary

4.3 Autosomal Recessive Traits

Characteristics:

For rare traits, most affected individuals have unaffected parents

All children of affected parents are affected

The risk of an affected child with heterozygous parents is 25%

The trait is expressed in both males and females

A Rare Autosomal Recessive Trait

Some Autosomal Recessive Traits

Example of an Autosomal Recessive Trait

Cystic fibrosis: A fatal autosomal recessive genetic disorder associated with abnormal secretions of the mucus, digestive enzymes, and sweat. In the pancreas, thick mucus clogs duct that carry enzymes

to the small intestines, reducing the efficiency of digestion. Affected children can be malnourished despite increased food

intake. Eventually clogged ducts lead to the formation of pancreatic

cysts and the organ degenerates into a fibrous structure – giving name to the disease

CF also causes production of thick mucus in lungs that blocks airways and most patients develop obstructive lung diseases and infections that lead to premature death.

Almost all CF children have phenotypically normal, heterozygous parents.

Example of an Autosomal Recessive Trait

Lungs

Mucus blocks airways

(a)

Stomach

Mucus blocks pancreatic ducts

Pancreatic duct Pancreas(b)

Example of an Autosomal Recessive Trait

The Frequency of the Gene for Cystic Fibrosis

1 in 25 Americans of European descent 1 in 46 Americans of Hispanic descent 1 in 65 African Americans 1 in 250 Asian Americans

Cystic Fibrosis Gene Product (CFTR)

The CFTR (Cystic fibrosis transmembrane conductance regulator) gene was identified in 1989. Located on long arm of chromosome 7. Identified by comparing DNA sequences of CF genes

in normal and affected individuals. CF gene codes for CFTR protein which controls the

movement of chloride ions across the plasma membrane In CF, the protein is absent or partially functional

Changes the transport of chloride ions – reduces amount of fluid added glandular secretion, making them thicker

Results in blocked ducts and obstructed airflow.

Cystic Fibrosis Gene Product (CFTR)

Outside of cellMembrane-spanning

segments

Plasma membrane

Site of most common

mutation 508

Binding region 1

Regulatory region

Binding region 2

Inside of cell

Exploring Genetics:Was Noah an Albino?

Noah’s “flesh was white as snow, and red as a rose; the hair of whose head was white like wool, and long, and whose eyes were beautiful”

From the Book of Enoch the Prophet

Phenotype: Lack of pigmentation Inheritance of albinism

Normal, heterozygous parents (may be closely related)

According to sources, Noah’s father (Lamech) and his mother (Betenos) were first cousins

Marriage between close relatives is sometimes involved in pedigrees of autosomal recessive traits, such as albinism

Homozygous recessive offspring (albino)

4.4 Autosomal Dominant Traits

Characteristics:

Heterozygotes have an abnormal phenotype Unaffected individuals carry two recessive alleles and have

a normal phenotype Every affected individual has at least one affected parent

(except in traits with high mutation rates) If an affected individual is heterozygous and has an

unaffected mate, each child has a 50% chance of being affected

Trait is autosomal – number of affected males and females are roughly equal

Two affected individuals may have unaffected child Two affected individuals can have an unaffected child Usually an affected family member in each generation

Some Autosomal Dominant Traits

Pedigree: An Autosomal Dominant Trait

Example of an Autosomal Dominant Trait

Marfan syndrome Affects the skeletal system, cardiovascular system, and eyes Individuals are tall, thin, long arms and legs–thin fingers Heart defects Found in all ethnic groups with a frequency of about 1 in

10,000 individuals About 25% of affected individuals appear in families with no

previous history, indicating gene has high mutation rate. Gene, FBN1, located on chromosome 15, encodes a protein,

fibrillin, a component of connective tissue Normal fibrillin protein also binds to a protein called TGF-β that

regulates growth and development of muscle fibers. Marfan syndrome – mutant fibrillin produces defective

connective tissue and excess TGF-β accumulates, further weakening connective tissue

Example of an Autosomal Dominant Trait

Marfan syndrome Most dangerous effect – on aorta

Normal aorta arches back and downward, feeding blood to all major organ systems

Marfan syndrome weakens connective tissue around base of aorta, causing it to enlarge and eventually split open.

Can be repaired by surgery if caught in time.

Aorta

Vena cavaPulmonary artery

Right auricle

Left ventricle

Right ventricle

Cardiovascular Effects of Marfan Syndrome

Aorta

Area of aorta affected in Marfan syndrome

Right auricle

Left ventricle

Right ventricle

Cardiovascular Effects of Marfan Syndrome

4.5 Sex-Linked Inheritance

Genes on sex chromosomes have a distinct pattern of inheritance Males (XY) pass their X chromosome to all of

their daughters but none of their sons Females (XX) pass an X chromosome to all of

their children, sons and daughters. X-linked – genes on the X chromosome Y-linked – genes on the Y chromosome Females have two X chromosomes and ,

therefore, two copies of all X-linked genes and can be heterozygous or homozygous for any of them.

4.5 Sex-Linked Inheritance (contd.)

Genes on sex chromosomes have a distinct pattern of inheritance Most genes on the X chromosome are not on the

Y chromosome Males carrying an X-linked

recessive allele express the recessive phenotype

Hemizygous

Because a male cannot be homozygous or heterozygous for genes on the X chromosome, males are said to be hemizygous for all genes on the X chromosome.

XNY or XnY

Male

XY

X Y

X XX XY

Female XX

X XX XY

Female offspring

Male offspring

Distribution of Sex Chromosomes from Generation to Generation

X-Linked Dominant Traits

Quite rare inheritance pattern Affected males produce all affected daughters

and no affected sons Because he always passes his X chromosome to

his daughter. A heterozygous affected female will transmit the

trait to half of her children Sons and daughters are equally affected

On average, twice as many daughters as sons are affected Because affected females can be heterozygous

or homozygous.

Pedigree of an X-linked Dominant Trait

Affected males transmit the trait to all of their daughters, but affected females have affected sons and daughters.

X-Linked Recessive Traits

Affect males more than females because males are hemizygous for genes on the X chromosome XnY

Affected males receive the mutant X-linked allele from their mother and transmit it to all of their daughters, but not to their sons

Daughters of affected males are usually heterozygous

X-Linked Recessive Traits (contd.)

Sons of heterozygous females have a 50% chance of being affected

Hemizygous males (only one X) and females homozygous for the allele are affected

XnY or XnXn

X-Linked Recessive Inheritance

Example of an X-linked Recessive Trait Color blindness

Defective color vision caused by reduction or absence of visual pigments

Three forms: red, green, and blue blindness Red blindness do not see red as a distinct color Green blindness cannot distinguish green or other

colors in the visual spectrum Blue color blindness (rare) is inherited as an

autosomal dominant condition that maps to chromosome 7.

About 8% of the male population in the US affected

Testing For Color Blindness

People with normal color vision see the number 29 in the chart; those who are color-blind cannot see the number

Color Blindness: Defect in the Retina

Defects in photoreceptor cells of the retina (cone cells) cause color blindness

Three genes controlling color vision encode three different but related proteins found in retinal cells Proteins normally found in cells sensitive to red, green,

or blue wavelengths of light Ex: Protein for red color vision is defective or absent, cells

that respond to red light are nonfunctional, resulting in red color blindness. Similar results with green and blue.

Color Blindness: Defect in the Retina

Light

RetinaOptic nerve

Color Blindness: Defect in the Retina

Photoreceptor cells:

Cone

Rod

Pigment layer

Example of an X-linked Recessive Trait Muscular dystrophy

A group of genetic diseases associated with progressive degeneration of muscle tissue

Duchenne and Becker muscular dystrophy are inherited as X-linked recessive traits

Duchenne muscular dystrophy (DMD) affects 1 in 3,500 males in the US

Progressive muscle weakness one of first signs Progresses rapidly, affected individuals are usually

confined to wheelchairs by 12 years of age because of muscle degeneration.

Death usually occurs by age 20 as a result of respiratory infection or cardiac arrest.

Molecular Characteristics of DMD

DMD gene encodes a protein called dystrophin. Dystrophin proteins that are flexible and normally

stabilize the muscle cells during contraction are defective

IN DMD, dystrophin is not present and cell membranes are torn apart during muscle contraction, eventually causing death of muscle tissue

Becker Muscular Dystrophy (BMD) – a shortened and partially functional form of dystrophin is made, producing a less severe form of the disease.

Distribution of Dystrophin in Muscle Cells

(a) normal cells (b) from a patient with DMD

Molecular Characteristics of DMD

Proteins

Bone Muscle cell membrane

TendonDystrophin

Muscle

Actin (thin) filament

Actin (thin) filament

Muscle filaments

Muscle fiber (cell)

Bundle of muscle fibers

VIDEO: Muscular Dystrophy

file:///D:/Media/PowerPoint_Lectures/chapter4/videos_animations/muscular_distrophy.mp4

Some X-Linked Recessive Traits

4.6 Paternal Inheritance

Only males have Y chromosomes Genes on the Y chromosome are passed directly from

father to son

All Y-linked genes are expressed Males are hemizygous for genes on the Y chromosome

To date only 36 Y-linked traits have been identified Many involved in male sexual development

Testis-Determining Factor – involved in determining maleness in developing embryos

Pedigree: Y-Linked Traits

4.7 Non-Mendelian Maternal Inheritance

Mitochondria Cytoplasmic organelles that convert energy from food into ATP Billions of years ago, ancestors of mitochondria were free-living bacteria

that adapted to live inside cells of primitive eukaryotes. Over time, most of the genes carried on the bacterial chromosome have

been lost, but as an evolutionary relic of their free-living ancestor, mitochondria carry DNA for 37 mitochondrial genes

Thirteen encode proteins that function in energy production Genetic disorders in mitochondrial DNA are associated with defects

in energy conversion Mitochondria are transmitted from mothers to all their offspring

through the cytoplasm of the egg Sperm do not contribute mitochondria at fertilization

Mitochondria (and genetic disorders caused by mutations in mitochondrial genes) are maternally inherited Affected females will transmit to all offspring. Affected males cannot

transmit to any of their children (no mitochondria in sperm).

Pedigree: Mitochondrial Inheritance

Mitochondria are energy producers. Mutations in mitochondrial genes reduce amount of energy

available for cellular functions. In general, tissues with high energy requirements are

affected most often. Include muscles and nervous system Mitochondrial myopathies – disorders that mainly affect the

muscles Symptoms: muscle weakness, weakness and death of muscle

tissue, affects movement of eyes causing droopy eyelids, problems with swallowing and speech difficulties

Mitochondrial encephalopathy – affect both muscles and nervous system

Symptoms: See above symptoms for mitochondrial myopathy, may also affect nervous system (ex: in addition to affecting muscles in eyes – may affect the eye itself and the regions of the brain associated with vision)

Some Mitochondrial Disorders

Exploring Genetics:Hemophilia and History Hemophilia – an X-linked recessive disorder, is

characterized by defects in the mechanism of clotting Hemophilia A – occurs in 1 in 10,000 males

Only homozygous recessive females can have hemophilia – the frequency in females is much lower – 1 in 100 million

Exploring Genetics:Hemophilia and History

Queen Victoria passed the X-linked recessive gene for hemophilia to several of her children Present royal family unaffected – descended from Edward VII,

an unaffected son of Victoria

IKing George III

II Duke of Saxe-Coburg Gotha

Edward Duke of Kent

Duke of Clarence

Duke of Cambridge

III Prince Albert

Queen Victoria

IV Victoria Empress Fredrick

King Edward

VII

Alice of

Hesse

Beatrice

Leopold, Duke of Albany

To English royal family

To Russian royal family

To Spanish royal family

4.8 An Online Catalog of Human Genetic Traits

OMIM (Online Mendelian Inheritance in Man) Genetic traits are described, cataloged, and

numbered in this database maintained by researchers at Johns Hopkins University

Updated daily and contains information about all known human genetic traits

Each trait is assigned an OMIM number (the MIM number) – you can obtain more information about traits by accessing the page and using this number.

There are more that 10,000 entries

OMIM Website

4.9 Many Factors can Affect the Pattern of Inheritance

Variations in gene expression affect pedigree analysis and assignment of genotypes to members of the pedigree

Several factors can affect gene expression Interactions with other genes in the genotype Interactions between genes and the environment

4.9 Many Factors can Affect the Pattern of Inheritance (contd.)

Phenotypes are often age related Example: Huntington disease – an autosomal dominant trait

Symptoms first appear between the ages of 30 and 50 years old Uncontrolled jerky movements of head and limbs, additional

neurodegenerative symptoms over time, disease progresses slowly, with death occurring 5 to 15 years after symptoms first appear.

By the time symptoms appear, affected heterozygous parent usually has children – each have 50% chance of being affected

Penetrance and expressivity cause variations in phenotype Penetrance: the probability the phenotype will be present when the

disease genotype is present Allele for a dominant disorder = 100% penetrance 25% of those who carry the mutant allele show phenotype = 25%

penetrance Expressivity: The range of phenotypes from a given genotype

Incomplete Penetrance and Variable Expression Camptodactyly

A dominant trait (immobile, bent little fingers) with variable expression

Fully shaded = both affected hands, Left shaded = left-hand affected, Right-shaded = right hand affected

No Penetrance in III-4, even though he passed the trait to his children

Variable expressivity includes several phenotypes, including no phenotypic expression, expression in one hand, and both hands

Common Recessive Alleles

Common recessive alleles can enter a pedigree from outside the family and thus appear dominant Allele for O blood type – often found in more than

50% of population