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Pedigree Analysis in Human Genetics
Chapter 4
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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
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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
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Human Pedigrees
The use of pedigrees is an important method for analyzing the inheritance of traits in human populations
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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
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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
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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
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A Rare Autosomal Recessive Trait
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Some Autosomal Recessive Traits
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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.
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Example of an Autosomal Recessive Trait
Lungs
Mucus blocks airways
(a)
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Stomach
Mucus blocks pancreatic ducts
Pancreatic duct Pancreas(b)
Example of an Autosomal Recessive Trait
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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
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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.
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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
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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)
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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
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Some Autosomal Dominant Traits
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Pedigree: An Autosomal Dominant Trait
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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
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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.
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Aorta
Vena cavaPulmonary artery
Right auricle
Left ventricle
Right ventricle
Cardiovascular Effects of Marfan Syndrome
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Aorta
Area of aorta affected in Marfan syndrome
Right auricle
Left ventricle
Right ventricle
Cardiovascular Effects of Marfan Syndrome
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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.
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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
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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
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Male
XY
X Y
X XX XY
Female XX
X XX XY
Female offspring
Male offspring
Distribution of Sex Chromosomes from Generation to Generation
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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.
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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.
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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
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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
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X-Linked Recessive Inheritance
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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
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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
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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.
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Color Blindness: Defect in the Retina
Light
RetinaOptic nerve
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Color Blindness: Defect in the Retina
Photoreceptor cells:
Cone
Rod
Pigment layer
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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.
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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.
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Distribution of Dystrophin in Muscle Cells
(a) normal cells (b) from a patient with DMD
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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
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VIDEO: Muscular Dystrophy
file:///D:/Media/PowerPoint_Lectures/chapter4/videos_animations/muscular_distrophy.mp4
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Some X-Linked Recessive Traits
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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
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Pedigree: Y-Linked Traits
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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).
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Pedigree: Mitochondrial Inheritance
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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)
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Some Mitochondrial Disorders
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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
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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
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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
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OMIM Website
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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
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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
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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
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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