Chapter 4
Genes and Genetic Diseases
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Definitions

Genetics—the study of biologic heredity


Gene—basic unit of heredity
Genomics—the field of genetics concerned
with the structural and functional studies of
the genome

Genome—DNA representing all of the genes for
a given species
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DNA



Pentose sugar (deoxyribose)
Phosphate molecule
Four nitrogenous bases


Pyrimidines: cytosine and thymine
Purines: adenine and guanine
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Nitrogenous Bases


Nucleoproteins created from amino acids
Purines



Adenine and guanine
Double-ring structures
Pyrimidines


Cytosine and thymine
Single-ring structures
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DNA Structure


Anti-parallel structure
Nucleotide pairings


Adenine with thymine
• 2 hydrogen bonds
Cytosine with guanine
• 3 hydrogen bonds
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DNA Organization

Chromosome



Temporary but consistent state of DNA
Composed of two longitudinal sister chromatids
1/10,000 as long as outstretched DNA
• 7.2 x 10-3 inches
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DNA Structure

3 billion DNA base pairs per human cell


On average, humans vary on 3 million base pairs
Human genome contains 20,000 to 25,000
genes
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Proteins


One or more polypeptides
Composed of amino acids


20 amino acids
Directed by sequence of bases (codons)
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DNA Replication

Untwisting and unzipping of the DNA strand


Single strand acts as a template
Complementary base pairing by DNA
polymerase

Adenine-thymine; cytosine-guanine
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Transcription




RNA is synthesized from the DNA template
via RNA polymerase
Results in the formation of mRNA
mRNA moves out of the nucleus and into
the cytoplasm
Gene splicing

Introns, extrons
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Transcription
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Translation




Process by which RNA directs the synthesis of
a polypeptide via interaction with transfer RNA
Site of protein synthesis is the ribosome
tRNA contains a sequence of nucleotides
(anticodon) complementary to the triad of
nucleotides on the mRNA strand (codon)
The ribosome moves along the mRNA
sequence to translate the amino acid
sequence
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Translation
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Chromosomes

Somatic cells



Gametes



Contain 46 chromosomes (23 pairs)
Diploid cells
Contain 23 chromosomes
Haploid cells
• One member of each chromosome pair
Meiosis

Formation of haploid cells from diploid cells
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Chromosome Structure

Short arm


Long arm


“q”
Centromere


“p”—petit
Region of attachment of sister chromatids
Telomere


Region containing multiple base pairs
Shorten with each cell division
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Chromosomes

Diploid (2n) number in humans is 46


Somatic cells contain the diploid number of
chromosomes (retained during mitosis)
Gametes contain the haploid number of
chromosomes (occurs through meiosis)
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Chromosomes

Autosomes

The first 22 of the 23 pairs of chromosomes in
males and females
 The two members are virtually identical and thus
said to be homologous

Sex chromosomes

Remaining pair of chromosomes
 In females, it is a homologous pair (XX)
 In males, it is a nonhomologous pair (XY)
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Karyotype

Ordered display of chromosomes
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Mutation

Any inherited alteration of genetic material


Chromosome aberrations
Base pair substitution
• One base pair is substituted for another; may result in change
in amino acid sequence
• Silent substitution


Does not result in an amino acid change
RNA codons GUU, GUC, GUA, GUG all code for the amino acid
valine
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Mutations



Mutations in somatic cells are not
transmitted to offspring
Mutations in gametes are transmitted to
offspring
Point mutation


A single nucleotide base-pair change in DNA
Rates of spontaneous mutation


Varies per gene
10-4 to 10-7 per gene per generation
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Mutagen

Agent known to increase the frequency of
mutations


Radiation
Chemicals
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Silent Mutation

A DNA sequence change that does not
change the amino acid sequence of a
gene
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Missense Mutation

A type of mutation that results in a single
amino acid change in the translated gene
product
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Nonsense Mutation

A type of mutation in which an mRNA stop
codon is:


Produced, resulting in premature termination of
the protein sequence or
Removed, resulting in an elongated protein
sequence
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Nonsense Mutation

Premature termination of the protein
sequence
THE FAT CAT ATE THE RAT
THE FAT CAT ATE

Elongation of the protein sequence
THE FAT CAT ATE THE RAT
THE FAT CAT ATE THE RAT AND THE HAT AND THE MAT
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Frameshift Mutation


An alteration of DNA in which an addition
or deletion of a base pair occurs
Results in a change in the entire “reading
frame”
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Consequences of Mutations

Gain of function




Associated with
dominant disorders
Production of new
protein product
Overexpression of a
protein product
Inappropriate
expression of a
protein product

Loss of function


Associated with
recessive disorders
Loss of 50% of the
protein product
• May or may not be
adequate for normal
function
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Chromosome Abnormalities

Euploid cells

Cells that have a multiple of the normal number
of chromosomes
 Haploid and diploid cells are euploid forms

When a euploid cell has more than the
diploid number, it is called a polyploid cell



Triploidy: a zygote having three copies of each
chromosome (69)
Tetraploidy: four copies of each (92 total)
Triploid and tetraploid fetuses don’t survive
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Chromosome Abnormalities

Disjunction


Normal separation of chromosomes during cell
division
Nondisjunction


Usually the cause of aneuploidy
Failure of homologous chromosomes or sister
chromatids to separate normally during meiosis
or mitosis
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Nondisjunction
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Chromosome Abnormalities

Aneuploidy




A somatic cell that does not contain a multiple of
23 chromosomes
A cell containing three copies of one
chromosome is trisomic (trisomy)
Monosomy is the presence of only one copy of
any chromosome
Monosomy is often fatal, but infants can survive
with trisomy of certain chromosomes
• “It is better to have extra than less”
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Chromosomal Disorders


Leading cause of mental retardation and
miscarriage
Incidence of chromosomal abnormalities




1/12 conceptions
Approximately 95% of conceptions with
chromosome disorders result in miscarriage
50% of first-trimester miscarriages associated with a
major chromosomal abnormality
1/150 live births with a major diagnosable
chromosomal abnormality
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Autosomal Aneuploidy

Down syndrome





Best-known example of aneuploidy
• Trisomy 21 (47, XX or 47, XY karyotype)
1:800 live births
Mentally retarded, low nasal bridge, epicanthal
folds, protruding tongue, poor muscle tone
Risk increases with maternal age
Increased risk of congenital heart disease,
gastrointestinal disease, and leukemia
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Down Syndrome
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Other Autosomal Aneuploidies

Trisomy 13 and 18


More severe clinical manifestations than trisomy
21
Death in early infancy is common
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Autosomal Aneuploidy

Partial trisomy


Only an extra portion of a chromosome is
present in each cell
Chromosome mosaics

Trisomies occurring only in some cells of the
body
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Sex Chromosome Aneuploidy


One of the most common is trisomy X. This is
a female that has three X chromosomes.
Termed “metafemale”


Symptoms are variable: sterility, menstrual
irregularity, and/or mental retardation
Symptoms worsen with each additional X
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Sex Chromosome Aneuploidy

Turner syndrome


Females with only one X chromosome
Characteristics
• Absence of ovaries (sterile)
• Short stature (~ 4'7")
• Webbing of the neck
• Edema
• Underdeveloped breasts; wide nipples
• High number of aborted fetuses
• X is usually inherited from mother
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Turner Syndrome
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Sex Chromosome Aneuploidy

Klinefelter syndrome

Individuals with at least two Xs and one Y
chromosome
 Characteristics
• Male appearance
• Develop female-like breasts
• Small testes
• Sparse body hair
• Long limbs
 Some individuals can be XXXY and XXXXY.
The abnormalities will increase with each X.
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Klinefelter Syndrome
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Alterations in Chromosome
Structure

Deletion


Loss of a sequence of DNA from a chromosome
Inversion

Chromosomal rearrangement in which a segment of a
chromosome is reversed end to end
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Alterations in Chromosome
Structure

Translocation


Transfer of one chromosome segment to another
Ring chromosome

Structurally abnormal chromosome in which the
telomere of each chromosome arm has been
deleted and the broken arms have joined
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Alterations in Chromosome
Structure

Chromosome breakage


If a chromosome break does occur, physiologic
mechanisms usually repair the break, but the
breaks often heal in a way that alters the structure
of the chromosome
Agents of chromosome breakage
• Ionizing radiation, chemicals, and viruses
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Alterations in Chromosome
Structure


Breakage or loss of DNA
Cri du chat syndrome



“Cry of the cat”
Deletion of short arm of chromosome 5 (5p-)
Low birth weight, metal retardation, and
microcephaly
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Alterations in Chromosome
Structure

Infant with cri du
chat (5p deletion)
syndrome
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Alterations in Chromosome
Structure

Duplication




A repeated gene or gene sequence
Rare occurrence
Less serious consequences because better to
have more genetic material than less (deletion)
Duplication in the same region as cri du chat
causes mental retardation but no physical
abnormalities
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Alterations in Chromosome
Structure

Inversions



Two breaks on a chromosome
Reversal of the gene order
Usually occurs from a breakage that gets reversed
during reattachment
• ABCDEFG may become ABEDCFG
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Alterations in Chromosome
Structure

Translocations

The interchanging of material between
nonhomologous chromosomes
 Translocation occurs when two chromosomes
break and the segments are rejoined in an
abnormal arrangement
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Alterations in Chromosome
Structure

Fragile sites


Fragile sites are areas on chromosomes that
develop distinctive breaks or gaps when cells are
cultured
No apparent relationship to disease
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Alterations in Chromosome
Structure

Fragile X syndrome



Site on the long arm of the X chromosome
Associated with mental retardation; second in
occurrence to Down syndrome
Higher incidence in males because they have only
one X chromosome
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Genetics

Gregor Mendel



Austrian monk
Garden pea experiments
Mendelian traits
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Genes


Basic units of heredity
Sequences of chromosomal DNA coding for
the production of a functional product


Templates for mRNA that code for specific
proteins
All genes are contained in each cell of the
body
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Genes


Locus: location occupied by a gene on a
chromosome
Allele: alternate version of a gene at a locus

Each individual possesses two alleles for each
gene
 Homozygous: possessing identical alleles of a
given gene
 Heterozygous: possessing two different alleles of
a given gene

Polymorphism

Locus that has two or more alleles that occur
with appreciable frequency
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Genetics

Homozygous



Loci on a pair of chromosomes have identical alleles
Example
• O blood type (OO)
Heterozygous


Loci on a pair of chromosomes have different alleles
Example
• AB blood type (A and B alleles on pair of loci)
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Genetics

Genotype (“what they have”)


Phenotype (“what they demonstrate”)


The genetic makeup of an organism
The observable, detectable, or outward appearance
of the genetics of an organism
Example

A person with the A blood type could be AA or AO. A
is the phenotype; AA or AO is the genotype.
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Genetics



If two alleles are found together, the allele that
is observable is dominant, and the one whose
effects are hidden is recessive
In genetics, the dominant allele is represented
by a capital letter, and the recessive by a
lowercase letter
Alleles can be codominant
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Genetics

Carrier



A carrier is one that has a disease gene but is
phenotypically normal
For a person to demonstrate a recessive disease,
the pair of recessive genes must be inherited
Example
• Ss = sickle cell anemia carrier
• ss = demonstrates sickle cell disease
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Pedigrees


Used to study specific genetic disorders within
families
Begins with the proband
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Pedigrees
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Single-Gene Disorders

Recurrence risk


The probability that parents of a child with a genetic
disease will have yet another child with the same
disease
Recurrence risk of an autosomal dominant trait
• When one parent is affected by an autosomal dominant
disease and the other is normal, the occurrence and
recurrence risks for each child are one half
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Single-Gene Disorders

Autosomal dominant disorder

Abnormal allele is dominant, normal allele is
recessive, and the genes exist on a pair of
autosomes
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Autosomal Dominant Disorders

Characteristics of autosomal dominant
disorders



Condition is expressed equally in males and
females
Approximately half of children of an affected
heterozygous individual will express the
condition
• Homozygous affected individuals are rare
No generational skipping
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Gene Mapping
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Single-Gene Disorders

Autosomal dominant traits
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Single-Gene Disorders

Autosomal dominant trait pedigree
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Penetrance

The percentage of individuals with a specific
genotype who also express the expected
phenotype

Incomplete penetrance
• Individual who has the gene for a disease but does not
express the disease
• Retinoblastoma (eye tumor in children) demonstrates
incomplete penetrance (90%)
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Expressivity



Expressivity is the variation in a phenotype
associated with a particular genotype
This can be caused by modifier genes
Examples:

von Recklinghausen disease
• Autosomal dominant
• Long arm of chromosome 17
• Disease varies from dark spots on the skin to malignant
neurofibromas, scoliosis, gliomas, neuromas, etc.
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Expressivity
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Single-Gene Disorders

Autosomal recessive disorder


Abnormal allele is recessive and a person must be
homozygous for the abnormal trait to express the
disease
The trait usually appears in the children, not the
parents, and it affects the genders equally because
it is present on a pair of autosomes
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Single-Gene Disorders

Autosomal recessive disorder recurrence risk

Recurrence risk of an autosomal dominant trait
• When two parents are carriers of an autosomal recessive
disease, the occurrence and recurrence risks for each
child are 25%
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Autosomal Recessive Disorder
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Autosomal Recessive Disorders

Characteristics


Condition expressed equally in males and females
Affected individuals most often the offspring of
asymptomatic heterozygous carrier parents
• Approximately 1/4 of offspring will be affected; 1/2 will be
•
asymptomatic carriers; and 1/4 will be unaffected
Individuals must be homozygous for the condition to be
expressed

Generational skipping may be present
 Consanguinity may be present
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Consanguinity


Mating of two related individuals
Dramatically increases the recurrence risk of
recessive disorders
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Sex-Linked Disorders


Disorders involve X and Y chromosomes
X-linked disorders usually expressed by males
because females have another X chromosome to
mask the abnormal allele


Most are recessive
Y-linked disorders uncommon because Y
chromosome contains relatively few genes


Father-son transmission present
No father-daughter transmission
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X-Linked Recessive Disorders

Characteristics

Males most commonly affected
• Affected males cannot transmit the genes to sons, but
they can to all daughters

Unaffected carrier females
• Sons of female carriers have a 50% risk of being
affected

Pedigree analysis
• Generational skipping often present
• No father-to-son transmission
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X-Linked Recessive Disorders
A.
B.
C.
Outcomes for offspring of an
unaffected father and a
heterozygous unaffected carrier
mother (most common scenario)
Outcomes for offspring of an
affected father and a homozygous
unaffected mother
Outcomes for offspring of an
affected father and a heterozygous
unaffected carrier mother
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X-Linked Recessive Disorders

Hemophilia

Bleeding disorders resulting from a congenital
deficiency of coagulation factors
• Hemophilia A: factor VIII deficiency

20.6/100,000 male births in U.S.
• Hemophilia B: factor IX deficiency


5.3/100,000 male births in U.S.
Mutations associated with factor VIII deficiency:
• Large deletions or insertions, frameshift and splice
junction changes, and nonsense and missense
mutations
• Mutations vary across families but tend to be similar
within families
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Multifactorial Inheritance

Characteristics of multifactorial disorders

Result from hereditary and environmental
factors
 Hereditary component is polygenic
• Individual involved genes follow mendelian principles
• Many genes act together to influence the expressed
trait
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Multifactorial Inheritance

Concordance and discordance

Concordance
• Expression of the disease in two related family
members

Discordance
• Expression of the disease in one family member but
not a second
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Multifactorial Inheritance

Twin studies and concordance

Genetic conditions
• Monozygotic (MZ) twins: 100% concordance
• Dizygotic (DZ) twins: less than 100% and similar to
that among other siblings


Environmental conditions
• Equal concordance rates among MZ and DZ twins
Multifactorial conditions
• MZ twins with greater concordance than DZ twins, but
rates are not 100%

Adoption studies

Gene-environment-lifestyle interaction
Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.
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