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Chapter 4 and 5
Genes and Genetic Diseases
Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.
Chapter 4
Genes and Genetic Diseases
Mosby items and derived items © 2010, 2006 by Mosby, Inc, an affiliate of Elsevier Inc.
Identify the different mechanisms of
mutation.
2. Identify the major Chromosomal
abnormalities and give examples of
each.
3. Differentiate between autosomal
dominant, autosomal recessive, and xlinked recessive inheritance modes.
4. Describe sex-limited and sex-linked
traits and give an example of each.
5. Discuss the concept of mutifactorial
Objectives
inheritance.
1.
3
Identify the different
mechanisms of mutation:
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
4
DNA Organization

Chromosome
◦ Temporary but consistent state of DNA
◦ Composed of two longitudinal sister
chromatids
5
Chromosomes

Gametes: sperm and egg
◦ Contain 23 chromosomes
◦ Haploid cells
 One member of each chromosome pair

Somatic cells: all other cells
◦ Contain 46 chromosomes (23 pairs)
◦ Diploid cells: one from father and one from
mother to each chromosome pair
6
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)
7
Karyotype

Ordered display of chromosomes
8
Mutation
 Any
inherited alteration of
genetic material
◦ Mutations in somatic cells are not
transmitted to offspring
◦ Mutations in gametes are transmitted to
offspring
9
Mutagen

Agent known to increase the frequency of
mutations
◦ Radiation
◦ Chemicals
10
 Gain
of
function
◦Associated
with
dominant
disorders
 Loss
of
function
◦Associated
with
recessive
disorders
Consequences of Mutations
11
2. Identify the major
Chromosomal abnormalities
and give examples of each.
12
Chromosome Abnormalities

Euploid cells: eu= “normal”

When a euploid cell has more than the
diploid number, it is called a polyploid
cell
◦ Cells that have a multiple of the normal
number of chromosomes
◦ Haploid and diploid cells are euploid forms
◦ Triploidy: a zygote having three copies of
each chromosome (69)
◦ Tetraploidy: four copies of each (92 total)

Triploid and tetraploid fetuses don’t
survive
13
Chromosome Abnormalities

Disjunction
◦ Normal separation of chromosomes during cell
division

Nondisjunction
◦ Usually the cause of aneuploidy
 Aneuploidy-does not contain 23 chromosomes
◦ Trisomy- 3 copies of one chromosome
◦ Monosomy-one copy of chromosome
 Loss of genetic material has >consequence than duplication of
material.
14
Nondisjunction
15
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”
16
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
17
Autosomal Aneuploidy

Down syndrome
◦ Best-known example of aneuploidy
 Trisomy 21
◦ 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
18
Down Syndrome
19
Other Autosomal
Aneuploidies

Trisomy 13 and 18
◦ More severe clinical manifestations than
trisomy 21
◦ Death in early infancy is common
20
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
21
Sex Chromosome Aneuploidy

Turner syndrome
◦ Females with only one X
chromosome
◦ Characteristics
 Absence of ovaries (sterile),
Underdeveloped breasts; wide nipples
 Short stature (~ 4'7")
 Webbing of the neck
 X is usually inherited from mother
22
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.
23
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
24
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
25
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
26


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
Alterations in Chromosome
Structure
27
Alterations in Chromosome
Structure

Fragile X syndrome
◦ Site on the long arm of the X chromosome
◦ 2nd in occurrence to Down syndrome
◦ Males > Females because they have only one
X chromosome
◦ Clinical Manifestations:
 Mental retardation
 Long face, large mandible, mitral valve
prolapse, hyperextendable joints, high arched
palate, macro-orchidism
28
Genetics

Gregor Mendel
◦ Austrian monk
◦ Garden pea experiments
◦ Mendelian traits
29
Genes



Basic units of heredity
Sequences of chromosomal DNA
coding for the production of a
functional product
All genes are contained in each cell of
the body
30


Genotype
◦ Gene composition
Phenotype
◦ Outward appearance

Dominant

Recessive

Carrier
◦ Observable effects
◦ Hidden effects
◦ Has diseased gene but phenotypically normal
Elements of Genetics
31
Genes

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
32
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)
33
Genetics

Genotype (“what they have”)
◦ The genetic makeup of an organism

Phenotype (“what they demonstrate”)
◦ 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.
34
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
35
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: 50:50
 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
36
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
37



Males=Females
No skipped
generations
Transmit to ½ of
offspring


Recurrence risk is
the probability of
disease in
subsequent
offspring.
May have delayed
age of onset.
◦ Huntington’s Chorea
Autosomal Dominant
38

Characteristics
◦ Condition expressed males = 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
◦ Generational skipping may occur
◦ Consanguinity may be present
 Mating of two related individuals
Autosomal
Recessive
Disorders
 Dramatically increases the recurrence risk of recessive
disorders
39
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
40
X-Linked Recessive
Disorders
Hemophilia

◦ Bleeding disorders resulting from a
congenital deficiency of coagulation
factors
◦ Mutations associated with factor VIII
deficiency

Duchenne Muscular Dystrophy
◦ Progressive proximal muscle weakness
41
Multifactorial Inheritance
 Environmental influenced
◦ Polygenic traits
◦ Several genes acting together
traits
 Examples
◦ Height
◦ IQ
42
Chapter 5
Genes, Environment, and
Common Diseases
Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.
Disease in Populations

Incidence rate
◦ Number of new cases of a disease reported during a
specific period (typically 1 year) divided by the
number of individuals in the population

Prevalence rate
◦ Proportion of the population affected by a disease at a
specific point in time

Relative risk
◦ Incidence rate of a disease among individuals
exposed to a risk factor divided by the incidence rate
of a disease among individuals not exposed to a risk
factor
44
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
45
Recurrence Risks
Recurrence risks vary due to
environment and lifestyle factors
among populations.
 Recurrence risk is higher if:

◦ more than one family member is affected
◦ the expression of the disease is more
severe, recurrence risk is higher
◦ the less commonly affected sex

Recurrence risk for the disease usually
decreases rapidly in remotely related
relatives
46
Nature and Nurture

Nature

Nurture

Twin studies used to study nature vs nurture
◦ Genetics
◦ Environment-lifestyle
◦ Monozygotic (identical)
◦ Dizygotic (fraternal)
◦ Concordant trait
 Both members of a twin pair share a trait
◦ Discordant trait
 A twin pair does not share a trait
47
Nature and Nurture

Adoption studies
◦ Children born to parents who have a disease
but are then subsequently adopted by
parents lacking the disease are studied for
the recurrence of the disease
48
Genetics of Common
Diseases

Congenital malformations
◦ Congenital diseases are present at birth or
shortly after birth
◦ Most congenital diseases are multifactorial
49
Adult Multifactorial Diseases

Coronary heart disease
◦ Potential mycocardial infarction caused by
atherosclerosis
◦ Risk increases if:
 There are more affected relatives
 Affected relatives are female rather than male
 Age of onset is younger than 55 years
◦ Autosomal dominant familial
hypercholesterolemia, high-fat diet, lack of
exercise, smoking, and obesity
50
Hypertension
Risk factor for heart disease, stroke, and
kidney disease
 20% to 40% of blood pressure variations
are genetic; this means that 60% to
80% are environmental
 Causes of hypertension

◦ Sodium intake, lack of exercise, stress, obesity,
smoking, and high-fat intake
51
Breast Cancer
Affects 12% of American women who
live to 85
 If a woman has a first-degree relative
with breast cancer, her risk doubles
 Recurrence risk increases if age of onset
in the affected relative is early and if the
cancer is bilateral

52
Colorectal Cancer

1 in 20 Americans will develop colorectal
cancer
◦ Second only to lung cancer

Risk factors
◦ Genetics
◦ High-fat and low-fiber diet are contributors
53
Diabetes
Leading cause of blindness, heart
disease, and kidney failure
 Two major types

◦ Type 1 (insulin-dependent diabetes mellitus)
◦ Type 2 (non–insulin-dependent diabetes
mellitus)
54
Type 1 Diabetes

Autoimmune destruction of insulinproducing beta cells in the pancreas
◦ T cell activation and autoantibody production
Onset before 40 years of age
 Higher incidence with offspring of
diabetic fathers

55
Type 2 Diabetes
80% to 90% of all diabetes cases
Neither HLA nor autoantibodies commonly
seen in type 2
 Person has insulin resistance or
diminished insulin production
 Risk factors


◦ High carbohydrate diet and obesity
56
Obesity

Body mass index >30
◦ BMI = W/H2 (weight in kg and height in meters)


Obesity is a substantial risk factor for heart
disease, stroke, and type 2 diabetes
Adoptive studies
◦ Body weights of adopted individuals correlated
significantly with their natural parents’ body
weights

Twin studies
◦ Higher concordance in MZ twins than DZ twins
57
Alzheimer Disease
Progressive dementia and loss of memory
Formation of amyloid plaques and
neurofibrillary tangles in the brain
 Risk of developing AD doubles in
individuals who have an affected firstdegree relative
 Mutations in any of three genes that
affect amyloid-beta deposition


58
Alcoholism
Risk is 3 to 5 times higher in individuals
with an alcoholic parent
 Adoption studies

◦ Offspring of nonalcoholic parents, when reared
by alcoholic parents, did not have an increased
risk
59
Psychiatric Disorders

Schizophrenia

Bipolar affective disorder
◦ Severe emotional disorder characterized by
delusions, hallucinations, and bizarre, withdrawn, or
inappropriate behavior
◦ Recurrence risk among the offspring of one affected
parent is 10 times higher than the general
population
◦ Twin and adoption studies indicate that genetic
factors are likely to be involved
◦ Genetics
◦ Minimal environmental influence
60
The End
Do you have Turning
Technology turned on?
61
Klinefelter’s syndrome is an
example of a(n)




Autosomal recessive25%
disorder
Autosomal dominant
disorder
Chromosomal
disorder
Multifactorial
inheritance disorder
1
Answer Now
25%
25%
25%
20
62
2
3
4
Type 2 diabetes is:




Highly correlated with
reduced BMI.
Caused by an absence of
insulin production.
Usually more prevalent in
individuals less than 40
years of age.
Often treated with lifestyle
modification including diet
and exercise.
Answer Now
25%
1
25%
25%
2
3
25%
4
20
63
The relative risk indicates
the:
Number of new cases of a disease
in a specific time period.
2. Proportion of a population with a
25%
25%
25%
disease at one time point.
3. Chance of developing a disease
relative to an exposure.
4. Ability of a causative factor to
produce a disease.

Answer Now
25%
20
64
1
2
3
4
Down Syndrome is/are:




Mutations on three
chromosomes
Translocation of one copy25%of25%
chromosome 21
Nondisjunction of one copy
of chromosome 21
Three copies of
chromosome 21
Answer Now
25%
25%
20
65
1
2
3
4
The following diet contributes to
the risk for Colorectal Cancer:




Low-fat and low
fiber
Low-fat and
high fiber
High-fat and
low fiber
High-fat and
high fiber
25%
1
Answer Now
25%
25%
25%
20
2
3
4
66