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Chapter 4 and 5Chapter 4 and 5Genes and Genetic Diseases
Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.
Genes and Genetic DiseasesGenes and Genetic Diseases
Chapter 4
Mosby items and derived items © 2010, 2006 by Mosby, Inc, an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc, an affiliate of Elsevier Inc.
ObjectivesObjectives
1. 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 x-linked recessive inheritance modes.
4. Describe sex-limited and sex-linked traits and give an example of each.
5. Discuss the concept of mutifactorial inheritance.
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Identify the different Identify the different mechanisms of mutation: mechanisms of mutation: DefinitionsDefinitions 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 OrganizationDNA Organization
Chromosome◦ Temporary but consistent state of DNA◦ Composed of two longitudinal sister
chromatids
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ChromosomesChromosomesGametes: 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
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ChromosomesChromosomesAutosomes
◦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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MutationMutation
Any inherited alteration of genetic material◦ Mutations in somatic cells are not
transmitted to offspring◦ Mutations in gametes are transmitted to
offspring
Consequences of MutationsConsequences of Mutations
Gain of function ◦Associated with dominant disorders
Loss of function◦Associated with recessive disorders
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2. Identify the major 2. Identify the major Chromosomal abnormalities Chromosomal abnormalities and give examples of each.and give examples of each.
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Chromosome AbnormalitiesChromosome AbnormalitiesEuploid cells: eu= “normal”
◦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 AbnormalitiesChromosome 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.
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Chromosome AbnormalitiesChromosome 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 DisordersChromosomal 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 AneuploidyAutosomal 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
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Other Autosomal Other Autosomal AneuploidiesAneuploidies
Trisomy 13 and 18◦ More severe clinical manifestations than
trisomy 21◦ Death in early infancy is common
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Sex Chromosome AneuploidySex 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 AneuploidySex Chromosome AneuploidyTurner 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
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Sex Chromosome AneuploidySex Chromosome AneuploidyKlinefelter 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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Alterations in Chromosome Alterations in Chromosome StructureStructure
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 Alterations in Chromosome StructureStructure
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 Alterations in Chromosome StructureStructure
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
Alterations in Chromosome Alterations in Chromosome StructureStructure
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 Alterations in Chromosome StructureStructure
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
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GenesGenes 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
Elements of GeneticsElements of Genetics
Genotype◦Gene composition
Phenotype◦Outward appearance
Dominant◦Observable effects
Recessive◦Hidden effects
Carrier◦Has diseased gene but phenotypically normal
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GenesGenes 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
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GeneticsGenetics
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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GeneticsGenetics
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 organismExample
◦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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GeneticsGenetics
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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Single-Gene DisordersSingle-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
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Autosomal Dominant Autosomal Dominant DisordersDisorders
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
Autosomal DominantAutosomal Dominant
Males=FemalesNo skipped
generationsTransmit to ½ of
offspring
Recurrence risk is the probability of disease in subsequent offspring.
May have delayed age of onset.◦Huntington’s Chorea
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Autosomal Recessive DisordersAutosomal Recessive Disorders
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 Dramatically increases the recurrence risk of recessive
disorders39
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Sex-Linked DisordersSex-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 X-Linked Recessive DisordersDisorders Hemophilia
◦ Bleeding disorders resulting from a congenital deficiency of coagulation factors
◦ Mutations associated with factor VIII deficiency
Duchenne Muscular Dystrophy◦ Progressive proximal muscle weakness
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Multifactorial InheritanceMultifactorial Inheritance
Environmental influenced traits◦Polygenic traits◦Several genes acting together
Examples◦Height◦IQ
Genes, Environment, and Genes, Environment, and Common DiseasesCommon Diseases
Chapter 5
Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.
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Disease in PopulationsDisease in PopulationsIncidence 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 timeRelative 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
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Multifactorial InheritanceMultifactorial 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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Recurrence RisksRecurrence RisksRecurrence 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 sexRecurrence risk for the disease usually
decreases rapidly in remotely related relatives
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Nature and NurtureNature and NurtureNature
◦ GeneticsNurture
◦ Environment-lifestyle
Twin studies used to study nature vs nurture◦ 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
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Nature and NurtureNature 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
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Genetics of Common Genetics of Common DiseasesDiseases
Congenital malformations◦Congenital diseases are present at birth or
shortly after birth◦Most congenital diseases are multifactorial
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Adult Multifactorial DiseasesAdult 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
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HypertensionHypertension
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
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Breast CancerBreast 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
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Colorectal CancerColorectal 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
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DiabetesDiabetes
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)
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Type 1 DiabetesType 1 Diabetes
Autoimmune destruction of insulin-producing beta cells in the pancreas◦T cell activation and autoantibody production
Onset before 40 years of ageHigher incidence with offspring of
diabetic fathers
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Type 2 DiabetesType 2 Diabetes
80% to 90% of all diabetes casesNeither HLA nor autoantibodies commonly
seen in type 2Person has insulin resistance or
diminished insulin productionRisk factors
◦High carbohydrate diet and obesity
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ObesityObesity
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
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Alzheimer DiseaseAlzheimer Disease
Progressive dementia and loss of memoryFormation of amyloid plaques and
neurofibrillary tangles in the brainRisk of developing AD doubles in
individuals who have an affected first-degree relative
Mutations in any of three genes that affect amyloid-beta deposition
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AlcoholismAlcoholism
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
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Psychiatric DisordersPsychiatric Disorders
Schizophrenia◦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
Bipolar affective disorder◦Genetics◦Minimal environmental influence
The EndThe End
Do you have Turning Do you have Turning Technology turned on?Technology turned on?
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Klinefelter’s syndrome is an Klinefelter’s syndrome is an example of a(n)example of a(n)
Autosomal recessive disorder
Autosomal dominant disorder
Chromosomal disorder
Multifactorial inheritance disorder
621 2 3 4
25% 25%25%25%
Answer NowAnswer Now
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Type 2 diabetes is: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.
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1 2 3 4
25% 25%25%25%
Answer NowAnswer Now
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The relative risk indicates The relative risk indicates the:the:Number of new cases of a disease
in a specific time period. 2. Proportion of a population with a
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. 64
1 2 3 4
25% 25%25%25%
Answer NowAnswer Now
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Down Syndrome is/are:Down Syndrome is/are: Mutations on three
chromosomes Translocation of one copy of
chromosome 21 Nondisjunction of one copy
of chromosome 21 Three copies of
chromosome 2165
1 2 3 4
25% 25%25%25%
Answer NowAnswer Now
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