Chapter 4 and 5Chapter 4 and 5Genes and Genetic Diseases

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Genes and Genetic DiseasesGenes and Genetic Diseases

Chapter 4

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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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KaryotypeKaryotypeOrdered display of chromosomes

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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

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MutagenMutagenAgent known to increase the frequency of

mutations◦Radiation◦Chemicals

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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NondisjunctionNondisjunction

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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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Down SyndromeDown Syndrome

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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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GeneticsGeneticsGregor Mendel

◦Austrian monk◦Garden pea experiments◦Mendelian traits

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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.

44

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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The following diet contributes to The following diet contributes to the risk for Colorectal Cancer: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

661 2 3 4

25% 25%25%25%

Answer NowAnswer Now

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