Power point: genes and genetic diseases , and genes,

These are two examples of the topics to be discussed, we need one that covers everything in summary.

Chapter 4

Genes and Genetic Diseases

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Deoxyribonucleic Acid (DNA)

Chromosomes contain genes.

Genes are the basic unit of inheritance and are composed of DNA.

DNA subunit or nucleotide contains

one pentose sugar (deoxyribose).

one phosphate group.

one nitrogenous base.

Cytosine (C), thymine (T), adenine (A), guanine (G)

DNA has a double helix structure.

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DNA (Cont.)

DNA structure

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DNA as the Genetic Code

DNA provides the code for all body proteins.

Proteins are composed of one or more polypeptides.

Polypeptides are composed of amino acids; there are twenty (20) amino acids:

The sequence of three bases (codons) direct the production of amino acids.

Termination and nonsense codons stop the production of protein.

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Replication

The DNA strand is untwisted and unzipped.

Single strand acts as a template.

DNA polymerase pairs the complementary bases.

Adenine-thymine; cytosine-guanine

DNA polymerase adds new nucleotides and “proofs” the new protein; if not correct, the incorrect nucleotide is excised and replaced.

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Replication (Cont.)

Replication process

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Replication
Question 1

Which information is correct regarding DNA polymerase?

DNA polymerase functions to

signal the end of a gene.

pull apart a portion of a DNA strand.

add the correct nucleotides to a DNA strand.

provide a template for the sequence of mRNA nucleotides.

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ANS: 3

This enzyme functions to add correct nucleotides to the DNA strand, to edit incorrect nucleotides, and enhance the accuracy of DNA replication.

1. Termination or nonsense codons signal the end of a gene.

2. RNA polymerase binds to a promoter site on DNA and pulls apart a portion of the DNA strand.

4. One of the DNA strands exposed by the action of RNA polymerase provides a template for the sequence of mRNA nucleotides.

Mutation

Is any inherited alteration of genetic material.

Chromosome aberrations in number or structure

Base pair substitution or missense mutation

One base pair is substituted for another; may result in changes in amino acid sequence.

May or may not cause disease or problems.

Frameshift mutation

Involves the insertion or deletion of one or more base pairs to the DNA molecule.

Mutagens: Are agents, such as radiation and chemicals, that increase the frequency of mutations.

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From Genes to Proteins

DNA is formed in the nucleus; protein is formed in the cytoplasm.

Transcription and translation: DNA code is transported from the nucleus to the cytoplasm, and protein is subsequently formed.

Ribonucleic acid (RNA) mediates both processes.

RNA is a single strand.

Uracil rather than thymine is one of the four bases; all the rest are the same as DNA.

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Transcription

RNA is synthesized from the DNA template via RNA polymerase.

RNA polymerase binds to the promoter site on DNA.

DNA specifies a sequence of mRNA.

Transcription continues until the termination sequence is reached.

mRNA then moves out of the nucleus and into the cytoplasm.

Gene splicing occurs.

Introns and exons

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Transcription (Cont.)

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Translation

Is the process by which RNA directs the synthesis of a polypeptide via the interaction with transfer RNA (tRNA).

tRNA contains a sequence of nucleotides (anticodon) complementary to the triad of nucleotides on the mRNA strand (codon).

Ribosome is the site of protein synthesis.

Ribosome helps mRNA and tRNA make polypeptides.

When ribosome arrives at a termination signal on the mRNA sequence, translation and polypeptide formation cease.

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Translation
Question 2

At what site does protein synthesis occur?

The site of protein synthesis is the

codon.

intron.

ribosome.

anticodon.

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ANS: 3

The ribosome is the site of actual protein synthesis.

1. The codon is a set of three adjacent nucleotides or a triplet that constitutes the genetic code for a particular amino acid that is to be added to a polypeptide chain in the synthesis of a protein.

2. The intron is an RNA sequence that has been removed by enzymatic action prior to translation.

4. The anticodon is a set of three adjacent nucleotides that undergo base pairing with the appropriate codon in the mRNA.

Chromosomes

Somatic cells

Contain 46 chromosomes (23 pairs).

One member from the mother; one from the father

Diploid cells

Gametes

Sperm and egg cells

Contain 23 chromosomes.

Haploid cells

One member of each chromosome pair

Meiosis

Formation of haploid cells from diploid cells

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Chromosomes (Cont.)

Autosomes

Are the first 22 of the 23 pairs of chromosomes in males and females.

The two members are virtually identical and are thus said to be homologous.

Sex chromosomes

Make up the remaining pair of chromosomes.

In females, it is a homologous pair (XX).

In males, it is a nonhomologous pair (XY).

Karyotype

The length and centromere location determine the ordered display of chromosomes.

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Chromosomal Aberrations

Euploid cells

Have a multiple of the normal number of chromosomes.

Haploid and diploid cells are euploid forms.

Polyploid cells: An euploid cell has more than the diploid number.

Triploidy: Is a zygote that has three copies of each chromosome.

Tetraploidy: Has four copies of each chromosome
(92 total).

Triploid and tetraploid fetuses do not survive
or are stillborn or spontaneously aborted.

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Chromosomal Aberrations (Cont.)

Aneuploidy

Is a somatic cell that does not contain a multiple
of 23 chromosomes.

Trisomy (trisomic): Is a cell that contains three copies of one chromosome.

Infants can survive with trisomy of certain chromosomes.

Monosomy

Is the presence of only one copy of any chromosome.

Is often fatal.

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Chromosomal Aberrations (Cont.)

Aneuploidy of sex chromosomes

Usually presents less serious consequences than autosomes.

Y chromosome usually causes no problems since it contains little genetic material.

For the X chromosome, inactivation of extra chromosomes largely diminishes their effect.

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Chromosomal Aberrations (Cont.)

Nondisjunction

Is usually the cause of aneuploidy.

Is the failure of homologous chromosomes or sister chromatids to separate normally during meiosis or mitosis.

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Chromosomal Aberrations (Cont.)

Nondisjunction (cont.)

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Autosomal Aneuploidy

Trisomy

Chromosomes 13, 18, and 21 can survive; most others do not.

Partial trisomy

Only an extra portion of a chromosome is present in each cell.

Is not as severe as trisomies.

Chromosomal mosaics

Are trisomies that occur in only some cells of the body.

Body has two or more different cell lines, each of which has a different karyotype.

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Autosomal Aneuploidy (Cont.)

Down syndrome

Is the best-known example of aneuploidy.

Trisomy 21

Occurs 1 in 800 live births.

Manifestations: Mental challenges; low nasal bridge; epicanthal folds; protruding tongue; flat, low-set ears; short stature; and poor muscle tone.

Risk increases with maternal age.

Has an increased risk of congenital heart disease, respiratory infections, and leukemia.

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Autosomal Aneuploidy (Cont.)

Down syndrome (cont.)

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Sex Chromosome Aneuploidy

Occurs 1 in 400 males and 1 in 650 females.

Trisomy X is one of the most common aneuploidy.

Females have three X chromosomes.

Occurs 1 in 1000 female births.

Symptoms are variable and include sterility, menstrual irregularity, and/or cognitive deficits.

Symptoms worsen with each additional X chromosome.

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Sex Chromosome Aneuploidy (Cont.)

Turner syndrome

Females have only one X chromosome.

Denoted as karyotype 45,X.

Characteristics include

absence of ovaries (sterile).

short stature.

webbing of the neck.

widely spaced nipples.

high number of aborted fetuses.

X chromosome that is usually inherited from the mother.

Occurs 1 in 2500 female births.

Teenagers receive estrogen.

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Sex Chromosome Aneuploidy (Cont.)

Turner syndrome (cont.)

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Sex Chromosome Aneuploidy (Cont.)

Klinefelter syndrome

Individuals with at least one Y and two X chromosomes.

Characteristics include:

male appearance.

femalelike breasts (gynecomastia).

small testes.

sparse body hair.

1 in 1000 male births.

Some individuals can be XXXY and XXXXY; will have male appearance; abnormalities will increase with each X; can also have an extra Y chromosome.

Disorder increases with the mother’s age.

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Sex Chromosome Aneuploidy (Cont.)

Klinefelter syndrome (cont.)

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Sex Chromosome Aneuploidy Question 3

A female has one X chromosome. Which diagnosis will the nurse observe documented on the chart?

Trisomy X syndrome

Klinefelter syndrome

Fragile X syndrome

Turner syndrome

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ANS: 4

Another sex chromosome aneuploidy is the presence of a single X chromosome and no homologous X or Y chromosome, resulting in a total of 45 chromosomes. The karyotype is designated 45,X, and it causes a set of symptoms known as Turner syndrome.

1. Instead of two X chromosomes, these females have three X chromosomes in each cell.

2. Individuals with at least two X chromosomes and a Y chromosome in each cell (47,XXY karyotype) have a disorder known as Klinefelter syndrome.

3. Fragile X syndrome is usually caused by an elevated number (more than about 200) of repeated DNA sequences in the first exon of the fragile X gene.

Abnormalities of Chromosomal Structure

Effects may or may not have serious consequences.

Chromosome breakage

If a chromosome break occurs, then the break is usually repaired with no damage.

Breaks can stay or can heal in a way that alters the structure of the chromosome.

Can occur spontaneously.

Agents of chromosome breakage include Ionizing radiation, chemicals, and viruses.

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Abnormalities of Chromosomal
Structure (Cont.)

Deletions

Chromosome breakage or loss of DNA

Example: Cri du chat syndrome or “cry of the cat”

Low birth weight, mentally challenged, and microcephaly

Duplications

Excess genetic material

Usually have less serious consequences.

Inversion

Chromosomal rearrangement in which a chromosome segment is inverted: ABCDEFG becomes ABEDCFG.

Usually affects offspring.

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Abnormalities of Chromosomal Structure (Cont.)

Infant with cri
du chat (5p deletion) syndrome

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Abnormalities of Chromosomal Structure (Cont.)

Translocation

Is the interchange of genetic material between nonhomologous chromosomes.

Types of translocation

Robertsonian: Long arms of two nonhomologous chromosomes fuse at the centromere, forming a single chromosome; is common in Down syndrome.

Reciprocal: Breaks take place in two different chromosomes, and the material is exchanged.

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Abnormalities of Chromosomal Structure (Cont.)

Chromosomal mutations

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Abnormalities of Chromosomal Structure (Cont.)

Fragile sites

Chromosomes develop breaks and gaps when the cells are cultured in a folate-deficient medium.

Most have no apparent relationship to disease.

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Abnormalities of Chromosomal Structure (Cont.)

Fragile sites (cont.)

Fragile X syndrome

Site is on the long arm of the X chromosome; has an elevated number of repeated DNA sequences.

Is associated with being mentally challenged; is second in occurrence to Down syndrome.

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Elements of Formal Genetics

Genetic inheritance

Mechanisms by which an individual’s set of paired chromosomes produces traits.

Explains the patterns of inheritance for traits and diseases that appear in families.

Mendelian traits

Are inherited traits primarily attributed to single genes.

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Elements of Formal Genetics (Cont.)

Locus: Is the location occupied by a gene on a chromosome.

Allele: Is one of several different forms of a gene at a locus.

One member of a gene from the mother; one member of a gene from the father

Homozygous: When genes are identical

Heterozygous: When genes are different

Polymorphism or polymorphic

Is a locus that has two or more alleles that occur with appreciable frequency.

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Elements of Formal Genetics (Cont.)

Genotype: Is the composition of genes at a given locus.

Phenotype

Is the outward appearance of an individual.

Results from genotype and the environment.

Example: Infant with phenylketonuria (PKU) has the PKU genotype.

If left untreated, the infant will have cognitive impairments, which is the PKU phenotype.

If treated, the infant will still have the PKU genotype but can have a normal phenotype.

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Elements of Formal Genetics (Cont.)

Dominance and recessiveness

If two alleles are found together, then the allele that is observable is dominant and the one whose effects are hidden is recessive.

In genetics, the dominant allele = a capital letter, and the recessive allele = a lowercase letter.

Alleles are either heterozygote or homozygote.

Alleles can be codominant; that is, both alleles are expressed.

Carrier

Has a disease allele but is phenotypically normal.

Can pass disease to offspring.

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Transmission of Genetic
Diseases

Mode of inheritance: Is the inherited pattern through the generations of a family.

Mendel’s two laws

Principle of segregation

Homologous genes separate from one another.

Each cell carries only one of the homologous genes.

Principle of independent assortment

Hereditary transmission of one gene has no effect on the transmission of another.

Chromosome theory of inheritance

Chromosomes follow Mendel’s two laws.

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Transmission of Genetic
Diseases (Cont.)

Four major types of genetic diseases

Autosomal dominant

Autosomal recessive

X-linked dominant

X-linked recessive

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Transmission of Genetic
Diseases (Cont.)

Pedigree

Is the tool used to study specific genetic disorders within families.

Begins with the proband.

Propositus (male) or proposita (female)

Usually the first person in the family diagnosed or seen in a clinic

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Transmission of Genetic
Diseases (Cont.)

Pedigree (cont.)

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Autosomal Dominant
Inheritance

Diseases are rare.

Occurs in fewer than 1 of 500 individuals.

The union of a normal parent with an affected heterozygous parent usually produces the affected offspring.

An affected parent can pass either a disease gene or a normal gene to his or her children; each event has a probability of 0.5; on average, half will be heterozygous and will express the disease and half will be normal.

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Autosomal Dominant
Inheritance (Cont.)

Characteristics of autosomal dominant inheritance

Condition is expressed equally in males and females, and males and females are equally likely to pass the gene to his or her offspring.

Approximately one-half of children of an affected heterozygous parent will express the condition (all or none of the children may have the condition).

No generational skipping occurs.

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Autosomal Dominant
Inheritance (Cont.)

Recurrence risk

Is the probability that a family member will have a genetic disease.

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.

Each birth is an independent event.

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Autosomal Dominant
Inheritance (Cont.)

Recurrence risk (cont.)

New mutation: Is when no history of an autosomal dominant condition is present, but the child develops the mutation.

Parent’s subsequent offspring is not greater than that of the general population.

Offspring of the affected child will have a recurrence risk of one half.

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Autosomal Dominant
Inheritance (Cont.)

Recurrence risk (cont.)

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Autosomal Dominant
Inheritance (Cont.)

Germline mosaicism

Two or more offspring have an autosomal dominant disease when the family has no history of the disease.

Parent carries the mutation in his or her germline but does not actually express the autosomal dominant disease but transmits it to his or her offspring.

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Autosomal Dominant
Inheritance (Cont.)

Pedigree

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Penetrance

Is 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

Example: Retinoblastoma (eye tumor in children) (90%)

Age-dependent penetrance

Does not express a disease until a certain age is reached.

Example: Huntington disease

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Expressivity

Is a variation in a phenotype associated with a particular genotype.

Can be caused by modifier genes, environmental factors, and mutations.

Example: von Recklinghausen disease

Is autosomal dominant.

Expressivity varies from brown spots on the skin to malignant tumors, scoliosis, gliomas, and neuromas.

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Expressivity (Cont.)

Examples

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Autosomal Recessive
Inheritance

Is rare, but many individuals are carriers.

Abnormal allele is recessive, and the person must be homozygous to express the disease.

Trait usually appears in the children, not in the parents.

Example: Cystic fibrosis

Gene forms chloride channels with defective transport, which leads to a salt imbalance that results in abnormally thick, dehydrated mucus. The lungs and pancreas are affected; the person does not survive past 40 years of age.

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Autosomal Recessive
Inheritance (Cont.)

Characteristics

Condition is expressed equally in males and females.

Is observed in siblings but not in parents.

Approximately one-quarter of offspring will be affected.

Consanguinity may be present.

Marriage between related individuals

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Autosomal Recessive
Inheritance (Cont.)

Recurrence risk

When both parents are heterozygous carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25%; one-quarter of the offspring are normal, and one-half are carriers.

Carrier detection tests are available.

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Autosomal Recessive
Inheritance (Cont.)

Recurrence risk (cont.)

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Consanguinity

Is known as inbreeding.

Is the mating of two related individuals.

Offspring are termed inbred.

Proportion of shared genes depends on the closeness of the biologic relationship.

Dramatically increases the recurrence risk of recessive disorders.

Offspring of marriages of first cousins who are affected by genetic diseases is approximately double that of the general population.

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X-Linked Inheritance

Is a disorder that involves X and Y chromosomes.

Y-linked disorders are uncommon because the Y chromosome contains relatively few genes.

Females: Have two X chromosomes; can be homozygous for the disease, homozygous for normal, or heterozygous.

Males: Have one X chromosome; are always hemizygous; if inherits an X recessive gene, then he will express the disease because no normal allele is present to counteract the diseased allele; males are affected more often with X recessive conditions.

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X-Linked Inheritance (Cont.)

X-inactivation

Is a process by which one X chromosome in the somatic cells of females is permanently inactivated.

Barr bodies: Inactivated X chromosome

Females have 1 inactive X chromosome.

Males have no inactive X chromosomes.

Is always one less than the number of X chromosomes in the cell.

Occurs early in embryonic development.

Can have incomplete inactivation.

X-inactive specific transcript (XIST) gene which causes X-inactivation uses methylation.

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X-Linked Inheritance (Cont.)

Sex determination

Begins during the sixth week of gestation.

One copy of the Y chromosome is sufficient to initiate the process of gonadal differentiation that produces a male fetus.

Number of X chromosomes does not alter this process.

Sex-determining region on the Y chromosome (SRY) gene begins male gonadal development.

Triggers other genes.

Can cross over to the X chromosome; is an apparently normal XX karyotype but with a male phenotype.

Can be deleted from the Y chromosome: XY female.

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X-Linked Inheritance (Cont.)

Characteristics of X-linked recessive inheritance

Occurs significantly more often in males than in females.

Females must inherit two copies of the recessive allele (one from each parent) to express the disease, whereas males need only one copy (from the mother) to express the disease.

Because a father can give a son only a Y chromosome, the trait is never transmitted from father to son.

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X-Linked Inheritance (Cont.)

Characteristics of X-linked recessive inheritance (cont.)

Gene can be transmitted through a series of female carriers, causing the appearance of a skipped generation.

Gene is passed from an affected father to all of his daughters, who, as phenotypically normal carriers, transmit it to approximately one-half of their sons, who are then affected.

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X-Linked Inheritance (Cont.)

Characteristics of X-linked recessive inheritance (cont.)

Example: Duchenne muscular dystrophy (DMD)

Occurs 1 in 3500 males.

Exhibits progressive muscular degeneration.

Deletion of DMD gene causes dystrophin not to work properly; consequently, muscle cells do not survive.

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X-Linked Inheritance (Cont.)

Recurrence risks for X-linked recessive inheritance

Outcomes for the offspring of an unaffected father and a heterozygous unaffected
carrier mother (most common scenario)

Outcomes for the offspring of an affected father and a homozygous unaffected mother

Outcomes for the offspring of an affected father and a heterozygous unaffected carrier mother

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X-Linked Inheritance (Cont.)

Sex-limited trait: Is a trait that can occur in only one of the sexes.

Sex-influenced trait: Is a trait that occurs significantly more often in one sex than in the other.

Evaluation of pedigrees

Is sometimes difficult to predict.

Uses computer programs and statistical techniques.

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X-Linked Inheritance
Question 4

Which information indicates that the nurse has a good understanding of X-linked recessive inheritance?

The gene is passed from an affected father to all of his daughters.

The trait is observed significantly more often in females than in males.

Males are said to be heterozygous for the X chromosome.

A sex-limited trait is one that occurs significantly more often in one sex than in the other.

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ANS: 1

The gene is passed from an affected father to all his daughters, who, as phenotypically normal carriers, transmit it to approximately half their sons, who are affected.

2. The trait is seen much more often in males than in females because females must inherit two copies of the recessive allele (one from each parent) to express the disease, while males need only inherit one copy (from their mother) to express the disease.

3. Males, having only one X chromosome, are said to be hemizygous for genes on this chromosome.

4. A sex-influenced trait is one that occurs much more often in one sex than in the other. A sex-limited trait is one that can occur in only one of the sexes.

Linkage Analysis and Gene Identification

Loci that are linked do not follow the principle of independent assortment.

Crossing over can create new alleles.

Recombination is the formation of new alleles.

Map units and pedigrees can help identify recombination rates.

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Linkage Analysis and Gene
Identification (Cont.)

Genetic testing and computer programs can help with analysis and identification and can

confirm the diagnosis of a genetic disease.

identify carriers of recessive diseases.

presymptomatically identify individuals who are at risk for inheriting a disease with delayed age of onset.

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Chapter 5

Genes, Environment–Lifestyle, and

Common Diseases

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Concepts of Incidence and Prevalence

Is the number of new cases of a disease reported during a specific period (typically 1 year) divided by the number of individuals in the population.

Incidence Rate

Prevalence Rate

Is the proportion of the population affected by a disease at a specific point in time.

Varies from population to population.

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Analysis of Risk Factors

Relative risk

Is the increased rate of a disease among individuals exposed to a risk factor divided by the incidence rate of the disease among individuals not exposed to a risk factor.

Many factors, including age, gender, diet, exercise, and family history of the disease, can influence the risk.

Complex interactions occur among genetic and nongenetic factors; each factor can be quantified in terms of relative risks.

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Analysis of Risk Factors
Question 1

Which information is correct regarding relative risk?

Relative risk indicates the

number of new cases of a disease in a specific time period.

proportion of a population with a disease at one time point.

chance of developing a disease relative to an exposure.

ability of a causative factor to produce a disease.

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ANS: 3

Relative risk is the ratio of the incidence a disease in those exposed to a risk factor to the incidence of the disease in those not exposed to the risk factor. This is a common indicator of the effects of specific risk factors.

1. The number of new cases of a disease in a specific time period is the incidence.

2. The proportion of a population with the disease at one time point is the prevalence.

4. Pathogenicity describes the ability of a particular disease agent to produce a disease.

Principles of Multifactorial
Inheritance

Polygenic traits

Effects of multiple genes cause the variations in traits.

Focus is on the genes—usually many (poly) genes.

Multifactorial traits

Environmental factors cause the variations in traits.

Quantitative traits

Are measured on a continuous numeric scale.

Follow a normal bell curve for distribution.

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Principles of Multifactorial
Inheritance (Cont.)

Threshold model

Liability distribution

Does not follow the bell-shaped distribution.

Appears to be either present or absent in individuals.

Does not follow the inheritance patterns expected of single-gene diseases.

Has a low end of getting the disease, compared with a high end of getting disease.

Threshold of liability

Below the threshold, an individual appears normal; above the threshold, the disease affects the person.

Examples: Pyloric stenosis, neural tube defects, cleft lip with or without cleft palate (CL/P), club foot, and some forms of congenital heart disease

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Principles of Multifactorial
Inheritance (Cont.)

Liability distribution shows the threshold for males and females.

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Recurrence Risks

Is hard to determine in multifactorial diseases.

Number of genes contributing to the disease is usually not known, precise allelic constitution of the parents is also not known, and the extent of environmental effects can vary substantially.

Empirical risks: Is based on direct observation of data; is specific for each multifactorial disease.

Recurrence risks of multifactorial diseases can substantially change because the gene frequencies, environment, and lifestyle factors can differ among populations.

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Recurrence Risks (Cont.)

Recurrence risk becomes higher if more than one family member is affected.

If the expression of the disease in the proband is more severe, then the recurrence risk is higher.

If the proband is of the less commonly affected sex, then the recurrence risk is higher.

Recurrence risk for the disease usually decreases rapidly in remotely related relatives.

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Recurrence Risks
Question 2

Recurrence risk in multifactorial diseases is

higher if more than one family member is affected.

lower if the disease is more severe in the proband.

higher if the proband is the more commonly affected sex.

rapidly increased when more distant relatives are affected.

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ANS: 1

First, the recurrence risk becomes higher if more than one family member is affected. For example, the sibling recurrence risk for a ventricular septal defect (VSD), a type of congenital heart defect) is 3% if one sibling has had a VSD but increases to approximately 10% if two siblings have had VSDs.

2. Second, if the expression of the disease in the proband is more severe, the recurrence risk is higher. This is again consistent with the liability model because a more severe expression indicates that the affected individual is at the extreme tail end of the liability distribution (see Figure 5-2). His or her relatives are thus at a higher risk for inheriting disease genes.

3. Third, the recurrence risk is higher if the proband is of the less commonly affected sex. This is because an affected individual of the less susceptible gender is usually at a more extreme position on the liability distribution.

4. Fourth, the recurrence risk for the disease usually decreases rapidly in more remotely related relatives (Table 5-2). Whereas the recurrence risk for single-gene diseases decreases by 50% with each degree of relationship (e.g., an autosomal dominant disease has a 50% recurrence risk for siblings, 25% for uncle–nephew relationships, 12.5% for first cousins), it decreases much more quickly for multifactorial diseases.

Nature and Nurture: Disentangling the
Effects of Genes and Environment

Nature

Genetics

Nurture

Environment

Attempting to determine the relative influence of the genetic and environmental factors is useful.

Two research strategies are often used to estimate the relative influence of genes and environment: twin studies and adoption studies.

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Nature and Nurture: Disentangling the Effects of Genes and Environment (Cont.)

Twin studies

Monozygotic (MZ) twins: Identical; natural clones

Dizygotic (DZ) twins: Fraternal

Twin studies usually consist of comparisons between MZ and DZ twins.

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 Nurture: Disentangling the
Effects of Genes and Environment (Cont.)

Adoption studies

Children born to parents who have a disease but are then subsequently adopted by parents lacking the disease are studied for disease recurrence.

A preliminary indication of the extent to which genetic factors may cause a multifactorial disease is provided.

Gene-environment interaction

A genetic predisposition may interact with an environmental factor to increase the risk for a disease to a much higher level than either factor would alone.

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Genetics of Common Diseases

Congenital malformations

Congenital diseases are present at birth.

Most congenital diseases are multifactorial.

Environmental factors can cause congenital malformations.

Having other disorders along with the congenital disease is common.

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Multifactorial Disorders in the
Adult Population

Coronary heart disease

Potential myocardial infarction caused by atherosclerosis in the arteries supplying blood to the heart

Potential cerebrovascular accident (stroke) caused by atherosclerosis in the arteries supplying blood
to the brain

Risk increases if

more affected relatives exist.

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 increase risk

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Multifactorial Disorders in the
Adult Population (Cont.)

Hypertension

Is a risk factor for heart disease, stroke, and kidney disease.

Between 20% and 40% of blood pressure variations are genetic, which means that environmental factors are important.

Important environmental factors include sodium intake, lack of exercise, stress, and obesity.

Blood pressure regulation is complex.

Research that focuses on individual components for gene involvement includes the renin-angiotensin system, nitric oxide, and kallikrein–kinin system.

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Multifactorial Disorders in the
Adult Population (Cont.)

Cancer

Is the second leading cause of death in the United States.

Many major cancers occur in families.

Environmental and lifestyle choices affect the risk for cancer.

Tobacco use accounts for one-third of all cancers.

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Multifactorial Disorders in the
Adult Population (Cont.)

Breast cancer

Affects 12% of American women who live to 85 years of age.

If a woman has a first-degree relative with breast cancer, then her risk doubles.

Recurrence risk increases if the age of onset in the affected relative is early and if the cancer is bilateral.

An autosomal dominant form (5% to 10%) has been linked to chromosomes 13 (BRCA2) and 17 (BRCA1).

This form causes a 50% to 80% lifetime risk of developing breast cancer and increases the risk for ovarian cancer.

Other genes are implicated.

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Multifactorial Disorders in the Adult Population
Question 3

Which statement made by the nurse indicates an accurate understanding of breast cancer?

“BRCA1 is on chromosome 13.”

“If a woman has one affected first-degree relative, then her risk of developing breast cancer triples.”

“Alterations in the kallikrein–kinin system increases the risk for breast cancer.”

“Women who inherit a mutation in BRCA2 experience a 50% to 80% lifetime risk of developing breast cancer.”

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ANS: 4

Genes responsible for this form of breast cancer have been mapped to chromosomes 17 (BRCA1) and 13 (BRCA2). It is possible to test each of these genes for inherited cancer-causing mutations. Women who inherit a mutation in BRCA1 or BRCA2 experience a 50% to 80% lifetime risk of developing breast cancer.

1. BRCA1 is on chromosome 17. Genes responsible for this form of breast cancer have been mapped to chromosomes 17 (BRCA1) and 13 (BRCA2).

2. If a woman has one affected first-degree relative, her risk of developing breast cancer doubles.

3. Kallikrein–kinin system is involved with blood pressure, not breast cancer.

Multifactorial Disorders in the
Adult Population

Colorectal cancer

Is second only to lung cancer in the number of deaths occurring annually in the United States.

The risk is two to three times higher than the general population in those with one affected first-degree relative.

Clusters in families.

Inherited adenomatous polyposis coli (APC) gene mutations play a vital role in familial adenomatous polyposis.

Somatic mutations are involved in common colon cancers.

Mutations in any of six genes cause hereditary nonpolyposis colorectal cancer.

Environmental factors include a high-fat, low-fiber diet.

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Prostate Cancer

Second most commonly diagnosed cancer in men (after skin cancer)

Second only to lung cancer as a cause of cancer death in men

Loss of heterozygosity in some regions

Several dozen polymorphisms associated with prostate cancer risk

High-fat diet is risk factor.

Detected by digital examination and prostate specific antigen (PSA) test

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Cancer Gene Identification

Large-scale DNA sequencing

Indentified hundreds of genes that are mutated in various cancers; some are considered primary causes of cancer.

Driver genes

Passenger genes

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Multifactorial Disorders in the
Adult Population

Diabetes mellitus

Is complex and not fully understood.

Is the 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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Multifactorial Disorders in the
Adult Population (Cont.)

Type 1 diabetes

Is caused by the autoimmune destruction of insulin-producing beta cells in the pancreas.

T-cell infiltration

Individuals with type 1 diabetes need insulin for life.

Siblings of individuals with type 1 diabetes face a substantial elevation in risk.

Incidence is higher in the offspring of diabetic fathers.

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Multifactorial Disorders in the
Adult Population (Cont.)

Type 1 diabetes (cont.)

Twin studies: MZ and DZ pairs have a 30% to 50% and a 5% to 10% increased risk, respectively.

Association of specific human leukocyte antigen (HLA) class II alleles is 40%.

Insulin gene: Genetic variation here is associated with a 10% increased risk.

Other genes are also implicated.

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Multifactorial Disorders in the
Adult Population (Cont.)

Type 2 diabetes

More than 90% of all individuals with diabetes have type 2.

Neither HMC associations nor autoantibodies are present.

Insulin resistance is present, or insulin production is diminished.

Risk factors include obesity and a positive family history.

Exercise has a preventive effect.

Recurrence risk

MZ twins have a 90% risk

First-degree relatives have a 15% to 40% risk.

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Multifactorial Disorders in the
Adult Population (Cont.)

Type 2 diabetes (cont.)

Genes

Variant of TCF7L2 is associated with a 50% increased risk.

Other genes: PPAR-γ and KCNJ11 are associated with increased risk.

Glucokinase gene is associated with maturity-onset diabetes of the young.

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Multifactorial Disorders in the Adult Population Question 4

Type 2 diabetes

is caused by an absence of insulin.

usually involves a gene identified as HLA.

is commonly associated with HLA associations or autoantibodies.

is often treated with lifestyle modification including diet and exercise.

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ANS: 4

This type of diabetes is highly associated with increased BMI and obesity, thus weight loss is one goal of therapy. Dietary modifications can aid weight loss and reduce total glucose load.

1. Type 2 diabetes is highly associated with obesity and an increase in BMI. Obesity is most commonly defined as a body mass index (BMI) greater than 30. Obesity increases insulin resistance.

Type 2 diabetes produces insulin resistance; cells have difficulty using the insulin that is produced. Type 1 diabetes is characterized by destruction of pancreatic beta cells and reduction/absence of insulin.

3. The most significant gene identified thus far is TCF7L2, which encodes a transcription factor involved in the secretion of insulin. A variant of TCF7L2 is associated with a 50% increased risk of developing type 2 diabetes. Neither HLA associations nor autoantibodies are seen commonly in this form of diabetes.

Multifactorial Disorders in the
Adult Population

Obesity

Is a BMI greater than 30.

BMI = weight in kilograms (W) divided by height in meters squared (H2) (BMI = W/H2)

Presents a substantial risk factor for heart disease, stroke, cancer (prostate, breast, colon), and type 2 diabetes.

Adoption studies

Body weights of adopted individuals correlated significantly with their natural parents’ body weights.

Twin studies

Genetics have an effect on body weight: most studies yielded heritability estimates between 0.60 and 0.80.

Gene for leptin and its receptors are related to obesity.

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Multifactorial Disorders in the
Adult Population (Cont.)

Alzheimer disease (AD)

Results in progressive dementia and a loss of memory.

Produces amyloid plaques and neurofibrillary tangles.

Risk doubles if a first-degree relative has AD.

Mutations for early-onset affect amyloid-beta deposition.

Presenilin 1 (PS1), presenilin 2 (PS2), and amyloid-beta precursor protein (APP) gene, which is the primary cause of AD

Mutations for late-onset AD

Allelic variation (ε2, ε3, and ε4) in apolipoprotein E (APOE)

One copy of the ε4 allele: at least two to five times at greater risk

Two copies of the ε4 allele: at least five to ten times more likely
to develop AD

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Multifactorial Disorders in the
Adult Population (Cont.)

Alcoholism

Risk is three to five times higher in the individual with an alcoholic parent.

Adoption studies

Offspring of an alcoholic parent, even when raised by nonalcoholic parents, have a fourfold increased risk.

Offspring of nonalcoholic parents, when reared by alcoholic parents, did not have an increased risk.

Twin studies: MZ and DZ pairs have a >60% and <30%, respectively, increased risk.

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Multifactorial Disorders in the
Adult Population (Cont.)

Alcoholism (cont.)

Genes

Individuals with ALDH2*2 allele are much less likely to become alcoholics.

Allelic variation of gamma-aminobutyric acid (GABA) receptors increase the risk.

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Multifactorial Disorders in the
Adult Population (Cont.)

Schizophrenia

Recurrence risk among offspring of one affected parent is 10 times higher than the general population.

If an individual has an affected sibling and an affected parent, then the risk is approximately 20%.

If an individual has two affected parents, then the risk is 50%.

Twin and adoption studies

MZ and DZ pairs have a risk of 47% and 12%, respectively.

If the offspring of a schizophrenic parent is adopted by normal parents, then the risk is approximately the same as the risk when raised by a schizophrenic biologic parent.

Brain-expressed genes whose products interact with glutamate receptors have been implicated.

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Multifactorial Disorders in the
Adult Population (Cont.)

Bipolar affective disorder

Is also called manic depressive disorder.

Risk rises between 5% and 10% if an individual has an affected first-degree relative, as compared with the normal risk of 0.5%.

Twin and family studies show 60% or bipolar risk is due to genetic factors; 30% of the risk for unipolar disorder (major depression) is due to genetics.

Genes that affect serotonin, dopamine, and noradrenaline systems have been implicated.

Schizophrenia and bipolar disorder

Both are heterogeneous—reflect the influence of numerous genetic and environmental factors, making the phenotype hard to identify and genetic analysis complicated.

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Multifactorial Disorders in the
Adult Population (Cont.)

Other complex disorders

Many other multifactorial diseases are also being studied.

Some susceptibility genes have been identified.

General principles of complex disorders

The more strongly inherited forms of complex disorders generally have an earlier age of onset.

Often represent single-gene inheritance.

When laterality is a component, the bilateral forms are more likely to cluster strongly in families.

The sex-specific threshold model fits some of the disorders (pyloric stenosis, CL/P, autism, heart disease), but it can also fail to fit other disorders (type 1 diabetes).

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Multifactorial Disorders in the
Adult Population (Cont.)

General principles of complex disorders (cont.)

The assumption that a genetic component means the course of a disease cannot be altered is incorrect; most diseases have both genetic and environmental aspects.

Identifying a specific genetic lesion can lead to more effective prevention and treatment of disorders.

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Power point: genes and genetic diseases , and genes,

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