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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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