Download Genes and Genetic Diseases Paula Ruedebusch

GENES AND GENETIC DISEASES
Paula Ruedebusch, ARNP, DNP
DNA
Pentose sugar (deoxyribose)
 Phosphate molecule
 Four nitrogenous bases:

Pyrimidines: cytosine and thymine
 Purines: adenine and guanine

Double helix model
 Nucleotide

2
DNA (CONT’D)
3
DNA VIDEO

https://www.youtube.com/watch?v=itsb2SqR-R0
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PROTEINS
One or more polypeptides
 Composed of amino acids

Twenty amino acids
 Directed by sequence of bases (codons)

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DNA REPLICATION

Untwisting and unzipping of the DNA strand


Single strand acts as a template
Complementary base pairing by DNA polymerase

Adenine-thymine; cytosine-guanine
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DNA
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MUTATION

Any inherited alteration of genetic material


Base pair substitution


Chromosome-aberrations
One base pair is substituted for another
Frameshift mutation


Insertion or deletion of one or more base pairs
Causes a change in the entire “reading frame”
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MUTATION VIDEO

https://www.youtube.com/watch?v=qxXRKVompI8
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MUTATION (CONT’D)

Spontaneous mutation


Mutation that occurs in absence of exposure to known
mutagens
Mutational hot spots

Areas of the chromosomes that have high mutation
rates

A cytosine base followed by a guanine is known to account
for a disproportionately large percentage of disease-causing
mutations
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MUTAGEN

Agent known to increase the frequency of
mutations
Radiation
 Chemicals


Nitrogen mustard, vinyl chloride, alkylating agents,
formaldehyde, sodium nitrite
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TRANSCRIPTION
RNA is synthesized from the DNA template
 RNA polymerase binds to promoter site
 Results in the formation of messenger RNA
(mRNA)
 RNA polymerase detaches
 mRNA moves out of the nucleus and into the
cytoplasm
 Transcription continues until termination sequence
is reached

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TRANSCRIPTION (CONT’D)
Transcription Video: https://www.youtube.com/watch?v=WsofH466lqk
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TRANSLATION
Process by which RNA directs the synthesis of a
polypeptide via interaction with tRNA
 Site of protein synthesis is the ribosome
 tRNA contains a sequence of nucleotides
(anticodon) complementary to the triad of
nucleotides on the mRNA strand (codon)
 The ribosome moves along the mRNA sequence
to translate the amino acid sequence

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TRANSLATION (CONT’D)
Translation Video: https://www.youtube.com/watch?v=5bLEDd-PSTQ
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CHROMOSOMES

Somatic cells:
Contain 46 chromosomes (23 pairs)
 Diploid cells


Gametes:
Contain 23 chromosomes
 Haploid cells


One member of each chromosome pair
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GAMETES VS. SOMATIC CELLS
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CHROMOSOMES (CONT’D)

Meiosis


Formation of haploid cells from diploid cells
Mitosis

Formation of somatic cells
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CHROMOSOMES (CONT’D)

Autosomes



The first 22 of the 23 pairs of chromosomes in males
and females
The two members are virtually identical and thus said
to be homologous
Sex chromosomes

Remaining pair of chromosomes
In females, it is a homologous pair (XX)
 In males, it is a nonhomologous pair (XY)


Karyotype (karyogram)
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KARYOTYPE

Ordered display of chromosomes
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CHROMOSOME ABERRATIONS

Euploid cells 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)


Neither triploid nor tetraploid fetuses survive
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CHROMOSOME ABERRATIONS (CONT’D)

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 lethal, but infants can survive with
trisomy of certain chromosomes


“It is better to have extra than less”
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CHROMOSOME ABERRATIONS (CONT’D)

Disjunction


Normal separation of chromosomes during cell division
Nondisjunction
Usually the cause of aneuploidy
 Failure of homologous chromosomes or sister
chromatids to separate normally during meiosis or
mitosis

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NONDISJUNCTION
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AUTOSOMAL ANEUPLOIDY

Partial trisomy


Only an extra portion of a chromosome is present in
each cell
Chromosomal mosaics

Trisomies occurring only in some cells of the body
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AUTOSOMAL ANEUPLOIDY (CONT’D)

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 >35

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DOWN SYNDROME
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SEX CHROMOSOME ANEUPLOIDY

One of the most common is trisomy X (a female
that has three X chromosomes)
Symptoms are variable: sterility, menstrual irregularity,
and/or mental retardation
 Symptoms worsen with each additional X

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SEX CHROMOSOME ANEUPLOIDY (CONT’D)

Turner syndrome
Females with only one X chromosome
 Characteristics:

Underdeveloped ovaries (sterile)
 Short stature (~ 4'7")
 Webbing of the neck
 Edema
 Underdeveloped breasts; wide nipples
 High number of aborted fetuses


X is usually inherited from mother
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TURNER SYNDROME KARYOTYPE
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SEX CHROMOSOME ANEUPLOIDY

Klinefelter syndrome
Individuals with at least two Xs and one Y
chromosome
 Characteristics

Male appearance
 Develop female-like breasts
 Small testes
 Sparse body hair
 Long limbs

Some individuals can be XXY and XXXY
 The abnormalities increase with each X

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KLINEFELTER SYNDROME
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ABNORMALITIES IN CHROMOSOME STRUCTURE

Chromosome breakage
If a chromosome break does occur, physiologic
mechanisms will usually repair the break, but the
breaks often heal in a way that alters the structure of
the chromosome
 Clastogens


Ionizing radiation, chemicals, and viruses
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ABNORMALITIES IN CHROMOSOME STRUCTURE
(CONT’D)
Breakage or loss of DNA (deletions)
 Cri du chat syndrome

“Cry of the cat”
 Deletion of short arm of chromosome 5
 Low birth weight, metal retardation, and microcephaly

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CRI-DU-CHAT DNA
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ABNORMALITIES IN CHROMOSOME STRUCTURE
(CONT’D)
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ABNORMALITIES IN CHROMOSOME STRUCTURE
(CONT’D)

Duplication
Presence of a repeated gene or gene sequence
 Less serious consequences because better to have
more genetic material than less (deletion)
 Duplication in the same region as cri du chat causes
mental retardation but no physical abnormalities

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ALTERATIONS IN CHROMOSOME STRUCTURE

Inversions
Two breaks on a chromosome
 Reversal of the gene order
 Usually occurs from a breakage that gets reversed
during reattachment



ABCDEFG may become ABEDCFG
Position effect
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ABNORMALITIES IN CHROMOSOME STRUCTURE

Translocations
The interchanging of material between
nonhomologous chromosomes
 Reciprocal translocation occurs when two
chromosomes break and the segments are rejoined in
an abnormal arrangement
 Robertsonian translocation occurs when fusion at
centromere, forming a single chromosome

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ABNORMALITIES IN CHROMOSOME
STRUCTURE (CONT’D)

Fragile sites
Fragile sites are areas on chromosomes that develop
distinctive breaks or gaps when cells are cultured
 No apparent relationship to disease

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ABNORMALITIES IN CHROMOSOME STRUCTURE
(CONT’D)

Fragile X syndrome
Site on the long arm of the X chromosome
 Associated with mental retardation; second in
occurrence to Down syndrome
 Higher incidence in males because they have only one
X chromosome

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FRAGILE X SYNDROME
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FRAGILE X SYNDROME DIAGNOSIS
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GENETIC DISORDERS WEBSITE

www.genefacts.org
-
Useful for information
Diagnostics
Management
Counseling
-
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GENETICS

Locus


Position of a gene along a chromosome
Allele
A different form of a particular gene at a
given locus
 Example: Hgb A vs. Hgb S
 Polymorphism


Locus that has two or more alleles that
occur with appreciable frequency
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GENETICS (CONT’D)

Homozygous
Loci on a pair of chromosomes have identical genes
 Example



O blood type (OO)
Heterozygous
Loci on a pair of chromosomes have different genes
 Example


AB blood type (A and B genes on pair of loci)
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GENETICS (CONT’D)

Genotype (“what they have”)


Phenotype (“what they demonstrate”)


The genetic makeup of an organism
The observable, detectable, or outward appearance of
the genetics of an organism
Example

A person with the A blood type could be AA or AO: A is
the phenotype; AA or AO is the genotype
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GENOTYPE VS. PHENOTYPE
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GENETICS (CONT’D)
If two alleles are found together, the allele that is
observable is dominant, and the one whose
effects are hidden is recessive
 In genetics, the dominant allele is represented by
a capital letter, and the recessive by a lowercase
letter
 Alleles can be codominant

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CODOMINANCE EXAMPLES
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GENETICS (CONT’D)

Carrier
A carrier is one who 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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CARRIERS
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GENETICS (CONT’D)

Transmission of genetic disease
Mode of inheritance
 Principle of segregation
 Principle of individual assortment
 Chromosome theory of inheritance

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PEDIGREES
Used to study specific genetic
disorders within families
 Begins with the proband

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PEDIGREES (CONT’D)
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SINGLE-GENE DISORDERS

Autosomal dominant disorder

Abnormal allele is dominant, normal allele is recessive,
and the genes exist on a pair of autosomes
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SINGLE-GENE DISORDERS (CONT’D)
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AUTOSOMAL DOMINANT EXAMPLES AND VIDEO
Myotonic dystrophy
 Marfan Syndrome
 Huntington disease
 Familial hypercholesterolaemia


https://www.youtube.com/watch?v=dw-raR6E9zU
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PENETRANCE

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
 Retinoblastoma (eye tumor in children) demonstrates
incomplete penetrance (90%)

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EXPRESSIVITY
Expressivity is the extent of variation in phenotype
associated with a particular genotype
 This can be caused by modifier genes
 Examples:

von Recklinghausen disease
 Autosomal dominant
 Long arm of chromosome 17
 Disease varies from dark spots on the skin to
malignant neurofibromas, scoliosis, gliomas,
neuromas, etc.

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EXPRESSIVITY EXAMPLE: NEUROFIBROMATOSIS
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SINGLE-GENE DISORDERS

Epigenetics

Same DNA sequence can produce different phenotypes due to
chemical modification that alters expression of genes
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SINGLE-GENE DISORDERS (CONT’D)

Autosomal recessive disorder
Abnormal allele is recessive and a person must be
homozygous for the abnormal trait to express the disease
 The trait usually appears in the children, not the parents, and it
affects the genders equally because it is present on a pair of
autosomes
 Cystic fibrosis gene encodes a chloride ion channel in some
epithelial cells that alters sodium balance

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CYSTIC FIBROSIS
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CYSTIC FIBROSIS TX
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SINGLE-GENE DISORDERS (CONT’D)

Autosomal recessive disorder recurrence risk

Recurrence risk of an autosomal dominant trait

When two parents are carriers of an autosomal recessive disease,
the occurrence and recurrence risks for each child are 25%
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Sickle Cell Anemia:
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AUTOSOMAL RECESSIVE DISEASE VIDEO

https://www.youtube.com/watch?v=oE9BUuv2pTo
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CONSANGUINITY
Mating of two related individuals
 Dramatically increases the recurrence risk of recessive
disorders

70
SEX-LINKED DISORDERS
The Y chromosome contains only a few dozen genes, so
most sex-linked traits are located on the X chromosome
and are said to be X-linked
 Sex-linked (X-linked) disorders are usually expressed by
males because females have another X chromosome to
mask the abnormal gene

71
X-LINKED RECESSIVE
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SEX-LINKED DISORDERS (CONT’D)

X-linked recessive
Most X-linked disorders are recessive
 Affected males cannot transmit the genes to sons, but they
can to all daughters
 Sons of female carriers have a 50% risk of being affected
 Examples: hemophilia, color-blindness

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SEX-LINKED DISORDERS
(CONT’D)
74
RECURRENCE RISKS
Recurrence risks of multifactorial diseases can
change substantially between populations
 Recurrence risk becomes higher if more than one
family member is affected
 Empirical risks have been derived via direct
observation

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RECURRENCE RISKS (CONT’D)
If the expression of the disease in the proband is
more severe, the recurrence risk is higher
 The recurrence risk is higher if the proband is of
the less commonly affected sex
 The recurrence risk for the disease usually
decreases rapidly in more remotely related
relatives

76
TEST YOURSELF!
1. Which of the following statements is TRUE?
A.
B.
C.
D.
RNA is double-stranded.
DNA is replicated in the cytoplasm.
RNA contains the same bases as DNA.
A mutation is an inherited alteration of DNA.
77
TEST YOURSELF!
2. Which term best describes an allele with an observable
effect?
A.
B.
C.
D.
Carrier
Dominant
Recessive
Homozygous
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