Patho 500 Ch 4 Genes & Genetic Disease
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| genetics | the study of biologic heredity
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| gene | basic unit of heredit
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| genomics | field of genetics concerned with s/f of genome
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| genome | DNA representing all genes for a given species
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| components of DNA | Pentose sugar (deoxyribose)
Phosphate molecule
Four nitrogenous bases
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| pyrimidines-single ring | cytosine and thymine
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| purines - double ring | adenine and guanine
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| DNA has antiparallel structure with these nucleotide pairings | Adenine with thymine
2 hydrogen bonds
Cytosine with guanine
3 hydrogen bonds
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| human genome contains how many genes | 20,000 - 25,000
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| proteins are composed of 20 amino acid polypeptides which are directed by . . . | directed by sequence of bases = CODONS
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| DNA replication - untwisting and unzipping of DNA strand where single strand acts as template with these complementary base pairings | adenine-thymine----------cytosine-guanine
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| What happens in transcription | RNA is synthesized from DNA template bwo RNA POLYMERASE----results in formation of mRNA---mRNA moves OUT of nucleus into cytoplasm
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| gene splicing occurs during | during transcription bwo introns and exons
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| translation | a process by which RNA directs synthesis of polypeptide bwo tRNA at ribosome---
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| tRNA contains the sequence of nucleotides called | called anticodon---which is complementary to the triad of nucleotides on the mRNA CODON
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| DNA organized on a xome composed of | composed of 2 longitudinal sister chromatids
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| xomes found in somatic cells, gametes and in meiosis. What number where? | somatic cells = 23 pairs/diploid----gametes 23 XOMES/haploid cells which have one member of each xome pair-----meiosis is the formation of haploid cells from diploid cells
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| 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
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| sex xomes | Remaining pair of chromosomes
In females, it is a homologous pair (XX)
In males, it is a nonhomologous pair (XY)
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| xome structure | has centromere, which is attachment of sister chromatids occur with SHORT ARM 'p' and LONG ARM 'q'
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| telomere | region with multiple base pairs that SHORTEN with each cell division
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| karyotype | is an ordered display of xomes
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| mutation | any inherited alteration of genetic material
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| mutations occur bwo chromosome aberrations one type is base pair substitution, another is silent substitution | which DOES NOT result in an amino acid change--for example---RNA codons GUU, GUC, GUA, GUG all code for the amino acid valine
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| are mutations in SOMATIC cells transmitted to offspring? | no--only mutations in gametes are transmitted to offspring
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| what is a point mutation | a single nucleotide base-pair change in DNA
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| do spontaneous mutations occur? | yes, varies by gene
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| examples of mutagens, which are agents known to increase frequency of mutations | radiation---chemicals
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| what is a silent mutation again? | A DNA sequence change that does not change the amino acid sequence of a gene
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| missense mutation | A type of mutation that results in a single amino acid change in the translated gene product
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| and what is a nonsense mutation | A type of mutation in which an mRNA stop codon is:
Produced, resulting in premature termination of the protein sequence or
Removed, resulting in an elongated protein sequence
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| in a nonsense mutation we have | premature termination of the protein sequence OR an elongation of the protein sequence
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| frameshift mutations | An alteration of DNA in which an addition or deletion of a base pair occurs
Results in a change in the entire “reading frame”
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| consequences of mutations with respect to GAIN of function | Associated with dominant disorders
Production of new protein product
Overexpression of a protein product
Inappropriate expression of a protein product
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| consequences of mutations with respect to LOSS of function | Associated with recessive disorders
Loss of 50% of the protein product
May or may not be adequate for normal function
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| chromosome abn - euploid cells | Cells that have a multiple of the normal number of chromosomes
Haploid and diploid cells are euploid forms
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| when a euploid cell has more than a diploid number, it is called a | polyplid cell
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| triploidy | a zygote having three copies of each chromosome (69)
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| tetraploidy | four copies of each (92 total)
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| do triploid and tetraploid fetuses survive? | no, they do not
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| disjunction | normal separation of xomes during cell division
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| nondisjunction | USUALLY THE CAUSE OF ANEUPLOIDY---failure of homologous xomes or sister chromatids to separate normally during meiosis or mitosis
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| xome aneuploidy | a somatic cell that does not contain a multiple of 23 xomes
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| an aneuploidy cell that contains 3 copies of one xome is called | trisomic or trisomy
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| monosome | is the presence of only one copy of any xome
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| monosomy is often fatal, but infants | infants can survivie with trisomy of certain xomes - is better to have extra than less!
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| xome disorders are the leading cause of | mental retardation and miscarriage
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| Incidence of xomal abns fun facts | 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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| Best example of aneuploidy is Trisomy 21 also known as | Down Syndrome---1:800 live births
Mentally retarded, low nasal bridge, epicanthal folds, protruding tongue, poor muscle tone
Risk increases with maternal age
Increased risk of congenital heart disease, gastrointestinal disease, and leukemia
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| other autosomal aneuploidies | Trisomy 13 and 18
More severe clinical manifestations than trisomy 21
Death in early infancy is common
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| autosomal aneuploidy - partial trisomy | Only an extra portion of a chromosome is present in each cell
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| autosomal aneuploidy - chromosome mosaics | trisomies occuring in only SOME cells of the body
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| sex xome aneuploidy - one of most common is Trisomy X where female has THREE X xomes | Termed “metafemale”
Symptoms are variable: sterility, menstrual irregularity, and/or mental retardation
Symptoms worsen with each additional X
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| sex xome aneuploidy - Turner syndrome | Females with only one X chromosome
Characteristics
Absence of 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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| sex xome aneuploidy - Klinefelter syndrome---individuals with AT LEAST 2 X's and one Y---have these 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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| alt in xome structure - deletion | loss of a sequence of DNA from an xome
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| alt in xome structure - inversion | xomal rearrangement in which a segment of xome is reversed END TO END
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| ALT IN XOME STRUCTURE - translocation | transfer of one xome segment to another
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| alt in xome structure - ring xome | Structurally abnormal chromosome in which the telomere of each chromosome arm has been deleted and the broken arms have joined
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| alt in xome structure - xome breakage - bwo ionizing radiation, chemicals and viruses | 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
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| alt of xome structure - break or loss of DNA - Cri du Chat syndrom | Deletion of short arm of chromosome 5 (5p-)
Low birth weight, metal retardation, and microcephaly
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| alt in xome structure - duplication - rare 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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| alt in xome 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
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| alt in xome structure - translocation | The interchanging of material between nonhomologous chromosomes
Translocation occurs when two chromosomes break and the segments are rejoined in an abnormal arrangement
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| alt in xome structure - 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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| alt in xome structure - 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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| genes are basic units of heredity, with sequences of xomal DNA coding for the production of a functional product | Templates for mRNA that code for specific proteins
All genes are contained in each cell of the body
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| genes - locus | location occupied by a gene on a xome
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| genes - allele - is an alternate version of a gene at a locus | Each individual possesses two alleles for each gene
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| genes - homozygous | possessing identical alleles of a given gene
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| genes - heterozygous | possessing two different alleles of a given gen
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| genes - polymorphism | locus that has 2+ alleles that occur with appreciable frequency
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| example of homozygous loci | Loci on a pair of chromosomes have identical alleles
Example
O blood type (OO)
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| example of heterozygous loci | 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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| genotype - what they have | the genetic makeup of an organism
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| phenotype - what they demonstrate | the observable, detectable or outward appearance of genetics
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| example of phenotype | 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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| genetics - if 2 alleles are found together, then | the allele that is observable is dominant, and the one whose effects are hidden is recessive
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| genetics - the dominant allele is represented by | a capital letter, and the recessive by a lowercase letter
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| true or false - alleles can be codominant | true
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| genetics, what is a carrier and give one example | 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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| what is a genetic pedigree | Used to study specific genetic disorders within families
Begins with the proband
Propositus (male)
Proposita (female)
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| single gene disorder - autosomal dominant disorder | Abnormal allele is dominant, normal allele is recessive, and the genes exist on a pair of autosomes
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| autosomal dominant disorders - characteristics | 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
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| autosomal dominant traits | see slide 66 and 67
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| single-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
When one parent is affected by an autosomal dominant disease and the other is normal, the
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| recurrence risk of autosomal dominant trait | 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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| penetrance | The percentage of individuals with a specific genotype who also express the expected phenotype
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| incomplete penetrance and example | 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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| gene mapping | see slide 70
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| expressivity definition and cause | Expressivity is the variation in a phenotype associated with a particular genotype
This can be caused by modifier genes
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| example of expressivity disorder - see slide 72 for image | 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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| single gene disorders - 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
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| autosomal recessive disorder recurrence risk | When two parents are carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25%
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| characteristics of autosomal recessive disorder - characteristics | Condition expressed equally in males and 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
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| autosomal recessive disorder characteristics #2 | Individuals must be homozygous for the condition to be expressed
Generational skipping may be present
Consanguinity may be present
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| autosomal recessive disorder - Cystic Fibrosis | Associated with mutation of the CF gene located on the long arm of chromosome 7
Abnormal expression CF transmembrane conductance regulator protein on epithelial cells
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| how does CF cystic fibrosis manifest? | Defect in chloride transport leading to salt imbalances, dehydrated mucus secretions plugging airways, digestive organ obstructions and malnutrition
Lung disease or heart failure is usual cause of death
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| autosomal recessive disorder | see slide 77 for image
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| Cosanguinity | Mating of two related individuals
Dramatically increases the recurrence risk of recessive disorders
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| sex-linked disorders - X linked | usually expressed by males because females have another X chromosome to mask the abnormal allele
Most are recessive
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| sex linked disorders - Y linked | uncommon because Y chromosome contains relatively few genes
Father-son transmission present
No father-daughter transmission
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| Characteristics of X-linked recessive disorders | Males most commonly affected
Affected males cannot transmit the genes to sons, but they can to all daughters
Unaffected carrier females
Sons of female carriers have a 50% risk of being affected
Pedigree analysis
Generational skipping often present
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| in X-linked recessive disorders, is there generational skipping? what about father-to son transmission? | Generational skipping often present
No father-to-son transmission
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| Example #1 of X-linked Recessive Disorders | Hemophilia
Bleeding disorders resulting from a congenital deficiency of coagulation factors
Hemophilia A: factor VIII deficiency
20.6/100,000 male births in U.S.
Hemophilia B: factor IX deficiency
5.3/100,000 male births in U.S
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| In hemophilia, mutations associated with factor VIII deficiency | Large deletions or insertions, frameshift and splice junction changes, and nonsense and missense mutations
Mutations vary across families but tend to be similar within families
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| X-linked recessive disorders - Duchenne muscular dystrophy | Characterized by progressive muscle degeneration
Mutation of dystrophin gene resulting in down-regulation or absence of dystrophin
Affects 1:3500 males, cardiac or respiratory failure before 20 years of age
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| manifestations of Duchenne muscular dystrophy | Produces generalized weakness, progressive muscle wasting, lethal
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| X-linked recurrence risk - see slide 83 for graphic | A. Outcomes for offspring of an unaffected father and a heterozygous unaffected carrier mother (most common scenario)
B. Outcomes for offspring of an affected father and a homozygous unaffected mother
C. (see next slide)
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| X-linked recurrence risk - part C | Outcomes for offspring of an affected father and a heterozygous unaffected carrier mother
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