1
Q
Congenital Vs. Genetic
A
- Congenital - born with it, may/may not be inherited
- Genetics - inherited, may/may not be present at birth.
- ex. Huntingon disease - you inherit the disease but does not manifest until later in life
2
Q
Normal human karyotype
A
23 pairs
p = short ; q = long arm
3
Q
Anatomy of chromosome
A
4
Q
Telomeres
A
- Telomere - region of repetitive nucleotide sequences at each end of chromosome
- They protect the end of the chromosome from deterioration or from fusion with neighboring chromosome
- The sequent of nucleotides in telomeres is TTAGGG, with the complementary strand being AATCCC
- This sequent of TTAGGG is repeated approximatley 2,500 times in humans
- In humans, the avg telomere length declines from about 11 kilobases at birth to less than 4 kilobases in old age, with avg rate of decline being greater in men than in women
- In each chromosomal duplication the telomere is shortened
5
Q
Describe the DNA molecule
A
6
Q
The Operon - Several related genes, regulatory & mRNA-coding
A
- Regulator gene - codes for the repressor
- The promotor gene - attachment for RNA polymerase
7
Q
Codons
A
A three base pair sequence, in mRNA, that encodes a specific aa. More than one triplet may encode a given aa.
8
Q
Transcription
A
- Copying the code, without changing the language (nucleic acids)
- When DNA is transcribed into mRNA, the initial product is a pre-mRNA composed of both introns & exons
- Introns do not code for protein
- cut out of pre-mRNA
- exons - contains condons that encode proteins
- spliced together to create the final mRNA
- begin with cap at 5’ and Poly A tail at 3’ end
- The mRNA is then ready to leave the nucleus for translation into protein by rRNA
9
Q
Translation
A
- Translates from the language of nucleic acids the language of protein synthesis
- Beyond the codons encoding the protein there is a start codon (usually methionine) and a stop codon that indicate where translation begins at 5’ end and ends at 3’ end
- Stop codon bind “release factors“ that cause the two ribosomal pieces to dissociate, ending the reading frame
10
Q
What are the major categories of genetic diseases?
A
- Disorders related to mutations in single genes with large effects
- Very rare unless they are maintained in a population by strong selective forces
- Chromosal disorders
- These arise from structural or numerical alteration in the autosomes and sex chromosomes (ex. trisomy 21 - Down)
- Complex multigenic disorders
- Most common. Caused by interactions between multiple variant forms of genes & environmental factors (aka polymorphisms). Each variant gene confers a small increase in disease risk, and no single susceptibility gene is necessary or sufficient to produce the disease.
11
Q
Describe Mendelian Disorders - Single gene traits
A
- Transmission patterns of single-gene disorders
- Autosomal dominant disorders are characterized by expression in heterozygous state
- M=F, both can transmit disorder
- Autosomal recessive disease occur when both copies of a gene are mutated
- M=F
- Enzymes proteins are frequently involved
- X-linked disorders are transmitted by heterozygous females to their sons, who manifest the disease
- Female carriers usually are protected because of random inactivation of one X chromosome
12
Q
Autosomal Recessive
A
- to express the trait, the proband must receive one allele from each parent, both of whom are carriers
- Odds are 25% will carry neither allele
- 50% will be carriers
- 25% will express the phenotype
13
Q
Autosomal Dominant
A
- Whether the affected allele is from the mother or father the odds of expressing the trait are 50% because only a single copy of the allele is required to express the trait
14
Q
X-linked recessive
A
- The mutant allele is on the X-chromosome, but women must inherit 2 mutated copies to be affected
- An affected father cannot pass the trait to a son but can make carriers of daughters
- All boys who inherit the mutate are affected (only one X chromosome)
15
Q
X-linked dominant
A
- With affected mother, 50% of sons & daughters affected
- If affected father, all daughters express the trait but sons unaffected
16
Q
Penetrance
A
- proportion of individuals carrying a particular allele of a gene that also express the associated phenotype
- A condition that shows complete penetrance is neurofibromatosis type 1 - every person who has the mutation in the gene will show sx of the condition. The penetrance is 100%
- Most common sign of neurofibromatosis - 1
- Lisch nodules of the iris
17
Q
Expression
A
- Measurement of expression is done by detected the final gene product (for many genes, this is the protein) .
- however, it is often easier to detect one of the precursors typically mRNA and to infer gene-expression levels from these measurements
- Diseases of OVER expression and UNDER expression
18
Q
Biochemical and Molecular Basis of Single-Gene (Mendelian) Disorders
A
- Enzyme defects & their consquences
- Defects in receptors and transport systems
- Alterations in structure, function or quantity of nonenzyme proteins
- Genetically determined adverse reactions ot drugs
19
Q
Enzymes defects & their consequences
A
- Accumulation of substrate, depending on the site of block, may be accompanied by accumulation of one or both intermediates
- An enzyme defect can lead to a metabolic block and a decreased amoutn of end product
- Tyrosine deficiency - albinism
- pink iris
- foveal hypoplasia
- Nystagmus
- Tyrosine deficiency - albinism
- Failure to inactivate a tissue damaging substrate as in a1 - anti - trypsin deficiency
20
Q
Defects in receptors and transport systems
A
- Familial Hypercholesterolemia - reduced synthesis or function of LDL receptors leads to defective transport of LDL into the cells and secondarily to excessive cholesterol synthesis by complex intermediary mechanisms
- Cystic fibrosis the transport system for chloride ions in the exocrine glands, sweat ducts, lungs, and pancreas is defective. By mechanisms not fully understood impaired chloride transport leads to serious injury to the lungs & pancreas.
21
Q
Alterations in Structure, Function, or Quanitity of Nonezyme Proteins
A
- Marfan syndrome - ectopia lentis (Subluxation of lens) defect in fibrillin-1, the substance composing the zonules
- Ehlers-Danlos Syndrome (EDS) - EDS is caused by defect in the structure production, or processing of collagen or proteins that interact with collagen. This disease is characterized by fragility of the soft CT and widespread manifestations in the skin, ligaments, joints, blood vessels, and internal organs.
22
Q
Ehlers - Danlos can cause breaks in which membrane?
A
Breaks in Bruch’s membrane
23
Q
Genetically determined adverse reactions to drugs
A
- G6PD - deficiency
- Under normal conditions glucose 6 phosphate dehydrogenase (G6PD) deficiency does not result in disease, but on administration, for ex, of the antimalarial drug primaquine, severe hemolytic anemia results
24
Q
Mutations
A
- Deletion - loss of portion of a chromosome. After deletion, a ring chromsomes do not behave normally in meiosis or mitosis and usually result in serious consequences
- Inversion refers to rearrangement that involves 2 breaks within a single chromosome with reincorporation of the inverted, intervening segment
- Translocation, when a segment of one chromosome is transferred to another robertsonian translocation (or centric fusion), a translocation between 2 acrocentric chromosomes. Typically the breaks occur close to the centromeres of each chromosome. Transfer of the segments then leads to one very lage chromsome and one extremely small one that is often lost. Because it carires only highly redundant genes (ex ribosomal RNA genes), this loss is compatible with a normal phenotype.
25
Types of focal mutations
* **Mutation** - permenant change in the DNA
* Mutations that affect **germ cells** are transmitted to the progeny & can give rise to inherited disease
* Mutatinos that arise in **somatic cells** do not cause hereditary diseases but are important in the genesis of cancers and some congenital malformations
* **Point mutation within coding sequences**
* **Point mutation within noncoding sequences**
* **Deletions & insertion s**
* **Single-Gene disorders with nonclassic inheritance**
26
Focal Mutations - **Point mutatins within coding sequences**
* point mutation is a change in which a single base is substituted with a different base.
* It may alter the code in a triplet bases and lead to the replacement of one aa by another in the gene product.
* Because these mutations alter the meaning of the sequence of the encoded protein, they are often termed missense mutations. The change may also produce a nonsense mutation
* Ex. sickle cell disease
* Normal hemoglobin aa sequence = Val-his-leu-thr-pro-**glu**-glu-
* Sickle cell hemoglobin aa sequence = Val-his -leu-pro-**val**-glu
* Hemoglobin & RBCs defective but this conefers immunity to malaria
27
types of focal mutations - point mutations within noncoding sequences
* point mutations or deletions involving regulatory sequences may interfere with binding of transcription factors & thus lead to a marked reduction in or total lack of transcription
* Point mutations within introns may lead to defective splicing of intervening sequences. This, in turn, interferes with normal processing of the initial mRNA. Therefore, translation cannot take place, and the gene product is synthesized
28
Types of focal mutations - Deletion & insertions
* Small deletions or insertions involving the coding sequence can have 2 effects on coding protein
* **If the number of base pairs 3 or multiple of three** = the reading frame remains intact, and an abnormal protein lacking or gaining one or more aa will be synthesized
* **If the coding bases is not a multiple of 3** = this will cause frameshift mutation (alter reading form of DNA strand). This can result in incorrect number of aa or premature stop codon.
29
Types of focal mutations - single - gene disorders with nonclassic inheritance
* Disease caused by **trinucleotide** - repeat mutations
* Fragile X syndrome Xq27-3 abnormal FMR-1 (familial mental retardation) protein due to CGG 6-55 55-200 (pre; \>230 (full) The causative mutations are associated with the expansion of a stretch of trinucleotides that usually share the nucleotides G & C. In all cases the DNA is unstable, and an expansion of the repeats above a certain threshold impairs gene function in various ways - 30% exhibit strabismus
* **Disorders caused by mutations in mitochondrial genes**
* **Disorders associated with genomic imprinting** ****
* **Disorders associated with gonadal mosaicism**
30
Leber' optic atrophy
* Leber's hereditary optic neuropathy is a prototype of this disorder
* Slowly progressive bilateral loss of central vision between 2nd & 4th decade
* M\>F
* Cardiac conduction defects and minor neurologic manifestations have also been observed in some families
31
Single gene disorders with nonclass inheritance:
## Footnote
**Disorders caused by mutations in mitochondrial genes**
* feature unique to mtDNA is maternal inheritance
* Ova contain numerous mitchondria, whereas spermatozoa contain few
* Hence, the mtDNA complement of the zygote is derived entirely from the ovum
* Thus, mothers transmit mtDNA to all their offspring, male and female; however, daughters but not sons transmit the DNA further to their progeny
* **Leber's hereditary optic neuropathy** is prototype of this disorder
32
Single-gene disorders with nonclassic inheritance
## Footnote
**Disorders associated with genomic imprinting**
* We all inherit 2 copies of each autosomal gene, carried on homologous maternal & paternal chromosomes
* It had been assumed that there were no functional difference between the alleles derived from the mother or father
* But with some genes, important functional differences exist between the paternal allele and the maternal allele - called **imprinting**
* **Imprinting** selectively inactivates either the maternal or paternal allele. Thus, **maternal imprinting** refers to transcriptional silencing of the maternal allele, whereas paternal imprinting implies the paternal allele is inactivated
* Imprinting occurs in the ovum or the sperm, before fertilization, and then is stably transmitted to all somatic cells through mitosis
* Ex: Prader-Willi Syndrome (paternal deletion - mental retardation, short starure, hypotonia, hyperphagia, small hands and feet, and hypogonadism)
* Angelman syndrome (maternal deleation same locus as above) Mental retardation, ataxia, seizures, and inappropriate laughter.
33
Single-gene disorders with nonclassic inheritance
## Footnote
**Disorders associated with gonadal mosaicism**
* Mosaicism results from a mutation that occurs postzygotically during early (embryonic) development
* If the mutation affects only cells destined to form the gonads, the gametes carry the mutation, but the somatic cells of the individual are completely normal
* A phenotypically normal parent who has gonadal masaicism can transmit the diseae-causing mutation to the offspring through their mutated gametes
34
Complex Multigenic Disorders
* Gene that has at least 2 alleles, each of which occurs at a freqeuncy of at least 1% in the population, is polymorhphic, and each variant allele is referred to as polymorphism
* Complex genetic disorders occur when many polymorphisms, each iwth a modest effect & low penetrance, are co-inherited
* Hair and eye color are inherited int his way
* Ex. type 2 diabetes
* POAG - (GLC1a) 3% of glaucoma
* Myopia
Pathophys
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