Genetics Flashcards
Examples of Autosomal dominant disease?
Adult polycystic kidney disease BRCA 1 and 2, MEN, Lynch, VHL Connective tissue disease e.g. Achondroplasia, Ehlers Danlos, Osteogenesis imperfecta FAP Familial hypercholesterolaemia Familial retinoblastoma Fragile X Hereditary Spherocytosis Huntington's Marfan's Myotonic dystrophy Neurofibromatosis Type 1 PCKD VWD
Examples of Autosomal recessive disease?
Alpha anti-trysan CF Factor V Leiden Friedrich’s ataxia Haemachromatosis PKU Sickle cell Thalassaemia Tay sacks
X-linked recessive conditions?
Duchenne
Haemophilia A
AD inheritance pattern?
Each child 50% risk No skipped generations Male to male transmission May have incomplete penetrance Occurs in each generation - if skipped may be due to non penetrance
AR pattern of inheritance?
Need one from each parent
Equally transmitted by males and females
Males are infertile
If a person is a carrier (heterozygote) of an AR allele, they always have a 1/2 (50%) chance of passing on allele
1/4 chance of next child
If one child affected, other children have 2/3 chance
chance of unaffected child having gene is 2/3
Consanguinity common, especially for rare disorder)
X linked dominant inheritance.
Pattern of inheritance?
Examples
Hemizygous males have full phenotype (severely affected, usually lethal in pregnancy or neonatal)
Heterozygous females are typically unaffected or only mildly affected
NO male to male transmission
examples:
Rett syndrome
Mitochondrial pattern of inheritance?
Examples
Females will pass on to all children.
Examples:
Leber Hereditary optic neuropathy (LHON)
MELAS (myopathy, encephalopathy, ALctic acidosis, Stroke like episodes)
Myoclonic epilepsy with Ragged Red Fibres (MERRF)
Neuropthy, Ataxia and Retinitis Pigementaosa (NARP)
Examples of triple repeat disorders?
Fragile X
Huntington’s
Myotonic dystrophy
What is Mosaicism vs. chimerism?
A mosaic individual has 2 or more genetically different cell lines derived from the same zygote.
A chimeric individual has 2 or more genetically different cell lines derived from 2 or more zygotes.
What is genome imprinting?
Epigenetic marking based on its parental origin that results in mono allelic expression
Imprinting = switched off
Female pt with Fragile X syndrome shown to carry a CGG repeat size of 180 (witin premutation range). What are the risks to her of transmitting Fragile X syndrome to her offspring?
50% chance of passing on the pre-mutation allele which could expand into full mutation as she is a female transmitting parent. AD inheritance unstable on maternal transmission -> anticipation
What level of repeat is required for triple repeat expansion for normal, intermediate, permutation and full mutation?
Normal 11-44 repeats
Intermediate 45-58 repeats
Premutaiton 59-200 repeats
Full mutation > 200
What is chromosomal microarrays?
A method to assess thousands of DNA sequences to detect sub-microscopic chromosomal imbalances (gains or losses).
Will not detect a balanced X-autosome reciprocal translocation
What are the features of mitochondrial inheritance?
Maternal, will pass on to all her children
High mutation rate
Multiple copies
Variable expressivity is common
X-linked dominant female carriers will show a phenotype. T/F
True, milder than males
X-linked recessive shows no phenotype
What is the inheritance of BRCA mutation?
AD
If concerns of BRCA mutation, test affected family member for mutation
Point mutation is a type fo DNA mutation? What are the 4 Types?
A change in a single base pair.
Missense = spelling mistake e.g. THE BIG RAD DOG -> gain of function
Nonsense = stop codon e.g. THE BIG RED -> loss of fucntion
Frameshift deletion = deletion e.g. THE BRE DDO G -> loss of function
Frameshift insertion = insertion e.g. THE BIG RED ZDO G -> loss of function
what is a splice site mutation?
A change that results in altered RNA sequence.
usually due to point mutations but can be insertions or deletions.
i.e. exon spliced out or intron left in. Introns are meant to be spliced out.
An intron is a region of a gene that does not code for a protein
What is linkage analysis?
A test to look for patterns of DNA markers near gene of interest that segregate with disease. Requires DNA analysis of multiple family members
What is the recombination fraction?
The freq with which a single chromosome cross over will take place between 2 genes during meiosis i.e. the chance they will break up
What would a deletion in an exon cause?
Leads to deletion of dystrophin protein resulting in Duchennes muscular dystrophy
How does silencing occur in imprinted genes?
Addition of methyl groups during egg or sperm formation
What is uniparental disomy?
Occurs when one person receives 2 copies of the chromosome from one parent and no copies from the other.
UPD can be the result of heterodisomy (a pair of non identical chromsoomes are inherited from one parent) or
isodisomy (single chromosome from one parent is duplicated).
Isodisomy is potentially dangerous as may lead to duplication of the lethal recessive gene.
HLA B*5701 +ve. What antiretroviral will cause an AE?
Abacavir (NRTI)
Can cause hypersensitivity in 5-8% of pts in 1st 6 weeks of therapy
HLA B*5701 allele occur 5% in Europeans and 1% in Asian and
What is the genetic defect in Prada Willi syndrome?
Del 15q11-q13
Deletion is always on the father’s chromosome 15
Deletion in Angelman syndrome?
15q11-q13
Deletion is always on the chromosome 15 derived from the mother
What is the molecular basis of Prada Willi and Angelman syndrome?
Involves imprinted domain of chromosome 15 (q11-q13)
PW - absence of paternal contribution
AS - absence of maternal contribution
What are the clinical features of Huntington disease?
Intellectual deterioration Personality change Progressive movement disorder Mean age onset 40 y Mean duration of disease 15 y
Fragile X. Mutation and clinical features?
CGG repeat in FMR1 (or GCC in FMR2- rarer)
Long big ears
females may be mildly affected
Anticipation
What is the role of FISH?
What does it not detect?
Fluorescent in-situ hybridisation
To identify common chromosomal deletion that are below the resolution of standard cytogenentics
Does not detect:
partial deletions
substitutions
duplications
Role of CGH microarrays?
Compares the number betweenthe control and test sample for thousands of genomic markers spaced over all chromosomes.
A powerful technique to identify chromosome abnormality in oncology and syndrome due to microdeletions e.g. Di George22q deletion,
Which genetic disorder displays homogeneity (same nature)?
Huntington’s disease
Trinucletoide repeat.
Working HD gene has 26 CAG repeats. When the gene is faulty it can repeat 40 x or more.
What is an intron?
found between exons (intervening regions), may be involved in regulation.
What is an exon?
contain sequences coding for specific polypeptide (expressing regions)
DNA is transcribed or translated into mRNA?
Transcribed
mRNA translated into a protein,
Genes expression is selective and determined by what 4 factors?
- Differential transcription
- Epigenetic mechanism
- Alternative RNA processing
- Translation and post-translational modification
What 4 factors complicate Mendelian patterns of inheritance?
- Anticipation
- Imprinting
- Mosacism
- Mitochondrial inheritance
What are the complicating factors in AD inheritance?
Anticipation
- the tendecny in a geentic condition for successive generations to present at an earlier age and/or with more severe manisfestations e.g. triplet repeat
Imprinting
- differential gene expression dependednt on the parent of origin (mother or father)
Moasaicism
- the post fertilisation occurrence of genetically different cell lines within an individual
What are the 4 mechanisms for imprinting causing phenotypes?
- deletion of one allele, effect depends on parent who transmitted allele
- Abnormal methylation- most common
- Uniparental disomy - both chromosomal regions inherited from same parent
- Mutations - in imprinted genes in the region or imprinting centre genes
List examples of diseases due to imprinting?
Prada Willi - 15q11.2 (paternal deletion)
Angelman syndrome 15q11.2 (maternal deletion)
Beckwith-Wiedemann syndrome 11p15
Russell-Silver syndrome 11p15
A;bright hereditary osteodystrophy
What are the types of mosaicism?
A mosaic individual has 2 or more genetically different cell lines derived from the same zygote.
Types:
- Chromosomal e.g. 45XO/46XY individual (rare disorder of sex development), trisomy 8 mosaicism, confined placental mosaicism e.g. turner’s 45X, NF1 and DMD (gonadal)
- Single gene - post fertilisation somatic mutation e.g. Proteus syndrome
- Germline (gonadal) mutation- (dominant) mutations in germ cells can be inherited and cause a full phenotype in offspring therefore a phenotypically normal parent can have multiple affected children
- inactivation in females
What is the most common mutation in CF?
Delta F508, Phe508 deletion
Cystic Fibrosis. Inheritance. 2 types.
AR condition Classic CF (no functional CFTR protein) - chronic sinusitis, severe hepatobiliary disease, pancreatic exocrine insuff, meconium ileus at birth, obstructive azoospermia) Nonclassical CF (some functional CFTR protein providing survival advantage) - chronic bacterial infection of airways, adequate pancreatic exocrine function, obstructive azoopsermia
Additions or deletions of base pairs in exons results in?
Frameshift - pathogenic
If you delete exon 1, what will happen to protein production during translation of RNA to protein?
There will be complete loss of protein production.
Exon 1 is usually the start/initiation codon.
On the other hand deletion of one nucleotide in exon will result in abnormal RNA/protein production.
What is the role of transcription factor?
Regulates the polyadenylation of messenger RNA.
Mutations in genes for transcription factor are responsible for many familial disorders.
What is linkage equilibrium?
is the non-random association of alleles at different loci i.e. the presence of statistical associations between alleles at different loci that are different from what would be expected if alleles were independently, randomly sampled based on their individual allele frequencies.
e.g. 20% heterozygous at codon 16 and 22% heterozygous at codon 27.
If there is no linkage disequilibrium between alleles at different loci they are said to be in linkage equilibrium.
Cell cycle phases.
Interphase
Mitotic phase
Ctokinesis
Interphase:
GO: Quescent/senescent
G1:
cell grow in size
G1 check point control prior to entering S (p53)
Synthesis:
DNA replicates into exactly 2 chromosomes. 30% of cells in this phase at any time.
G2:
Significant biosynthesis to ensure cell growth and production of microtubules required for mitosis.
G2M checkpoint (p53)
Mitosis:
Cells divide into cytokines to produce identical daughter cells.
Division of mother cell into 2 daughter cells.
Metaphase checkpoint in the middle of mitosis.
Where does CTx act on the cell cycle?
Synthesis: Alkylating agents e.g. cyclophosphomide Antibiotic - doxorubicin Antimetabolites - 5FU, Gemcitabine, MTx Hydroxyurea
G2:
Bleomycin
M
Taxanes (antimicrotubule) e.g. paclitaxol, doxetaxol
Vinca alkaloids (spindle cell einhibitors) e.g vincristine, vinelrelbine
Etoposide
Chromosome deletions cause more severe effects than inserttion. T/F
True
47 XXY - Klineelters
45 XO - Turner
Creuzfeldt Jakob disease: what type og mutation identified in the prion protein?
Missense
Cell Cycle:
- quiescent/senescent
- Interphase
- Cell division
- quiescent/senescent
- G0: resting phase - Interphase
G1 = growth of cell
S= synthesis, doubling of the same cell
G2= preparing for mitosis, increase of microtubles. - Cell division
Mitosis: 2 daughter cells from the one cell
CTx on cell cycle
Bleolycin
Synthesis:
anthracyclines
hydroxyurea
5FU
Mitosis:
taxanes
