Genetics Pre-Midterm Flashcards
What is a phosphodiester bond?
Sugar-Phosphate
Why do we 5’ cap & 3’ poly-A tail mRNA?
- Protection from exonucleases/increase 1/2 life
- Necessary for nuclear export
- Cap binding complex necessary for translation
What are the 2 sites called before and after an intron?
- Donor site
2. Acceptor site
What holds everything together during splicing?
Spliceosome
Give an example of RNA editing
Apo-B-100 (liver) & Apo-B-48 (intestine)
* C –> U; a premature stop codon for the intestine isoform
What is a Lariat structure?
Circular structure that forms as 5’ donor site links to an invariant part of the intron
Humans only have 30,000 genes, but..
Alternative splicing can increase this in 60% of the genes
What are enhancers and activators and transcription factors?
All elements that regulate/stimulate transcription; can be upstream/downstream, in an intron, etc.
What is Chargoff’s rule?
A=T; G=C
Purines = Pyrimidines
How many H bonds are A-T vs. G-C
A-T: 2; G-C: 3
Who is bicyclic: purines or pyrmidines?
Purines
mRNA is linear or circular; single or double stranded?
Linear; single-stranded
A mutation in a donor site results in…
Longer gene
The regulatory sequences of genes regulate…
Rate of transcription
What does methylation do to DNA?
Inactivate / regulate the rate of transcription
How many genes do humans have?
25-30,000
What is the largest gene?
Dystrophin - 2.5Mb
Where on a chromosome are the genes located?
Between the telomere and the centromere
What are the 3 main divisions of DNA?
Nuclear, extragenic, mitochondrial
What are the 2 divisions of nuclear DNA?
Single gene, Multigene families (Classic, superfamilies)
What are the major divisions of multigene family genes?
- Classic - high degree of homology (HOX)
2. Supergene - low homology, similar fx (HLA, T cell receptor)
The 2 major categories of extragenic DNA:
- Tandem repeat (satellite, mini-telomeric, hypervariable-VNTR, micro-STR)
- Interspersed (short-Sines (30-40%) & Alu elements, long-Lines (20% & reverse transcriptase))
What part of DNA is used for fingerprinting & why?
STR (short tandem repeat)
STR & VNTR are polymorphic and inherited in a co-dominant fashion from mom/dad
Mitochondiral DNA is inherited…
Mother (cytoplasm of oocyte)
Differentiate between metacentric, submetacentric and acrocentric DNA.
Meta: P=Q – Chromo 1
Sub: P < Q – Chromo 4
Acro: P «< Q (satellite P) – Chromo 13,14,15,21,22
A karyotype is viewed during…
Metaphase
What is it called when both chromosomes of a pair are derived from the same parent?
Uniparental disomy
In what order are chromosomes arranged?
Largest to smallest (1-21)
What is asymmetric X inactivation?
When more than 50% of the cells of the maternal/paternal X is active
What is the barr body?
The inactivated X chromosome in females
When does lyonization take place?
After the development of female sexual organs
Who regulates Lyonization?
XIST (X inactivation center); which coats the inactivated X-chromosome
What is an epigenetic mechanism of DNA modification?
Imprinting: Methylation of CG islands close to the promoter; results in transcriptional repression
Differentiate between locus and allele
Allele: homologous chromosomes (homo/hetero)
Locus: location on a chromosome
Huntington’s disease is located …
Chromosome 4P
Which are the tumor suppressor genes (with respect to the cell cycle)?
p53 & Rb
* Between G1 & S
Who regulates the tumor suppressor genes?
Cyclins
What are the 3 major types of cells (with respect to the cell cycle)?
- Labile – multiply throughout life
- Stable – G0; can undergo division if stimulated
- Permeant – arrested in G0 (neuron, cardiac)
How does a cell in G0 get to S phase?
Through G1
Which stage of the cell cycle is most variable (time)?
G1
Cell spends maximum amount of time in Interphase or Mitosis?
Interphase
What is Turner Syndrome?
45, X (Non-disjunction)
What is Klinefelter Syndrome?
47, XXY
Differentiate between XYY & XXX (with respect to fertility)
XYY – fertile
XXX – infertile
Differentiate between the beginning of gametogenesis in males/females
Males: puberty
Females: embryonic life
Differentiate between number of mitoses in male sex cells vs. female
Male: 30-500; female 20-30
Males produce ___ gametes; females produce _____
4 spermatids; 1 ovum/3 polar bodies
Differentiate between nondisjuction in meiosis I vs. 2
I: XY, XY, no sex chromo * 2
II: XX, YY; no sex chromo * 2
How many chromosomes and chromatids at the beginning of mitosis?
46 chromosomes; 92 chromatids
Where is the second check point in the cell cycle?
After G2
What is the difference between cis & trans regulatory proteins?
Cis – same chromsome; trans – different chromosome
Differentiate between (lac operon) with glucose, lactose, & glucose/lactose
Glucose: negative
Lactose: positive
Glucose+lactose: no cAMP (but also no repressor)
In proks, what are the components of an operon?
promoter, operator (repressor), cAMP-binding
What are the two different terms for the level of gene transcription in proks?
Constituitive (always on)
Regulated (on with certain conditions)
How does the tryptophan operon function in proks?
In the absence of Trp, an inactive repressor is made & tryptophan is synthesized
What suppresses/activates the operator in the lac operon?
Normally, suppressed; but when lactose is present, allolactose binds to and suppresses the suppressor
Differentiate between the following mutations: non-functional repressor and a super-repressor in the lac operon.
Non-functional repressor: can’t bind to the operator (Lots of transcription!)
Super-repressor: repressor has mutation and is unable to bind to allocatose, so it won’t dissociate from the operator (NO transcription)
Transcription factors have 3 domains (euks)
- DNA binding domain
- Dimerization domain
- Enhancer binding proteins
What are the two different types of transcriptional modification in euks?
- Basal transcription
2. Enhancer transcription
How do transcriptional repressors work in euks?
Competition, Quenching, Blocking
What are hypoxia response elements?
HIF1-alpha, HIF1-beta;
Under normal conditions, HIF1-alpha is degraded by O2-dependent prolyl hydroxylase and FIH hydroxylase
In anoxia, the 2 proteins dimerize; angiogenesis, vasodilation, etc.
What are hormone response elements?
Up/down regulate inflammation (glucocorticoids)
What are MAX/MYC
MYC+MAX = gene activation
MAX alone = gene repression
MAX mutations – pheochromocytoma
Describe the regulation of iron in the body.
Translational modification
Ferritin & Transferrin
What are miRNA’s?
Gene silencing; Drosha–long pre-miRNA’s processed to mature miRNA’s
DICER processes them to ssRNA & forms RISC (RNA induced silencing complex)
- Regulation gene expression by BP’ing to 3’UTR
What is siRNA?
Short, interfering RNA; can silence genes
How is Fragile X related to miRNA/siRNA?
Misprocessing, low levels of FMRP gene; RISC complex
What are the features of autosomal dominant disorder?
- Vertical – doesn’t skip generations
- Equal M/F
- Father –> Son
Define recurrence risk
Probablity that offspring will have the disorder
What are the characteristics of autosomal recessive?
- Horizontal inheritance; skips generations
* M/F equal distribution
What are the major autosomal dominant disorders & characteristics?
Huntington's Disease Myotonic dystrophy (DMPK gene) Familial hypercholesterolemia Margan Achondroplasia (FGF3); cartilage-->bone OI (alpha-1) Neurofibromatosis (NF1) Acute intermittent prophyria
What disorders are triplet repeat disorders?
Huntington
Myotonic dystrophy
What are two examples of dominant negative mutations?
Mutant gene interferes with normal gene function (Marfan, OI)
What is an example of a haplo-insufficiency disorder?
Familial hypercholesterolemia; half normal levels of the gene (LDL receptors) defected
What are two examples of gain-of-function mutations?
Huntington/Achondroplasia; increased level of gene expression; ne functional gene producyt
What is the classical variable expressivity autosomal dominant mutation?
Neurofibromatosis I
Define incomplete penetrance
An autosomal dominant mutation skips a generation
- Pt has genotype, but not phenotype (Huntingtons)
- Can calculate the penetrance risk
Define variable expression
Spectrum of the disorder (different phenotypic manifestations)
I.E. Hemochromatosis, Xeroderma pigmentosum, OI, NF
Define Pleiotropy
Affects multiple organ systems (Marfans)
Define locus heterogeneity
Same phenotype, different location of the mutation, i.e. NF, BRACA1/2
Define allelic heterogeneity
Different mutations at the same loucs (and same phenotype, i.e. CF
Define new mutation
Father (increased paternal age) has germ-line mutation due to decreased recognition of DNA errors, i.e. Achondroplasia, Apert, Marfans
Differentiate between the 2 causes of Prader-Willi & Angelman.
Microdeletion
Uniparental disomy
Describe the genetic differences between Prader-Willi & Angelman
Prader-Willi: deletion of paternal SNRPN
Angelman: deletion of maternal UBE3A
Describe the 4 triplet repeat disorders
Promoter: Fragile X (CGG)
Intron: Fredrich Ataxia (GAA)
Exon: Huntington (CAG)
3’ UTR: Myotonic Dystrophy (CTG)
There is a high/low chance of recombination for genes far apart from one another.
High; genes CLOSE to each other are considered LINKED
ASO probes can be used for…
CF, hemochromatosis
What are the limitations of PCR
- Won’t ID Heterozygous/Homozygous
- Won’t ID carriers
What are the limits of karyotype analysis?
Unable to detect microdeletions
What is CGH used for?
Tumor biology
Describe the following terms: silent, missense, nonsense, transversion, transition
Silent: no change in AA code Missense: change in protein Nonsense: stop codon Transition: purine for purine, etc. Transversion: purine for pyr, etc.
PCR won’t detect…
heterozygotes
What is the poly T tract in CF?
Associated with alternative splicing / mRNA is less stable
What are the 4 major types of OI?
- Classic, blue sclera
- Lethal, fetal
- Progressive onset
- No blue sclera
Describe MM, MZ, SZ, ZZ mutations in A1AT deficiency.
Less –> Most severe
Dominant negative mutation
A dysfunctional protein is incorporated into a multisubunit protein (Sickle Cell)
Gain of function mutation
Huntington
Haploinsufficiency
Familial hypercholesterolemia
Heteroplasmy
Mitochondiral inheritence
Anticipation
Triplet repeat disorders (increasing severity with newer generations
Overexpression of SHH
Hypertelorism
Differentiate between CGH and microarray cDNA
CGH: copy number variants
Microarray: gene expression
* Can both be used for tumors
Children with increased number of cervical ribs have a higher frequency of __________ due to ____________.
Cancer; loss of HOX gene
An example of a gain of function mutation is…
Achondroplasia; causes a decrease in chondrocyte differentiation and the formation of osteoblasts
46 XY - Swyer (Pure Gonadal Dysgenesis)
Loss of function of the SRY gene
- Female genatalia, clitoromegaly, bilateral gonads
- Increased risk of germline tumors; gonads removed
46 XX - Male Syndrome – de la Chappelle syndrome
Caused by a translocation of the SRY gene
* Typical boys and men; hypospadias, no Mullerian duct; infertile
AZF (azoospermia factor) mutation
Infertile men
FGF3 mutations (Most –> least severe)
Most severe least severe
* Thanatophoric dysplsia (lethal) – Saddan dysplasia – ACH – hypochondroplasia
Achondroplasia
AD; FGF3 mutation (FGFR normally inhibits chondrocyte growth)
G-C transversion at 1138: glycine arginine
* Sperm with the mutation actually have selective advantage
* A gain of function mutation
SHH-PTCH Gli Pathway Disorders
Holoprosencephaly: SHH or Six3 gene; single incisor; cyclopia
SLOS: 7-dehydrocholestrol reductase (in the SHH pathway); retardation
Gorlin (Nevoid basal cell carcinoma): PTCH – early basal cell ca
Pallister Hall: Brain tumor, polydactly
Rubenstein-Taybi: CREBP gene; broad thumbs, small stature
Rubenstein-Taybi
CREBP gene; broad thumbs, small stature (SHH)
Pallister Hall
Brain tumor, polydactly (SHH)
Gorlin (Nevoid basal cell carcinoma)
PTCH – early basal cell ca (SHH)
SLOS
7-dehydrocholestrol reductase (in the SHH pathway); retardation (SHH)
Holoprosencephaly
SHH or Six3 gene; single incisor; cyclopia
Define the 4 categories of single developmental anomolies.
Malformation: primary genetic problem (congenital heart defect)
Disruption: Short arms secondary to a decreased vascular supply (phocomelia)
Deformation: Club foot (due to low amniotic fluid)
Dysplasia: Monogenic; problems with tissue organization (FGF)
Define the 3 categories of multiple developmental anomolies.
Sequences: cascade effects
Syndromes: groups of anomolies
Associations: traits
Phocomelia
Disruption: Short arms secondary to a decreased vascular supply
Sonic Hedgehog protein
Tissue patterning, ventral floor plate, hair, tooth, lung, pancreas; limb patterning
On what chromosome is SHH?
Long arm 7
What are the HOX genes?
Anterior/Posterior axis; segmentation; gradient is important
* Kids with an extra cervical rib –> higher risk of cancer
