Molecular Genetics Flashcards
Describe telomers in humans.
repeats of 5’- TTAGGG -3’ (10-15 thousand bps) at end there is a long end overhang without a complimentary sequence that loops back on itself to form a complex structure
Why are telomers required?
because lagging strand synthesis at the end of the chromosome requires a free 3’-hydroxyl group to elongate from, but there is not room for a new RNA primase sometimes, so one DNA molecule per replication would be lost at the end of the chromosome
When is telomerase expressed?
most somatic cells in mammals do not make telomerase (so the telomeres get shorter every cell division and cells will only divide a limited number of times and the amount of divisions decreases as we age)
Tumor cells DO express telomerase, though, and cancer cells replicate indefinitely
anomalies in pigmentation of finger nails
premature graying
bone marrow failure
liver cirrhosis
lung scarring
somewhat shortened lifespan (median age at death >50 years)
Dyskeratosis congenita
AD
het loss of RNA component of telomerase
What is the first line of defense for DNA repair?
proofreading by DNA polymerase (3’ to 5’ exonuclease)- the next nucleotide will not be added unless there is good base pairing at the new 3’ end, if not, the incorrectly paired base at 3’ is removed
(highly accurate, but not perfect)
Name the mismatch repair enzymes and what condition(s) are caused by mutations to these enzymes.
MLH1, MSH2, MSH6, and PMS2
Lynch syndrome
What genetic disease is associated with loss of BER function?
mutations in MUTYH (which produces a specific glycosylase)
AR form of colorectal polyposis with increased colon cancer risk
Describe the special case of 5’-methyl C.
Deamination of C gives U, but deamination of methylated-C (which is important in turning off gene expression) gives a T - this leads to TG base pair that is repaired by a unique glycosylase (through BER) that is inefficient (results in 1/3 of single gene bp mutations) causing mutation hot-spots in these highly methylated regions that are not easily repaired
What genetic diseases are associated with defects in NER?
Xeroderma pigmentosum
Cockayne syndrome
UV sensitivity- photophobia keratitis atrophy of the skin lids Increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) Variable expressivity
Xeroderma pigmentosum
AR
7 different genes (damage recognition- APC, XPE, XPA, helicase- XPB, XPD, nuclease- XPF, XPG) associated with NER (loss of function results in inability to repair DNA with NER)
What causes double stranded breaks?
ionizing radiation
replication errors
oxidative damage
metabolic processes
cerebellar ataxia oculomotor apraxia choreoathetosis telangiectasias of the conjunctivae immunodeficiency (frequent infections) increased risk for malignancy (esp. leukemia, lymphoma)
ataxia-telangiectasia
AR
due to loss of signal that double strand breaks are present and repair is necessary
What genetic conditions/genes are associated with homologous recombination repair?
BRCA1, BRCA2
BARD1, BIRP1, NBN
Describe how methylation in early embryonic development is different for imprinted genes vs most genes.
for most genes DNA methylation is removed around fertilization (allows for early embryonic cells to be totipotent) and re-methylation occurs around the time of implantation
for imprinted genes, de-methylation/re-methylation occurs during gametogenesis prior to fertilization (establishes parent of origin methylation patterns)
hypotonia
developmental delay hypogonadism
mild ID
initial difficulty feeding with progression to hyperphagia later in childhood
Prader Willi syndrome
15q11-13 imprinting disorder (missing information from the paternal copy of the gene)
severe intellectual disability severe speech impairment gait ataxia seizures unique behavior
Angelman Syndrome
15q11-13 imprinting disorder (missing information from the maternal copy of the gene)
Also single gene disruption in UBE3A is most important
What are the possible causes of imprinting disorders?
mutation in a particular gene or imprinting control region microdeletion uniparental disomy (both copies of a portion of the genome come from one parent)
What genetic conditions have been identified as being differentially expressed through imprinting?
Beckwith Wiedman Syndrome (UPD 11p15.5 pat)
Silver Russell Syndrome (Loss of methylation on paternal chr11p15.5; some cases caused by UPD 7 mat)
Transient neonatal diabetes mellitus 1 (UPD 6 pat)
Temple Syndrome (UPD 14 mat)
Kagami-Ogata syndrome (UPD 14 pat)
Angelman syndrome (15q11-13 mat)
Prader Willi Syndrome (15q11-13 pat)
What are nonsense mutations?
introduce premature termination codon (results in a nearly complete protein with reduced activity, dramatically shortened protein with no activity, shortened protein that interferes)
What are missense mutations?
replace one amino acid with another
may affect protein structure and/or function
What are silent mutations?
due to redundancy in genetic code, some base substitutions will not change amino acid (can still have an effect on splicing though)
involuntary movements and clumsiness
depression, irritability, and obsessiveness
loss of ability to recall information, loss of attention, and difficulty with decision making
progressive (with onset between 30’s-40’s)
Huntington Disease
AD
HTT CAG trinucleotide repeat (expands paternally)
Describe the repeat levels for Huntington Disease.
Normal- <26 CAG repeats (average 19)
Intermediate (no symptoms)- 27-35 CAG repeats
Reduced-penetrance- 36-39 CAG repeats
Fully penetrant- >40 (adult onset between 36 and 55 repeats; juvenile onset with repeats greater than 60)
What is the mechanism of Huntington disease?
repeats increase numbers of glutamine residues that form aggregates that are neurotoxic
Name the disorders associated with CAG repeats within protein.
Huntington Disease Dentato-rubropallidoluysian Atrophy (DRPLA) Spinobulbar Muscular Atrophy (SBMA) Spinocerebellar Ataxias (SCA1, 2, 6, 7) Machado-Joseph syndrome (SCA3)
cataracts and mild myotonia (sustained muscle contraction)
normal lifespan
Myotonic dystrophy type 1 (mild form)
AD
DMPK- CTG repeats (in 3’ UTR)
muscle weakness myotonia cataracts cardiac conduction abnormalities can result in shortened lifespan
Myotonic dystrophy type 1 (classic form)
AD
DMPK- CTG repeats (in 3’ UTR)
severe hypotonia and weakness
can have respiratory insufficiency
ID (usually)
Myotonic dystrophy type 1 (congenital form)
AD
DMPK- CTG repeats (in 3’ UTR)
almost always passed down from mothers
Describe the repeat levels for Myotonic Dystrophy.
Normal- 5-34 CTG repeats
Premutation (no symptoms)- 35-49 CTG repeats
Full penetrance- >50 CTG repeats (anticipation very much present- up to 1000 in congenital)
Describe the mechanism of Myotonic Dystrophy type 1.
expanded CUG (in mRNA) pairs to itself creating a hairpin of double stranded RNA which binds to transcription factors and splicing factors (esp those involved in alternative splicing of proteins necessary for muscle development) resulting in alternative patterns of transcription and alternative splicing
muscle weakness, spasticity scoliosis bladder dysfunction cardiomyopathy diabetes slow progressing age of onset between 10-25 y/o
Friedreich Ataxia
AR (can have compound hets)
FXN- GAA repeats (in the first intron)
Describe the repeat levels for Friedrich Ataxia.
Normal- 5-33 GAA repeats (although >27 is rare)
Premutation (no phenotype)- 34-65 GAA repeats
Borderline (small risk of developing Late Onset FA at 26-39 y/o/Very Late Onset FA at 40 y/o)- 44-66 GAA repeats
Disease causing- 66-1700 GAA repeats
What is the mechanism for Friedrich Ataxia?
expanded repeats in the intron result in abnormal DNA structure of frataxin (a mitochondrial protein involved in synthesis of enzymes in the respiratory chain) which interferes with transcription and promotes formation of heterochromatin (shutting off gene expression)
Name repeat disorders that are not trinucleotides.
Myotonic Dystrophy Type 2 (tetranucleotide repeat disorder)
Spinocerebellar ataxia type 10 (pentanucleotide repeat disorder)
C9orf72 (hexanucleotide repeat disorder)
gradual onset, generally painless progressive muscle weakness
loss of motor neurons
onset between 30-70 y/o
Amyotrophic Lateral Sclerosis (ALS)
C9orf72- GGGGCC repeats (in non-coding sequence)
can also present with symptoms of FTD
Describe the repeat lengths for C9orf72.
Normal- 20 GGGGCC repeats
Affected- >30 GGGGCC repeats
ANTICIPATION UNCLEAR
changes in behavior, loss of inhibition and impulse control loss of word comprehension difficulty producing speech early onset dementia onset between 30-70 y/o
Frontotemporal dementia (FTD)
C9orf72- GGGGCC repeats (in non-coding sequence)
can also present with symptoms of ALS
