Genetics (Grody) Flashcards
Euchromatin vs. Heterochromatin
Euchromatin: light staining, decondensed, active chromatin, MORE transcription
Heterochromatin: dark staining, condensed, inactive chromatin, LESS transcription
2 types of heteroploidy
In general, chromosome number other than 46
Euploid: exact multiple of haploid chromosome number (2n, 3, 4n); sprem/egg problems
Aneupolid: not exact multiple of haploid chromosome number (47XY+21); nondisjunction
Partial hydatidiform mole
Two sperm fertilize one egg or diploid sperm (two copies of every chromosome) fertilizes an egg
69, XXY (triploid)
Remnants of fetal tissue produced, with placenta and sometimes small atrophic fetus
Complete mole
Two sperm (or one diploid sperm?) fertilizes an egg that has no DNA
46XX or 46XY (diploid, with only paternal genes)
No fetal tissue, risk of ovarian teratoma or choriocarcinoma
What happens if you have triploidy with an extra maternal set of genes?
Spontaneous abortion
What is tetraploidy?
Always 92, XXXX or 92, XXYY because always twice 46XX or twice 46XY
Early defect in embryogenesis, failure of early cleavage division in zygote
Down Syndrome
Trisomy 21
4% have unbalanced translocation with one chromosome Robertsonian translocation (21q + 14 or 22 q)
Robertsonian Translocation
Translocation between acrocentric chromosomes (13, 14, 15, 21, 22) where no DNA lost (balanced translocation) so individual is normal
FISH
Label specific DNA sequence with a fluorescent probe
Use when you know what you’re looking for
Don’t need to culture cells
Chromosomal painting
Label entire chromosome with a dye specific to that chromosome
Detect complex gene rearrangements
Oogenesis
All primary oocytes at Prophase I by birth, stay in Prophase I until time for ovulation
Finish Meiosis I as follicle matures (get rid of first polar body)
At ovulation, start Meiosis II and goes up until Metaphase II
If fertilization occurs, Meiosis II completes
Spermatogenesis
Spermatogonia in seminiferous tubules –> at puberty they divide to produce primary spermatocytes –> Meiosis I to make two haploid secondary spermatocytes –> Meiosis II to create spermatids –> grow into sperm
Takes 64 days, happens constantly after puberty
When does crossing over happen?
Pachytene stage of prophase
When does nondisjunction happen?
Anaphase
Nondisjunction in meiosis I vs. meiosis II
Meiosis I: both parental chromosomes present (one of each of homologous chromosomes)
Meiosis II: two copies of only one parental chromosome (two of the same homologous chromosome)
Examples of autosomal recessive
Sickle cell disease
Phenylketonuria
Cystic fibrosis
Tay Sachs
Examples of autosomal dominant
Huntington disease
Neurofibromatosis
Familial breast/ovarian cancer
Marfan Syndrome
Examples of X-linked recessive
Duchenne muscular dystrophy
Color blindness
Hemophilia A
Fragile X syndrome
Examples of mitochondrial inheritance
several myopathies
Note: mictochondrial inheritance stops at affected male!
Fragile X Syndrome
“X-linked dominant”
CGG repeat >200 right before FMR1 gene
Normal <45; Gray 46 - 54; Premutation 55 - 199
Use PCR amplification or Southern Blot to determine size of repeat (note: PCR will give blank because DNA too long to stably amplify)
Anticipation through mother (repeats get longer)
Premutation in females: primary ovarian insufficiency/primary ovarian failure
Premutation in male: Fragile X Associated Tremor Ataxia Syndrome
Mental retardation, prominent ears, long face…
Huntington’s Disease
Autosomal dominant
CAG repeat >40 in gene IT15
Normal <26; Mutable 27 - 35; Reduced penetrance 36 - 39
Use PCR amplification or Southern Blot to determine size of repeat
Anticipation through father
Age of onset can decrease over generations because of anticipation
Neurodegenerative: unsteady gait, cognitive decline
Cystic Fibrosis
Autosomal recessive
Mutation in CFTR gene, commonly del F508 doesn’t allow protein folding, also W1282X
Normal: CFTR secretes Cl- in lungs and GI; and reabsorbs Cl- from sweat
Disease: No Cl- secretion w/water following in lungs, so secrete thick mucus that plugs lungs so you can’t breathe
Cystic Fibrosis Screening/Tests
Strip with 50 DNA probes of common CF mutations (but not all!)
Can be “compound heterozygote” with 2 diff mutations (will have CF)
In people with CF, might have to sequence genome to definitively find mutation
Sweat test shows increased Cl- in people with CF (because CFTR usually reabsorbs Cl-)
BRCA Breast and Ovarian Cancer
Autosomal dominant
Myriad discovered BRCA sequence and patented it
2.5% in Ashkenazi Jews
Early onset, bilateral presentation
Sickle Cell Disease
Autosomal recessive
HbS has mutation in 6th amino acid (Glu –> Val) of beta chain
Causes mutated deoxygenated hemoglobin (HbS) to polymerize and precipitate sickling
Get anemia and veno-occlusive disease
(Qualitative problem)
Sickle Cell Heterozygote Advantage
Heterozygous HbS/HbA are resistant to malaria
Malaria parasite replicates in RBC and releases H+ but HbS precipitates, causing RBC membrane leakage and kills parasite
Still have good, soluble HbA
Thalassemia
Globin chain of hemoglobin is either absent or present at reduced levels
Autosomal recessive
(Quantitative problem)
Alzheimer’s Disease
Complex genetic disease, but 10% of AD patients have a familial form associated with these genes:
Beta-amyloid precursor protein (APP), Presenilin 1 (PS1), Presenilin 2 (PS2)
ApoE2 protein is protective
ApoE4 protein is detrimental (although not completely…)
Allele-specific oligonucleotide (ASO)
Short DNA probe
Use to probe for specific mutation
Array comparative genomic hybridization (aCGH)
1 million DNA probes of 1MB size spread across all chromosomes. Run pt and ctrl DNA and look at red, yellow, green color of each dot to determine mutations
Better than FISH because high reproducibility and precise mapping of aberrations
Dot blot
Hybridization of DNA probe to target specimen spotted onto filter membrane
Southern blot
Restriction endonuclease digestion then gel electrophoresis, then transfer DNA fragments onto filter membrane then hybridize with DNA probe
Use to determine gross structure/length of gene
Amniocentesis
Needle into mother’s abdomen to get 50mL amniotic fluid containing fetal tissues
16-17 weeks pregnancy
Chorionic villus samples (CVS)
Syringe/catheter into vagina, get sample of placenta that contains fetal and maternal cells and sort out fetal cells
10-12 weeks pregnancy
How do you test for a disease whose genes have not yet been identified?
Linkage analysis–If genes involved have at least been mapped to a chromosome
Heritability
Percentage of population variation in a trat that is due to genes as opposed to environmental factors
Note: Autism is very heritable but we still don’t know the genes involved
Preimplantation Genetic Diagnosis (PGD)
Do IVF, let grow until blastocyst, extract a single cell, do single cell PCR to look for mutation
Hardy-Weinberg Equilibrium
Freq(aa) = q2
Freq (Aa) = 2pq
Can survive after nondisjunction of which chromosomes?
13, 18, 21, X, Y
Rett Syndrome
Mutation on MECP2 gene which is on X chromosome
Neurodevelopmental disorder
Mostly females that are affected because is embryonic lethal in males (you need a normal copy of MECP2 on one X to survive)
