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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



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



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



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?



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


Cystic fibrosis

Tay Sachs


Examples of autosomal dominant

Huntington disease


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



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



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



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)