Genetics (Grody)

Question 1

Euchromatin vs. Heterochromatin

Answer 1

Euchromatin: light staining, decondensed, active chromatin, MORE transcription

Heterochromatin: dark staining, condensed, inactive chromatin, LESS transcription

Question 2

2 types of heteroploidy

Answer 2

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

Question 3

Partial hydatidiform mole

Answer 3

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

Question 4

Complete mole

Answer 4

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

Question 5

What happens if you have triploidy with an extra maternal set of genes?

Answer 5

Spontaneous abortion

Question 6

What is tetraploidy?

Answer 6

Always 92, XXXX or 92, XXYY because always twice 46XX or twice 46XY

Early defect in embryogenesis, failure of early cleavage division in zygote

Question 7

Down Syndrome

Answer 7

Trisomy 21

4% have unbalanced translocation with one chromosome Robertsonian translocation (21q + 14 or 22 q)

Question 8

Robertsonian Translocation

Answer 8

Translocation between acrocentric chromosomes (13, 14, 15, 21, 22) where no DNA lost (balanced translocation) so individual is normal

Question 9

FISH

Answer 9

Label specific DNA sequence with a fluorescent probe

Use when you know what you’re looking for

Don’t need to culture cells

Question 10

Chromosomal painting

Answer 10

Label entire chromosome with a dye specific to that chromosome

Detect complex gene rearrangements

Question 11

Oogenesis

Answer 11

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

Question 12

Spermatogenesis

Answer 12

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

Question 13

When does crossing over happen?

Answer 13

Pachytene stage of prophase

Question 14

When does nondisjunction happen?

Answer 14

Anaphase

Question 15

Nondisjunction in meiosis I vs. meiosis II

Answer 15

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)

Question 16

Examples of autosomal recessive

Answer 16

Sickle cell disease

Phenylketonuria

Cystic fibrosis

Tay Sachs

Question 17

Examples of autosomal dominant

Answer 17

Huntington disease

Neurofibromatosis

Familial breast/ovarian cancer

Marfan Syndrome

Question 18

Examples of X-linked recessive

Answer 18

Duchenne muscular dystrophy

Color blindness

Hemophilia A

Fragile X syndrome

Question 19

Examples of mitochondrial inheritance

Answer 19

several myopathies

Note: mictochondrial inheritance stops at affected male!

Question 20

Fragile X Syndrome

Answer 20

“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…

Question 21

Huntington’s Disease

Answer 21

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

Question 22

Cystic Fibrosis

Answer 22

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

Question 23

Cystic Fibrosis Screening/Tests

Answer 23

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-)

Question 24

BRCA Breast and Ovarian Cancer

Answer 24

Autosomal dominant

Myriad discovered BRCA sequence and patented it

2.5% in Ashkenazi Jews

Early onset, bilateral presentation

Question 25

Sickle Cell Disease

Answer 25

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)

Question 26

Sickle Cell Heterozygote Advantage

Answer 26

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

Question 27

Thalassemia

Answer 27

Globin chain of hemoglobin is either absent or present at reduced levels

Autosomal recessive

(Quantitative problem)

Question 28

Alzheimer’s Disease

Answer 28

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…)

Question 29

Allele-specific oligonucleotide (ASO)

Answer 29

Short DNA probe

Use to probe for specific mutation

Question 30

Array comparative genomic hybridization (aCGH)

Answer 30

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

Question 31

Dot blot

Answer 31

Hybridization of DNA probe to target specimen spotted onto filter membrane

Question 32

Southern blot

Answer 32

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

Question 33

Amniocentesis

Answer 33

Needle into mother’s abdomen to get 50mL amniotic fluid containing fetal tissues

16-17 weeks pregnancy

Question 34

Chorionic villus samples (CVS)

Answer 34

Syringe/catheter into vagina, get sample of placenta that contains fetal and maternal cells and sort out fetal cells

10-12 weeks pregnancy

Question 35

How do you test for a disease whose genes have not yet been identified?

Answer 35

Linkage analysis–If genes involved have at least been mapped to a chromosome

Question 36

Heritability

Answer 36

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

Question 37

Preimplantation Genetic Diagnosis (PGD)

Answer 37

Do IVF, let grow until blastocyst, extract a single cell, do single cell PCR to look for mutation

Question 38

Hardy-Weinberg Equilibrium

Answer 38

Freq(aa) = q²

Freq (Aa) = 2pq

Question 39

Can survive after nondisjunction of which chromosomes?

Answer 39

13, 18, 21, X, Y

Question 40

Rett Syndrome

Answer 40

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)