Chromosomes

Question 1

Basic features of a chromosome

Answer 1

One centromere
Two telomeres
>=1 replication origin

Question 2

Types of chromosomes (by shape)

Answer 2

Metacentric
Telocentric (not human)
Acrocentric (chr 13, 14, 15, 21, 22)
Submetacentric

Question 3

Types of chromatin

Answer 3

1. Heterochromatin
   - -> Constitutive heterochromatin
   - -> Faculative heterochromatin
2. Euchromatin

Question 4

Constitutive heterochromatin

Answer 4

Repetitive DNA. Different for each chromosome (can use for FISH)
Found in: Centromere, C-band positive, Satellite DNA (stalks)

Question 5

Facultative heterochromatin

Answer 5

involved in regulation of genetic activity
More heavily methylated than active genes
X inactivation, cell type specificity,

Question 6

Euchromatin

Answer 6

less condensed during interphase. active

Question 7

Major chromosome abnormalities found in:

Answer 7

8% of all conceptuses
50% of all SABs
0.7% of all live births
Most cancer cells

Question 8

Position effects

Answer 8

Two genes put next to each other through translocation that alter the regulation of one or both with deleterious effects
(i.e. Philadelphia chromosome)

Question 9

Major indications for chromosome studies

Answer 9

1. Child w/multiple congenital anomalies, dysmorphic features, intellectual disability, and/or developmental delay
2. Individual w/known chromosomal syndrome
3. Couple w/>=2 unexplained 1st trimester SABs or unexplained infertility
4. AMA
5. Individual w/hematologic disorder (pancytopenia, preleukemia, leukemia)
6. Individual w/neoplastic disorder assoc w/known chromosomal abnormality ( i.e. Burkitt lymphoma, Ewing sarcoma)

Question 10

Trisomy 21 recurrence risk (Robertsonian translocation)

Answer 10

14;21: 10% if maternal, 2-3% if paternal

21;21: 100%

Question 11

Function of centromere

Answer 11

1. provide site of attachment for spindle
2. hold 2 chromatids together during metaphase
3. site of motor responsible for chromosome movement at anaphase

Question 12

Non-disjunction

Answer 12

Chromosomes don’t segregate properly.
Can occur during mitosis, 1st meiotic division, or 2nd meiotic division.
Almost all non-disjunction is Maternal meiosis I

Question 13

Euploidy

Answer 13

abnormal number of whole sets of chromosomes

haploidy, triploidy, tetraploidy

Question 14

Uniparental disomy

Answer 14

Both copies of one chromosome from same parent. Isodisomy (both chr are identical) or heterodisomy (both chr are different)
Concern for imprinting effects or recessive conditions.
Caused by:
1. fertilization of nullisomic gamete by disomic gamete
2. mitotic non-disjunction in monosomic zygote
3. loss of chromosome in trisomic zygote

Question 15

Aneuploidy

Answer 15

Abnormal number of individual chromosomes, not whole sets (monosomy, trisomy)

Question 16

Meiotic segregation of reciprocal translocation

Answer 16

Form tetrads: one of each normal (N1, N2) and one of each translocation (T1, T2).

1. Alternate segregation: T1 and T2 go to one pole, N1 and N2 go to the other pole. All are balanced.
2. Adjacent-1 segregation: homologous centromeres disjoin. T1 and N2 go to one pole, T2 and N1 go to the other. All unbalanced.
3. Adjacent-2 segregation: homologous centromeres segregate together. T1 and N1 go to one pole, T2 and N2 go to the other. All unbalanced.
4. 3:1 segregation: 3 chromosomes go to one pole while 1 chromosome goes to opposite pole.

Question 17

Reciprocal translocation

Answer 17

Balanced in parent. Can be balanced or unbalanced in offspring.
Overall risk for unbalanced karyotype at amnio for reciprocal translocation: 12% (i think they quote 25% at CHP?).
1/3-1/2 of unbalanced probands inherit from carrier parent.

Question 18

Meiotic segregation for robertsonian translocation

Answer 18

Form triads: N1, N2, T1/2

1. Alternate segregation: T1/2 goes to one pole, N1 and N2 go to the other. All balanced.
2. Adjacent-1 segregation: N1 goes to one pole and N2, T1/2 goes to the opposite. Unbalanced.
3. Adjacent-2 segregation: N2 goes to one pole and N1, T1/2 goes to the opposite. Unbalanced.

Question 19

Sister Chromatid Exchanges (SCEs)

Answer 19

Exchange of DNA between sister chromatids at homologous sites.
SCEs at repeats can result in amplification, deletion or duplication.
Increase in SCEs indicate environmental mutagens.
Increased by 10-12x in Bloom syndrome

Question 20

Prader Willi syndrome (cause)

Answer 20

Imprinting disorder of Chr 15q12. (need paternal chr).
50% due to microdeletion of paternal 15q12, 50% due to uniparental disomy of maternal 15.
Maternal methylation of SNRPN blocks expression of ~20 other genes.

Question 21

X inactivation

Answer 21

aka Lyon hypothesis: 1 X chr is inactivated early in random and fixed manner. Xq13.2
X inactivation center (XIC): counting mechanism that initiates XIST
X Inactive Sequence Transcripts (XIST): long non-coding RNAs that coat X chr and initiates inactivation, induces methylation

Question 22

Chromosomal aberrations detected by aCGH (microarray)

Answer 22

Copy number variations: deletions, duplications, insertional translocations, mosaicism (whole chr or segment), complex rearrangements.

Does not detect: balanced rearrangements, inversions, low level mosaicism

Question 23

SNP arrays detect:

Answer 23

CNVs
Uniparental disomy
Absence of heterozygosity
Loss of heterozygosity (cancer cells)
Identity by descent
Consanguinity

Question 24

Indications for SNP array

Answer 24

Suspected UPD/conditions associated w/imprinting.
Suspected AR condition due to common ancestry or consanguinity.
Determine parental origin of chr abnormality by trio analysis.

SNPs must exist/be known for gene of interest in order to be useful.

Question 25

Indications for prenatal diagnosis (amnio/CVS)

Answer 25

1. AMA
2. Previous aneuploidy
3. Parental chr abnormality
4. Family history of diagnosable genetic disorder
5. Prior child or parent w/NTD
6. Abnormal screen
7. Abnormal U/S