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2 - Clinical Genetics > Chromosomal abnormalities I > Flashcards

Chromosomal abnormalities I Flashcards

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1
Q

what are histones?

A

highly positively charged proteins that are attracted to the negative charge of DNA
-give the DNA a support to wrap around

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2
Q

what is a chromosome?

A

an organized package of DNA found in the nucleus of the cell

  • half of your chromosomes come from your mother and half from your father
  • Different organisms have different numbers of chromosomes
  • exist in homologous pairs
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3
Q

how do chromosome usually exist?

A

as chromatin (hetero/euchromatin)

  • DNA double helix bounds to histones
  • Octamer of histones form a nucleosome
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4
Q

what is a nucleosome?

A

a fundamental unit of DNA – eight histones and two turns of DNA

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5
Q

2 forms of chromatin?

A 
Euchromatin
-Extended state, dispersed through nucleus
Allows gene expression
-Transcriptionally activate
-Loosely packed

Heterochormatin
Highly condensed, genes not expressed

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6
Q

what is a locus?

A

location of a particular gene on a chromosome

at each locus, an individual has 2 alleles, one on each chromosome - they can be heterozygous or homozygous dominant/recessive

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7
Q

cell cycle phases

A

G1 - cellular contents excluding chromosomes are duplicated

S - synthesis, each of the 46 chromosomes are duplicated so that each chromosome now consists of 2 identical sister chromatids

G2 - synthesis of proteins (microtubules), error checks made in respect to the duplicated chromosomes, repair if needed

M - mitosis

G0 = resting phase, cells not dividing nor preparing to divide

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8
Q

how many pairs of chromosomes do humans have?

A

23
22 pairs of autosomes
1 pair of sex chromosomes (XX or XY)

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9
Q

what keeps the sister chromatids separate?

A

the centromere

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10
Q

name some classifications of chromosomes based on the centromere position?

A

Metacentric
p & q arms even length

Submetacentric
p arm shorter than q

Acrocentric
long q, small p
p contains no unique DNA
13-15, 21-22, Y

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11
Q

what are some types of chromosomal changes and how can they be detected?

A

numerical and structural

numerical can be detected by traditional karyotyping, FISH, QF-PCR, NGS
eg. Down’s (trisomy 21)

structural can be detected by raditional karyotyping, FISH

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12
Q

definitions of numerical abnormalities:

haploid
diploid
polyploid
aneuploid

A

HAPLOID:
one set of chromosomes (n=23) as in a normal gamete

DIPLOID:
cell contains two sets of chromosomes (2n=46, normal in human)

POLYPLOID:
multiple of the haploid number (e.g. 4n=92)

ANEUPLOID:
chromosome number which is not an exact multiple of haploid number - due to extra or missing chromosome(s) (e.g. 2n+1=47

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13
Q

forms of aneuploidy?

A

Trisomy - a type of aneuploidy in which there are three instances of a particular chromosome, instead of the normal two, eg. downs

Monosomy - a form of aneuploidy with the presence of only one chromosome from a pair, eg. turners syndrome

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14
Q

Mosaicism and its importance

SLIDE 20 diagram

A

mixed group of cells, some haploid, some diploid

Mosaicism is important wrt clinical presentation, for examples downs syndrome
-Down’s can have varying levels of severity depending on how many of the cells are trisomic for ch 21

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15
Q

examples of trisomy

A

3 copies of the chromosome (13, 18, 21)

pateu’s, edward’s and down’s respectively

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16
Q

disjunction

A

Pulling apart at anaphase

17
Q

with non-dysjunction, what is the result?

A

with mitotic cell divisions you can have a non dysjunction occurring
-the daughter cells will not have identical copies of chromosomes, instead they will have three copies or one which, leading to trisomic and monosomic cells

monosomic cells break down but trisomic remain, so you get the formation of a mosaic blastocyst

18
Q

2 causes of numerical abnormalities

A

Post-zygotic nondisjunction, i.e. mitotic non-disjunction = All 2n to mixture of 2n and 2n+1

Anaphase lag, i.e. trisomic rescue = All 2n+1 to mixture of 2n+1 and 2n. Anaphase lag can also cause aneuploidy.

19
Q

explain anaphase lag

A

process gets paused and doesn’t work properly

meiotic non dysjunction, generating a cell that is 100% trisomic wrt ch 21.

post zygotic proliferation with occur, and anaphase lag occurs, and one of those 3 chromosomes gets pocketed off into a vesicle and kicked out of the cell, resulting in 2 chromosmes remaining

all daughter cells after that will be disomic, but in the cells where that didn’t happen they will be trisomic

20
Q

Sex chromosomes abnormalities vs autosome chromosomal abnormalities - which are more severe?

A

autosomal chromosomal abnormalities are far more severe

21
Q

which type of abnormalities are very very rare?

A

Autosomal monosomy - 1 copy of the chromosome, and partial monosomies are far more common

Relatively common sex chromosome monosomy = Turner’s

22
Q

possible combination for nullisomic gametes?

A

Nullisomic gametes fertilised with a sperm carrying an X chromosome will be XO (Turners)

Nullisomic gametes fertilised with a sperm carrying a Y chromosome will be YO - this is in-utero lethal

23
Q

possible combination for disomic gametes?

A

XX
+ X chr = XXX = triple X syndrome
+ Y chr = XXY = Klinefelter’s (physically male)

XY
+ X chr = XXY = Klinefelter’s
+Y chr = XYY = XYY syndrome

24
Q

Summary of numerical abnormalities

A 
Types (all can be mosaic)
Autosomal
Trisomy 13, 18, 21
Sex chromosomes
XO, XXY, XYY

Mechanism
Nondisjunction
Anaphase lag

25
Q

How do we show there is an incorrect karyotype?

A

need to access the blood and generate a group of cells, culture them and get them dividing (specifically in metaphase as they are in their most condensed phase and easy to visualise)

  • venous blood
  • culture
  • add hypotonic saline and fix cells to the slide
  • digest with trypsin
  • stain with giemsa
  • analyse metaphase spread
  • karyotype
26
Q

Prenatal Diagnosis - methods

A

INVASIVE
miscarriage rate 0.5% to 1% for both

  1. Chorionic Villus Sampling at 11-14 weeks
    - placental cells
    - risks of maternal contamination
    - risk of transverse limb defects to foetus
  2. Amniocentesis at 14-20 weeks
    - extraction of amniotic fluid
    - biochemical diagnosis possible

NON INVASIVE

  1. Cell free foetal DNA (cffDNA) from 10 weeks onwards
    - DNA fragments in maternal plasma

For trisomies still need confirmation with amnio/CVS

27
Q

what is G banding and what does it involve?

A

Standard karyotyping methodologythat is good at detecting big deletion events, not small subtle events

  • Giemsa stain
  • Metaphase
  • Line-up based on: Size, Banding and Centromere position
28
Q

most common chromosome banding?

A

giemsa

29
Q

with giemsa banding, why do we get band formation?

A

giemsa highlights heterochromatic regions

Euchromatin = GC-rich; loosely packed; genes active, lighter bands

Heterochromatin = AT-rich; tightly packed; genes inactive, darker bands

Stain differently

30
Q

FISH

A

Fluorescent in situ hybridisation
Cultured cells, metaphase spread
Microscopic (5-10Mb)

  1. Fluorescent probe
  2. Denature probe and target DNA
  3. Mix probe and target DNA - probe will preferentially bind to the DNA and integrate into the patients genome
  4. Probe binds to target, under uv light the probe will glow on the metaphase chromosome
31
Q

drawbacks of FISH and g banding?

A

need to culture cells and get to the metaphase stage to visualise properly

32
Q

Quantitative fluorescence PCR

A

amplifies specific chromosomal regions using microsatellite markers

2 - Clinical Genetics (9 decks)

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