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Life Cycle > Chromosomes and Cytogenetic Abnormalities > Flashcards

Chromosomes and Cytogenetic Abnormalities Flashcards

1
Q

Which histone proteins exist within the octameric core?

A

H2A
H2B
H3
H4

[2 of each type]

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2
Q

What is the function of the histone H1?

A

holds the octameric core together and the core DNA wrapped around it

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3
Q

What length is the linker DNA on average?

A

~ 20bp

=> DNA between 2 nucleosome

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4
Q

How many turns of DNA are there per nucleosome?

A

2 turns of DNA within one nucleosome/octameric core

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5
Q

What are the different types of chromosomes?

A

22 autosome pairs + 1 pair sex chromosomes

METACENTRIC
p and q arms even length
centrally located centromere
chr 1-3, 16-18

SUBMETACENTRIC
p arm < q arm length
centromere is slightly off centre
chr 4-12, 19-20, X

ACROCENTRIC
long q arm, small p arm
p contains no unique DNA
chr 13-15, 21-22, Y

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6
Q

What is polyploidy?

A

multiple (complete) sets of chromosomes

e.g. triploidy 3n=69

not usually compatible with human life (would be embryonic lethal)

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7
Q

What is aneuploidy?

A

extra or missing chromosomes

extras are not present in all chromosomal pairs

e.g. trisomy 21
(2n+1=47)

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8
Q

What are the main features of mitosis?

A
  • cell division that occurs in somatic cells
  • sister chromatids are identical
  • 2 daughter cells made from each parent cell
  • each daughter cell receives 1 chromatid of each chromosome
  • daughter cells are identical to parent
  • each chromosome behaves independently
    (homologues do not interact, align as 46 separate chromosomes)
  • process usually takes 1-2hr
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9
Q

What are the main features of meiosis?

A
  • two phases: meiosis I and II
  • important to introduce natural variation
  • daughter cells are genetically unique

MEIOSIS I

  • align as homologous pairs
  • allows for chiasma (crossing over, recombination) formation
  • pulls apart homologues from one another (with mix of maternal/paternal alleles)
  • daughter cells have 23 chromosomes each with 2 chromatids (diploid)

MEIOSIS II

  • align as independent chromosomes
  • sister chromatids pull apart
  • daughter cells have 23 chr with 1 chromatid each (haploid)
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10
Q

How is natural variation introduced in meiosis?

A
  • independent assortment of chromosomes

- recombination

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11
Q

What is ‘crossing over’ in meiosis?

A

reciprocal breaking and rejoining of homologous chromosomes

  • occurs during metaphase I of meiosis I
  • results in new allele combinations (between maternal and paternal homologues)
  • resulting haplotypes: recombinants
  • original haplotypes: non-recombinants
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12
Q

What are the broad types of chromosomal changes?

A
  • numerical

- structural

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13
Q

What are the types of numerical chromosomal abnormality?

A

AUTOSOMAL ANEUPLOIDY
T13: Patau syndrome
T18: Edward syndrome
T21: Down syndrome

SEX CHR ANEUPLOIDY
47 XXY: Klinefelter's syndrome 
45 XO: Turner's syndrome 
47 XYY: XYY syndrome (over-represented in violent male community - dubious study) 
47 XXX: Triple X syndrome
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14
Q

Aneuploidy in what type of chromosome is more severe?

A

Autosomal aneuploidies much more severe than those in sex chr

sex chr aneuploidies therefore have a higher prevalence in the general population

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15
Q

What is non-disjunction?

A

failure of chromosomes (meiosis I) or chromatids (meiosis II) to separate

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16
Q

What is disomic non-disjunction?

A

in meiosis I

when both chromatids (from one chr) get sorted into the same daughter cell

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17
Q

In what cell types is non-disjunction more commonly seen?

A

female gametes

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18
Q

Is chromosomal monoploidy compatible with life?

A

sex chr monoploidy = Turners syndrome (45XO)

autosomal monoploidy: lethal
likely premature embryonic lethality

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19
Q

How are aneuploidies visualised?

A
  • G-banding (karyotype analysis)
  • FISH
  • QF-PCR
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20
Q

What is the procedure for G-banding?

A
  • dividing cells must be in metaphase
  • controlled partial digestion of chromosomes with trypsin
  • stain with Giemsa
  • produced alternating light (GC-rich) and dark (AT-rich) bands
  • binding pattern: allows chr ID
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21
Q

How does G-banding stain the chromosomes?

A

patterns such that heterochromatin stains as dark bands whilst euchromatin is paler

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22
Q

What is Giemsa?

A

DNA binding chemical dye
used in G-banding
to stain partially digested chromosomes

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23
Q

Why must cells be in metaphase for G-banding?

A

chromosomes are in their most condensed form

therefore most easily visualised

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24
Q

Why is the nature of euchromatin? (context of karyotyping)

A

GC-rich
loosely packed
actively transcribed genes

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25
Q

Why is the nature of heterochromatin? (context of karyotyping)

A

AT-rich
densely packed
genes are inactive/repressed

26
Q

What are the disadvantages of G-banding?

A

subtle chromosomal abnormalities cannot be distinguished

takes several days (need to culture cells first)

27
Q

What abnormalities can G-banding identify?

A

aneuploidies
translocations
very large deletions

28
Q

What is FISH?

A

= fluorescence in situ hybridisation

  • requires fluorescent probe complimentary to desired DNA sequence
  • probe hybridises to metaphase spread of chr
  • excite probe with UV to visualise chosen locus
29
Q

How is FISH used clinically?

A

often used to detect T21 and T13 simultaneously
(Down and Patau)

presence of 3 separate fluorescent probes for either locus will confirm trisomy

30
Q

What is QF-PCR?

A

= quantitative fluorescent PCR

uses known microsatellites on chromosomes (CNVs) to identify abnormalities such as trisomy (should be 2 copies of each microsatellite usually, so if this is disturbed then suggests abnormality)

QF-PCR currently only used as part of national screening programmes

uses extracted DNA

takes ~48h

31
Q

What are microsatellites?

A

di-, tri-, tetra-nucleotide sequence with variable number of repeats

number of repeats varies between individuals
total length of microsatellite sequence varies between individuals

32
Q

What do the readouts for QF-PCR look like?

A

For microsatellite:
HOMOZYGOUS DISOMY: single peak of high intensity signal
HETEROZYGOUS DISOMY: two peaks of similar (lower) intensity signal
TRISOMY: 3 peaks of low signal or more likely 2 peaks (one of high signal and one of low signal)

33
Q

What are the genetic abnormalities underlying T21?

A

COMPLETE TRISOMY 21 (95%)

ROBERTSONIAN TRANSLOCATION (4%)

MOSAICISM (1%)
usually much milder features, since this occurs post-zygotically due to mitotic non-disjunction

34
Q

What happens to monosomic cells produced from post-zygotic mitotic non-disjunction?

A

they will be destroyed (apoptosis)

autosomal monosomy not compatible with life

35
Q

What is mosaicism?

A

presence of 2 or more genetically different cell lines derived from a single oocyte

usually arises from non-disjunction in mitosis (occurs post-zygotically)

36
Q

What is the clinical relevance of mosaicism?

A
  • phenotypes are generally less severe
  • can be difficult to assess (which tissues are affected, how many different genotypes are there)

e.g.
Klinefelters (15%)
Downs (~2%)
Turners (<25%)

37
Q

What is the genetic pathophysiology of the majority of Turners syndrome cases?

A

partial monosomy/micro-deletion syndrome
(= one full copy of X chr and one missing a chunk)

(rather than occurring via non-disjunction)

38
Q

How does Turners syndrome arise?

A

= 45 X- (45XO)

45XO
nullisomic gametes fertilised with sperm carrying an X chr

45YO
nullisomic gametes fertilised with a sperm carrying a Y chromosome
this is LETHAL

39
Q

What are the different types of chromosomal translocations?

A

RECIPROCAL
between two non-homologous chromosomes

ROBERTSONIAN
between any two acrocentric chromosomes

40
Q

What is the prevalence of chromosomal translocations?

A

~ 1:500
carriers of balanced translocations are generally ok
BUT can produced unbalanced gametes

41
Q

Where are gene repair genes located?

A

chromsome 2

42
Q

What are balanced translocations?

A

have the correct number of each (region of each) chromosome

just maybe mot in the expected place

43
Q

What are unbalanced translocations?

A

too much or too little of a particular chromosome

44
Q

Where do clinical issues arise with translocations?

A

clinical problem arises for children of balanced translocation carriers

can produce unbalanced gametes through the process of meiosis

45
Q

What is the Robertsonian translocation?

A

when two acrocentric chromosomes break at or near their centromeres

fragments are then joined together again to make 1 metacentric chr (loss of 1 chr entity)

its possible for just the 2 sets of long arms to be brought together and there’s loss of satellites

46
Q

What happens to the cell when there’s a Robertsonian translocation?

A

there will be 45 chromosomes (instead of 46)
have only lost microsatellites, so not really a problem for the cell

will only affect acrocentric chromosomes

47
Q

Which chromosomes are commonly affected by Robertsonian translocation?

A

chr 13/14 (33% of all RobTr)

48
Q

Which chromosomes are acrocentric?

A

[small stubby p arms]

chr 13, 13, 15, 21, 22

49
Q

When do Robertsonian translocation become a (clinical) problem?

A

in gamete formation

because chromosomes can’t segregate properly

most abnormal combinations will be lethal

50
Q

What are the clinical outcomes of translocations?

A
  • v. difficult to predict
  • some unbalanced outcomes may lead to spontaneous abortion (v. early)
  • other unbalanced outcomes may lead to miscarriage later and present clinically
  • some may result in a live-born baby with various problems
51
Q

What are the other type of structural chromosomal abnormalities?

A

DELETION
terminal (loss of telomere, will result in cell death)
interstitial

INVERSION

DUPLICATION

RING CHROMOSOME

can all be detected with G-banding and FISH

52
Q

What is the nature of chromosomal deletions?

A

~ 1:7000 live births

  • may be interstitial or terminal
  • can cause monosomic region
  • gross deletions will be detected on G-banding spread
53
Q

What are the outcomes when a chromosomal deletion causes a monosomic region?

A
  • Haploinsufficiency of some genes
  • monosomic region may carry distinct phenotypes
  • phenotype will be specific and proportional to the size anyplace of deletion
54
Q

What is an example of a gross chromosomal deletion syndrome?

A

DiGeorge syndrome

22q deletion 
(deletion of q arm on chr 22)

can be detected with FISH

55
Q

What is the Cri-du-chat structural anomaly?

A

= 5p minus syndrome

Sx: intellectual deficit, developmental delay, microcephaly

can be detected with G-banding and FISH

56
Q

What are microdeletions?

A

small deletions not easily identified using standard karyotyping

=> unequal cross over in meiosis I causes loss or gain of a few genes

57
Q

What is array CGH used to detect?

A

= array comparative genomic hybridisation

used to see microdeletions and microduplications

58
Q

What is another name for ‘unequal crossing over’?

A

non-allelic homologous recombination

occurs in meiosis I ONLY

59
Q

What are common types of microdeletion syndromes?

A

WOLF-HIRSCHORN
4p16

WILLIAMS
7q11

DIGEORGE
22q11

60
Q

Why does unequal crossing over in meiosis I occur?

A

homologous chromosomes need to be correctly aligned in a complex in order for correct equal recombination to occur

in the unequal type: there is misalignment of the chromosomes and therefore are out of sync with each other

this means you can get deletion of one allele and gain of another allele (1 copy for A, 3 copies for B for eg)

61
Q

What is the process of array CGH?

A
  • patient and control DNA labelled with fluorescent dyes (probes)
  • these are then applied to microarray
  • patient and control DNA compete to hybridise to the microarray
  • measure fluorescent signals
  • computer software analyses output

if normal, then the control and patient DNA should behave similarly (both should be disomic for each genome region)

can calculate the dosage of patient/control DNA for each probe to assess for micro- deletion/duplication status

Life Cycle (29 decks)

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