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BMS2042 > Chromosomal abberration > Flashcards

Chromosomal abberration Flashcards

1
Q

Karyotype

A

• The number and structure of chromosomes
within a cell is called a karyotype
• Chromosomes are often rearranged in order of size and
position of the centromere to form a karyogram

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2
Q

Karyotyping method (basic)

A
  1. Blood, AFT (or CVS) or bone marrow
    are common specimens
  2. Cells must be cultured in vitro, typically 3 days
  3. After incubation, colcemid is added
    • Arrests mitosis at metaphase
  4. Cells fixed to slide and stained with Giemsa
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3
Q

Pre-natal screening

A

Genetic analysis of unborn foetuses common for the diagnosis of:
• Autosomal aneuploidies (next week)
• Sex chromosome aneuploidies
• Chromosomal re-arrangements
• Previously relied on amniocentesis (AFT) or chorionic villus sampling
(CVS) & karyotyping
• Dangerous for unborn child – spontaneous abortion
• Both require the culturing of cells post-collection – slow
• Move towards DNA testing

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4
Q

How prenatal DNA testing is achieved via obtaining sample from maternal blood?

A 
• During pregnancy foetal DNA is shed
into the maternal blood stream
• Apoptosis of placental cells during
embryogenesis
• Foetal DNA consists < 3-10% plasmaderived DNA
• Purification of foetal DNA obtained by
epigenetic patterns
• Foetal DNA differently methylated
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5
Q

Detection of foetal aneuploidies

1. Quantitative PCR methods

A 
• Example: Harmony®
• Determination of copy number of aneuploidic markers
• Typically directed towards common
abnormalities (such as Chromosomes
13, 18, 21, X & Y)
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6
Q

Detection of foetal aneuploidies

2. Next-generation sequencing

A

• Shows promise for the detection of chromosomal
translocations
• Detection of common genetic mutations

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7
Q

Aneuploidy vs Euploidy

A
  • Aneuploidy
  • A loss or gain of a single chromosome
  • E.g. Monosomy, trisomy, tetrasomy
  • Euploidy
  • An increase in a complete set of chromosomes (i.e. chromosome number doubles)
  • Examples:
  • Triploidy – 3n
  • Tetraploidy – 4n
  • Polyploidy – 3n, 4n, 5n, 6n
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8
Q

Naming of aneuploids

A

Chromosome number, genotype
For example:
47, XXX
47, 21+

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9
Q

Aneuploids are the result of

A

non-disjunction of chromosomes during meiosis
1st meiosis: homologous chromosome separate
2nd meiosis: Sister chromosome separates

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10
Q

If ND occurs during meiosis I,

A

gamete carries different recombinant chromosomes
• Mendel - segregation
2 Gamete with no chromosome and 2 gamete with 2 chromosome
when fused with egg
50% monosomy and 50% Trisomy

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11
Q

If ND occurs during meiosis II,

A

gamete carries same recombinant chromosomes
• Useful to determine when the ND occurred
50% normal
25% monosomy
25% Trisomy

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12
Q

Gene dosage responsible for

A

abnormal phenotypes
Diploid individuals has 2 copies of every gene
Trisomy has three copies of every gene
Monosomy has only one copy of every gene

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13
Q

Departures from normal gene dosage consequences

A
  1. The abnormal phenotype is characteristic for each chromosome
  2. Monosomy generally results in the worst phenotype (compared to
    trisomy)
  3. Aneuploidy of larger chromosomes results in a more severe
    abnormal phenotype
  4. Severe imbalance of genes leads to inviability
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14
Q

Sex aneuploids

A 
Generally better tolerated
18 different combinations are possible, but four are more common
• Monosomy X – Turner syndrome
• XXY – Klinefelter syndrome
• Trisomy X – Triple X syndrome
• XYY – Double Y syndrome
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15
Q

Non disjunction of sex chromosomes

Female meiosis

A

ND 1 = 50% XX and 50% 00

ND 2 = 50% X and 25% XX 25% 00

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16
Q

Non disjunction of sex chromosomes male meiosis

A

Normal : 4 gametes with 2 with X and 2 with Y

ND 1 = 50% XY 50% 00
ND 2= 25% XX 25% YY 50% 00

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17
Q

Why are sex aneuploids better tolerated?

A

• Two reasons:
1. X-inactivation
• XXX individuals will have two Barr bodies instead of one
• XXY will have one Barr Body
• Imprinting retains inactivated X chromosomes in subsequent cellular
generations
2. Y chromosome encodes only a few gene

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18
Q

So where do the abnormalities come from?

A 
• Not the entire X chromosome is
inactivated
• Hypothesis:
• Abnormalities due to excess/deficit
gene dosage within pseudo-autosomal
regions
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19
Q

Why are two fertile and the others not?

A

Triple X and Double Y are fertile
• During embryonic development, normal genotype restored
• Oocytes – 46, XX
• Spermatogonia – 46, XY
• One sex chromosome must be lost to develop germline
• ND or lagging during early mitosis

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20
Q

Turner syndrome (45, XO)

A
  • Female
  • 1/5000 – 10000 live births
  • Mild phenotype
  • Near normal intelligence
  • Short stature
  • Webbed neck
  • Sterile (ovaries degenerate)
21
Q

Mosaic Turner Syndrome

A

The missing X chromosome may not occur in the germline
• X chromosome could be lost in early foetal development
• Leads to only some cells being monosomic X (45, XO), while others are normal (46, XX)
• Called mosaicism

22
Q

Klinefelter (47, XXY)

A
  • Male
  • 1/1000 live births
  • Mild phenotype
  • Slightly lower IQ
  • Taller than average (long legs)
  • 30% show breast development
  • Sterile (devolved testes – no spermatogonia)
23
Q

Triple X (47, XXX)

A
  • Female
  • 1/1000 live births
  • Very mild phenotype – many women unaware
  • Mild reduction in IQ
  • Tend to be very tall
  • Occasionally behavioural problems reported (i.e. ADHD)
  • Fertile
24
Q

Double Y (47, XYY)

A
  • Male
  • 1/1000 live births
  • Very mild phenotype
  • Very tall
  • Rarely a slight reduction in IQ
  • Learning difficulties reported (delayed speech)
  • Rarely antisocial behaviour
25
Q

Uniparental diploidy

A 
• Uniparental diploidy – generation of
diploid set of chromosomes from a
single parent
• i.e. sperm carries 46 chromosomes; egg carries 0
• Very rare event (requires multiple errors in
meiosis in both parents)
• Foetuses don’t develop correctly
• Possibly due to genetic imprinting?
26
Q

Uniparental disomy

A 
• Uniparental disomy – inheritance of
both chromosomes from a single parent
e.g. normal sperm and egg which has 
• A chromosome is lost during an early
mitotic division in the foetus
• Only a 1/3 chance
• Range of symptoms
• Many go undiagnosed
• Abnormalities arise – imprinting errors?
Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent.
27
Q

Prader-Willi syndrome

A

• Deletion of paternal 15q11-13
• Or uniparental disomy where both copies of Chr 15 are inherited
from the mother
• Maternal copies of this region are silent due to imprinting
• Conversely, maternal deletion of the same region –
Angelman syndrome
• Symptoms
• Poor muscle tone
• Insatiable appetite - obesity
• Cognitive delays

28
Q

Autosomal aneuploidies

A
  • Arise due to errors in meiosis
  • Monosomy – one chromosomal homolog missing
  • Trisomy – extra chromosome
  • Normally not well tolerated
  • Compared to sex aneuploids (Triple X, Turner)
  • Why?
29
Q

Autosomal Monosomies

A

(2n – 1)
• Autosomal monosomies are not tolerated in humans
• Exception Turner syndrome (but that’s a sex aneuploid which is tolerated better due
to X-inactivation)
• In humans, monosomic foetuses die in utero
• Generally better tolerated in the plant kingdom
• Monosomic tobacco & Jimson weed have been isolated
• Tend to be less viable and often sterile

30
Q

how Monosomies unmask recessive alleles

A
  • Lethal alleles can be tolerated in the host, if an intact non-lethal homolog available
  • Similar to X-linked inherited traits being more common in males
31
Q

Haploinsufficiency

A

• When a single copy of an allele is NOT sufficient to
perform biological function
Example:
• DiGeorge Syndrome (22q11.2 deletion syndrome)
• TBX1 mutations

32
Q

Trisomies (2n + 1)

A
  • Accumulation of an additional chromosome
  • Generally better tolerated in humans than monosomy
  • i.e: trisomies more likely to survive (0.3% live births)
  • Survivability increased if trisomy is in small chromosome
  • Trisomy in all chromosomes occur, but only 3 survive
  • Trisomy accounts for 35% spontaneous abortions
33
Q

Trisomy in plants

A
  • Trisomic plants viable, but infertile
  • Typically associated with phenotypic differences
  • Trisomics of Jimson weed (Datura)
  • Diploid number 24
  • Trisomy of each chromosome results in a different capsule phenotype
34
Q

Down Syndrome (Trisomy 21 or 47, 21+)

A 
• Occurs in 1/800 live births
• Phenotypically variable
• Commonly presents with:
• Short stature
• Mental retardation
• Epicanthic fold (give eye characteristic
almond-shape)
• Heart and nervous system abnormalities
• Life expectancy not common beyond 60s
35
Q

Down Syndrome Critical Region (DSCR)

A

• A hypothetical region on chromosome 21 thought to be involved in
the phenotypes observed
• 21q22.2 = DSCR
• In a mouse DS model, identified candidate genes
1. DYRK – reproduces dosage-sensitive learning defects in Drosophila and mice
2. DSCAAM – reproduces heart and nervous system defects

36
Q

Maternal age effect and Down syndrome

A

Prevalence of Down Syndrome
births increases with maternal
age (at conception)

• In human females, meiosis starts in the foetus, but stops at diplotene
(prophase I)
• Meiosis only continues upon ovulation
• Therefore women in the late 30s early 40s produce eggs that are older (been arrested
in prophase I) for longer
• Spindle fibres less effective at older ages?

37
Q

Patau syndrome (Trisomy 13 or 47, 13+

A 
• 1/15000 live births
• A higher proportion die in utero
• Risk increases with maternal age
• Poor prognosis
• Few survive beyond 1 year
• Survivors affected with severe learning
difficulties, psychomotor difficulties,
cardiac abnormalities
38
Q

Edward’s syndrome (Trisomy 18 or 47, 18+

A 
• 1/8000 live births
• Most foetuses result in spontaneous
abortion
• Few (5-10%) survive beyond 1 year
• Common phenotypes:
• Failure to thrive, microcephaly skull
deformities, born with clenched hands
39
Q

Polyploidies

A

Term used to describe instances where more than 2, complete sets of the genome are available

40
Q

Polyploidies in animal and plants

A 
• Stable polyploidy un-common in animals
1. Reproduction of polyploid leads to aneuploidy
2. Interferes with gene dosage
• But polyploidy is seen in fish,
lizards and amphibians
• Batura toad(Bufotes baturnae)
• Much more stable in plants
41
Q

Autopolyploidy

A

• More than 2 sets of chromosomes all derived from one ancestral species
• Can happen naturally if:
1. Fusion of non-diploid gametes
2. The cell re-enters interphase after prophase I (mitosis) in early
embryonic development
• Can also be induced experimentally using colchicine
• Tolerated in plants and of important commercial significance

42
Q

New species by autopolyploidy

A

Once produced, an autotetraploid is an “instant” new species
So tetraploid is reproductively isolated from its diploid ancestor
Diploid X Tetraploid = Triploid (sterile)

43
Q

Allopolyploidy

the progeny will be fertile if……

A

• Generation of a polyploid individual from the fertilisation of two closely related but different species
• Progeny will be fertile if:
1. The progeny has a diploid number of chromosomes AND
2. There is sufficient similarity between genes for synapsis to occur

44
Q

Allopolyploidy -Inter-species hybrid

A

Inter-species hybrid
• Often done to create progeny with the most desirable characteristics of both parents
• The hybrid has one set of chromosomes from each parent (e.g. AB)
• Allopolyploidy is tolerated well in plant species, used frequently in commercial crops
• Rarer in mammals and other animals

mule
Donkey = 62 chromosomes
Horse = 64 chromosomes
Mule = 63 chromosomes (infertile)

45
Q

Creation of allopolyploids

how Interspecies hybrids can be made fertile

A

• Interspecies hybrids can be made fertile if made polyploidic
• Use colchicine to arrest mitosis during embryogenesis, then remove (chromosome doubling)
at fertlization AAABB after inducing it to re-enter interphase AA AA AA BB BB
• Generates a fertile amphidiploid
(or an allotetraploid)

46
Q

Somatic cell hybrids

A
  • The fusion of two somatic cells (from different species) into a single hybrid cell
  • Generates a hybrid that contains the genetic material of BOTH species
  • Valuable technique for mapping genes and determining genetic function
47
Q

Somatic cell hybrids

Example:

A 
• Mouse cell line defect in Thymidine
kinase (TK gene)
• Generate SCH with human cell line
with functional TK gene
• Redundant human chromosomes
lost
• Only chromosomal segment that
complements mouse mutation remains
48
Q

Endopolyploidy (somatic polyploidy)

A

• The situation where certain cells within a diploid organism become polyploidic
• A type of tissue mosaicism
• Can happen by:
1. Cells entering the mitotic cycle (prophase), without progressing through the other
stages – re-enter interphase
2. The cell can progress through the normal steps of mitosis, except that a single
nuclear membrane will form over all DNA during telophase

49
Q

Endopolyploidy in humans

A 
• Humans liver cells can be polyploidic
• 3n, 4n or 8n
• Sometimes chromosomes remain
attached – called polytene chromosomes
• Unclear why polyploidy happens
• Produce high levels of gene products?
• To generate larger cells?

BMS2042 (6 decks)

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