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2042 DYLAN > aneuploidys > Flashcards

aneuploidys Flashcards

1
Q

Karyotype

A
  • The number of a chromosome within a cell is called a karyotype
    Chromosomes are rearranged in order of size and position of centromere to form a karyogram
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2
Q

Karyotyping methods (basic)

A
  • Blood, Amnionic Fluid (AFT) (or cvs) or bone marrow are common specimens
    • Cells must be cultured in vitro, typically 3 days
    • After incubation, colcemid is added
      ○ Arrests mitosis at metaphase
      Cells fixed to slide and stained Giemsa
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3
Q

FISH- staining

A
  • Identifying small translocations using giemsa staining is almost impossible
    • We use FISH staining
      ○ using probe DNA (labelled with dye)
      ○ Denature and hybridise
      ○ Where sequence is homologous to the probe DNA there is binding
      ○ Shine UV light
      ○
      Probe bound to chromosome 1 that should come from homologous 3 - translocation
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4
Q

Pre-natal screening

A
  • Genetic analysis for unborn foetus to diagnose aneuploidies or chromosomal rearrangement
    • Previously relied on AFT or CVS and karyotyping
      ○ Dangerous
      ○ Require culturing - slow
      Move towards DNA testing
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5
Q

Cell-free DNA

A
  • Detection of foetal DNA in bloodstream - during pregnancy foetal DNA is shed
    ○ Apoptosis of placental cells during embryogenesis
    • Purification of foetal DNA obtained by epigenetic patterns
      ○ Foetal DNA primarily unmethylated
      ○ Maternal DNA displays unique epigenetic marker for the mother
      Thus we can detect foetal DNA
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6
Q

Detection of foetal aneuploidies

A
  1. Quantitative PCR methods
    • E.g. Harmony
      ○ Probes that are unique to areas commonly aneuploidy
      § Chromosomes 13, 18, 21, x and y
    • Not good for rare (not in probe library)
      2. Next-generation sequencing
      We can detect copy number by number of contigs that come back for a chromosome result
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7
Q

Terminology

A 
- Aneuploidy
		○ 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) (e.g.46 chr -> 92 chr)
		○ E.g. 
			§ Triploidy - 3n
			§ Tetraploidy - 4n
Polyploidy - 3n, 4n, 5n, 6n
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8
Q

Naming aneuploids

A
  • Chromosome number, genotype
    • E.g.
      ○ 47, XXX - 47 chromosomes in total, 3 x chromosomes
      47, 21+ - 47 chromosomes in total, one extra chromosome 21
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9
Q

Origins of aneuploidy

A

Non-disjunction (ND) during either meiosis 1 or 2

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10
Q

Aneuploidy during meiosis 1

A
  • If ND occurs during meiosis 1, gamete carries different recombinant chromosomes
    ○ Mendel - segregation
    ○
    ○ The bottom two left gametes have one too many chromosomes (called disomic)
    ○ The bottom two right gametes called empty
    ○
    § When combined with other parent can cause a trisomy (3 copies)
    § The other two are monosomy
    ○ 100% gametes are abnormal
    § 50% trisomy
    50% monosomy
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11
Q

Aneuploidy at meiosis 2

A
  • If ND occurs during meiosis 1, gamete carries same recombinant chromosomes
    • ○ One disomy, one empty and two normal
    • ○ 25% trisomy
      ○ 25% monosomy
      50% disomy (normal)
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12
Q

Gene dosage effects

A
  • Usually 2 copies are required for normal gene function
    ○ In some cases with monosomy you have haploinsufficiency (not enough of a gene product for normal phenotype)
    In some cases having more than a disomy may lead to problems as well
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13
Q

Departures from normal gene dosage

A
  • Abnormal phenotype is characteristic for each chromosome
    • Monosomy generally results in the worst phenotype (compared to trisomy)
    • Aneuploidy of larger chromosomes results in more severe abnormal phenotype
    • Severe imbalance of genes leads to inviability
      ○ Most autosomal aneuploidies aren’t tolerated in humans
      Embryo doesn’t survive
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14
Q

Sex aneuploidy

A
  • Sex aneuploidies are better tolerated
    • 4 most common (there is a total of 18)
      ○ Monosomy x - turner syndrome
      ○ XXY - Klinefelter syndrome
      ○ XXX - triple x syndrome
      XYY - double Y syndrome
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15
Q

Male and female aneuploidy are different

A
  • Females only have x chromosomes
    ○ Non-disjunction in females only results in the case of meiosis 1 or 2 (look above)
    • In males there is more variety
      ○ In M1 you get gametes that carry both X&Y or neither (Klinefelter syndrome)
      ○ In M2 you get disomy x (triple x syndrome) or disomy Y (double Y syndrome) depending on which doesn’t segregate
      For XXXX, XXXY, XXYY, XX - you need multiple non-disjunction events in both parents - rare
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16
Q

Why are sex-chromosomes better tolerated

A
  • X-inactivated
    ○ XXX individuals will have two Barr bodies instead of one
    ○ XXY will have one Barr body
    ○ Increase Barr bodies to make gene dosage normal
    • Y chromosome encodes only a few genes
      ○ Only for sperm viability or spermatogenesis
      Not critical
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17
Q

Where do the abnormalities come from

A
  • Not the entire x chromosome is inactivated

Abnormalities due to excess/deficit gene dosage with PAR1 and to a lesser extent in PAR2

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18
Q

Alterations in sex chromosome number does not necessarily make the person sterile

A

klinefelter and turner syndrome are infertile - In Klinefelter most likely the testes don’t develop
- Why are two fertile
§ Possibly during embryonic development, normal genotype is restored
Possibly one sex chromosome must be lost to develop germline

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19
Q

Turner syndrome (45, XO)

A
  • Female (missing SRY)
    • Near normal intelligence
    • Short
    • Webbed neck
      Sterile
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20
Q

Mosaic Turner syndrome

A
  • In germline one chromosome is lost

- In some areas of tissue the cells come from precursor where one chromosome was last

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21
Q

Klinefelter (47, XXY)

A
  • Male
    • Slightly lower IQ
    • Taller
    • 20% breast dev
    • Sterile
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22
Q

Triple x (47, XXX)

A
  • Female
    • Very mild - most don’t know they have it
    • Mild reduction in IQ
    • Tend to be very tall
    • Occasionally behavioural problems
      Fertile
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23
Q

Double Y (47, XYY)

A
  • Male
    • Very mild
    • Rarely a slight reduction in IQ
    • Learning difficulties
      Rarely antisocial behaviour
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24
Q

Uniparental diploidy

A
  • Generation of diploid set of chromosomes from a single parent
    - i.e. sperm carries 46 chromosomes and egg carries 0
    - Very rare requires many errors in both parents
    • Foetuses don’t develop correctly
      • Typically dead, or with severe morbidity
      • Possibly due to genetic imprinting
        Maintain epigenetic markers of parents
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25
Uniparental disomy
- Inheritance of both chromosomes from a single parent - For example; you have multiple copies of a chromosome in the egg, but no copies in a normal sperm both copies would then come from one parent - A chromosome is lost during early mitotic division in foetus - Many go undiagnosed Abnormalities - imprinting errors?
26
Prader-Willi syndrome
- Deletion of paternal 15q11-13 - Or uniparental disomy where both copies of Chr 15 come from the mother - Maternal copies of this region are silent due to imprinting - Conversely, Angelman syndrome - maternal deletion of the same region - Symptoms - Poor muscle tone - Insatiable appetite Cognitive delays
27
Autosomal aneuploidy
Autosomal aneuploidies have the same proportions as sex aneuploidies
28
Why are they so badly tolerated
``` - Autosomal Monosomies (2n-1) ○ Not tolerated in humans ○ Die in utero ○ Better tolerated in plants Tend to be less viable and less sterile ```
29
Monosomies unmask recessive alleles
- In empty (seen above) they will have one chromosome (i.e. monosomic) - the phenotype will be determined by that chromosome (dominant or recessive) ○ Tendency to shoer greater expression of recessive phenotypes - Lethal alleles can be tolerated if non-lethal homolog available Traits more common in males
30
Haploinsufficiency
- Accumulation of an additional chromosome - Better tolerated in humans than monosomy ○ More likely to survive - Survivability increased if trisomy is in small chromosome - Trisomy in all chromosomes can occur, but only 3 survive Trisomy accounts for 35% of spontaneous abortions
31
Trisomy in plants
- viable but infertile | Phenotypic differences
32
Down syndrome (trisomy 21 or 47, 21+)
- Phenotypic variable - Short stature - Mental retardation - Epicanthic fold - Heart and nervous system abnormalities Life expectancy not common after 60s
33
Down syndrome critical region (DSCR)
- hypothetical region on chr 21 thought to be involved in abnormal phenotype ○ 21q22.2 = DSCR - In mouse DS model, identified candidate genes ○ DYRK - reproduces dosage-sensitive learning defects in fly and mice DSCAAM - reproduces heart and nervous system defects
34
Maternal age down syndrome
- Prevalence od DS births increases with maternal age ○ Ovum the source of extra chr 21 in 95% ○ Most ND events occur at anaphase 1 - Paternal age not important ○ Spermatogenesis continuous doesn’t arrest - Maternal oogenesis arrests at diplotene ○ Reduction in spindle fibers - don’t function properly ND more likely
35
smal syndrome (Trisomy 13 or 47, 13+)
- Risk increases with maternal age - Few survive beyond 1 yr Mental defects
36
Edwards syndrome (trisomy 18 or 47, 18+)
- Most spontaneous abortions - Few survive beyond 1 yr - Skull deformity, clenched hands
37
Polyploidies
- Duplication of every chromosome in a set - Not tolerated in humans - In other animals some times tolerated ○ In toads ○ Fish or lizards Much more stable in plants
38
Autopolyploidy
- More than 2 sets of chromosomes all derived from one ancestral species - Can happen naturally if ○ Fusion of non-diploid gametes ○ Cell re-enters interphase after prophase - Can induce experimentally using colchicine Tolerated in plants
39
Experimentally induced polyploidy
- During prophase add colchicine - arrests at metaphase ○ Reversible ○ Cell re-enters interphase when colchicine is removed - duplication (results in tetraploid) - Can result in larger fruit Sterile due to the imbalance of chromosomes cant synapse correctly during meiosis
40
In salmon
- Randomly duplication occurred and produced tetraploid (4n) ○ If mated with diploid ancestor they would produce triploid (sterile) - Tetraploid reproductively isolated from its diploid ancestor
41
Allopolyploidy
- Generation of polyploid from the fertilisation of two closely related but different species - Progeny only fertile if: ○ The progeny has a diploid number of chromosomes AND ○ There is sufficient similarity between genes for synapsis to occur - For example ○ Radage Combination between radish and cabbage similar enough genes
42
Allopolyploidy in animals
``` - Mules ○ Donkey x horse § Donkey = 62 chr § Horse = 64 chr Mule = 63 chr (infertile) not balanced ```
43
Creation of Allopolyploidy
- Interspecies hybris can be made fertile if made polyploidic - Use colchicine to arrest mitosis then remove Generate fertile amphidiploid
44
Somatic cell hybrid
- The fusion of two somatic cells from 2 different species into a single hybris cell ○ Hybrid that contains the genetic material of both species - Valuable technique for mapping genes and determining gene function - Example ○ Mouse cell line defect in thymidine kinase (TK gene) ○ Generate SCH with human cell line with functional TK gene Redundant human chromosomes lost
45
Endopolploidy
- Certain cells within diploid organism become polyploidic ○ Tissue mosaicism - Can happen if ○ Cells enter mitotic division (prophase), without progressing through the other stages - re-enter interphase ○ The cell can progress through normal steps of mitosis, except the nuclear membrane will form over all DNA during telophase - Humans liver cells can be polyploidic ○ 3n, 4n or 8n Unclear why
46
Chromosomal rearrangements
``` - Chromosomes are fragile, regions can ○ Break off ○ Invert ○ Duplicate - Changes to chromosome structure have varies phenotypes ○ Sometimes nothing happens Sometimes disease results ```
47
Chromosome fragile sites
- Littered with tiny gaps or 'pinches' which tend to break - Not prone to spontaneous breaks ○ Unless other factors influence chromosomal instability ○ Such as alcohol Interest to cancer genetics
48
5 main types of chromosomal aberrations
- Deletions - Duplications - Inversions - Ring chromosomes Translocations
49
Deletions
- Region of chromosome breaks off and is lost ○ Terminal deletion ○ Intercalary deletion § Internal - Severity depends on size of deletion - Also depends on what genes are deleted ○ Important regulatory systems of later genes i.e. loss of gene C affects gene E expression
50
What is the outcome of an acentric deletion
Acentric chromosome would be lost coz it cant bind to the spindle
51
Mitosis or meiosis with deletion chromosomes
- Partial chromosomes can't pair properly - Leads to formation of a deletion loop ○ Aka compensation loop Allows for synapsis to occur
52
Cri du Chat syndrome
``` - Partial deletion of chr 5 ○ 46, 5p- - Partial monosomy - Affected tend to be: ○ Anatomical deformities glottis and larynx § Results in unique cry ○ Mental retardation ○ Normal life expectancy ```
53
Duplication
- Abnormal crossover - Where a portion of a chromosome is duplicated - Commonly produced by ○ Un-even cross over ○ Errors in DNA replication High degree of phenotypic variation
54
Positives affects of duplication
- Gene redundancy ○ Having a backup copy of that gene § Can complement mutation or increase the production of certain gene products ○ Having multiple copies of the rRNA gene allows for significant numbers to be generated - Evolution Paralogous genes arose from a genetic duplication event
55
selective pressure on duplication
- If selective pressure is on both genes ○ The genes stay similar - If selective pressure is on just one of the genes ○ One copy degrades Or one copy can undergo spontaneous mutation and acquire a new function
56
Negatives of duplication
``` - MECP2 duplication syndrome ○ Duplication of a region on x, q-arm ○ X-linked inheritance (100% penetrant) - Twice the amount of MECP2 can result in overexpression of overactivation which down regulates key neuronal genes - Presents with ○ Intellectual disability ○ Hypotonia ○ Predisposition to infections Epileptic seizures ```
57
Inversions
- Occurs when a chr breaks at two points and flips - 2 types ○ Paracentric - centromere outside inverted regions ○ Pericentric - centromere inside inverted region - Arise from unusual looping of chr ○ Odd twist that breaks the chromosome and improper repair results in flip - Genes are in balance - minimal effect on individual ○ Consequences on offspring If the inversion interferes the expression of other genes (oncogenes)
58
Meiosis continues normally if homozygous for inversion
- Genes pair up during prophase | Inversion will be passed onto offspring
59
If heterozygous for inversion
- To allow pairing during prophase one inversion must make an inversion loop to fit with the normal chromosome
60
If heterozygous for inversion- no cross-over
meiosis will continue normally ○ 50% will have inverted chromosome 50% will have a normal chromosome
61
If heterozygous for inversion- cross-over in pericentric inversion
○ 50% normal gametes (1 inverted, but balanced) ○ 50% abnormal gametes ( carrying deletions ) Deletions = unbalanced = infertility
62
If heterozygous for inversion- cross over in paracentric inversion
○ Gametes produced § 50%n normal, 50% abnormal ○ Acentric fragment (no centromere) get lost - cannot attach to spindle Dicentric chromosome forms dicentric bridge - fragment lost
63
Dicentric chromosome
- At meiosis there will be a break between the two bridges and fragment will be lost - 2 normal gametes (with 1 balanced inversion) 2 deletion chromosomes - if fused with normal gamete foetus not viable
64
Ring chromosomes
- Form when break occurs on both arms and the middle bit joins together to form a loop ○ Loss of genetic material at the terminal ends - Effects are severe Ring chromosome 14 syndrome
65
Translocations overview
- Transfer of genetic material from one location to another ○ Can occur within the same homologous pair (intrachromosomal) ○ Or between non-homologous pairs (interchromosomal) - Reciprocal translocations ○ Exchange of genetic material with replacement - Non-reciprocal translocations Transfer of genetic material without replacement
66
Effects of translocations
- As long as the genetic material is balanced ○ May effect meiosis - Can disrupt important genes ○ Interrupt important genetic regulatory sequences Origins of translocations - Chromosomal break and re-joining Abnormal cross-over
67
Meiosis with chromosomes with translocations
- Similar to inversions, if homozygous for translocation - meiosis will continue normally - If heterozygous, how do the chromosomes synapse Form a translocation cross (quadrivalent)
68
3 methods of segregation
The same kinetochore complex cannot migrate to the same pole 1. alternate - two normal cells + 2 cells with balanced translocations 2. adjacent-1 segregation - all 4 unbalanced cells - horizontal 3. adjacent-2 segregation - all 4 unbalanced cells - vertical - exception (same kinetochore)
69
Outcomes of 3 forms of segregation
- If unbalanced gamete fuses with a normal gamete - zygote unviable - Therefore reduced fertility in heterozygotes Recurrent miscarriage
70
Robertsonian translocation
- Break occur on p-arms of acrocentric chromosomes - Will reduced chromosome number by 2 - The p-arm are lost, and the two q arms fuse ○ Only tolerated if p-arms are non-essential E.g. familial down syndrome
71
Familial down syndrome
- ~3% total DS births ○ Very common to give birth to many DS children Robertsonian translocation between chr 14 & 21
72
Chromosomal rearrangements
- Can promote speciation if spread through population ○ Heterozygotes have reduced fertility thus favours homozygous Sometimes the homozygous translocation cannot mate with normal = new species can occur
73
Reconstruction of human evolution from primates
- Examined G-banding patterns between closely related species - Human chromosome ○ Chr 3 - arose from pericentric inversion on p-arm ○ Chr 2 - arose from Robertsonian translocation from primate chr ○ Chr 1 arose from a paracentric inversion on q-arm

2042 DYLAN (11 decks)

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