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L3 Clinical Genomics > PND structural abnormalities > Flashcards

PND structural abnormalities Flashcards

1
Q

What are the 3 main balanced chromosomal rearrangements?

A
  • Inversion
  • Insertion
  • Translocation
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2
Q

What causes the formation of gross structural abnormalities in the genome? (3)

A
  • Recombination events between homologous sequences in an illegitimate manner
  • DNA damage are usually repaired using homologous sequences located in equivalent positions in the sister chromatid (mitosis) and the homolog (meiosis)
  • Illegitimate recombination describes events where the template and repair sites are at non-allelic genomic positions
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3
Q

What are the 2 types of inversion?

A
  • Pericentric
  • Paracentric
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4
Q

What is pericentric inversion? (2)

A
  • 2 breaks occur in the same chromosome on different arms so the DNA fragment between the breaks includes the centromere
  • Causes a change to the G banding structure and obvious change to chromosome morphology
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5
Q

What is the most common inversion seen in humans? (3)

A
  • Inversions of chromosome 9
  • Carriers are often not identified until adulthood because the inversions don’t disrupt gene function/expression as the regions proximal to the centromere of 9 tend to be heterochromatin
  • However inversions create abnormal chromosome structures during meiosis which can be disruptive to spermatogenesis
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6
Q

What is paracentric inversion? (2)

A
  • When the chromosome breakpoints don’t flank the centromere
  • Disrupt the G banding structure of chromosomes but not morphology so more difficult to spot in a karyotype
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7
Q

Why are insertions rarer than inversions?

A

Insertions require more events to take place in the same time frame (2 breakpoints in the same chromosome and 1 in another) than inversions (2 breakpoints in the same chromosome)

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8
Q

What do all carriers of structural rearrangements have in common?

A

Homologous chromosomes form highly abnormal pairing structures when paired in prophase and metaphase I

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9
Q

Why are male carriers of structural rearrangements more likely to be infertile than females? (2)

A
  • Spermatogenesis is highly susceptible to abnormal pairing structures in MI so males are often unable to form mature spermatids resulting in oligospermia or azoospermia
  • Oogenesis is more robust
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10
Q

What is oligospermia?

A

Low sperm count

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11
Q

What is azoospermia?

A

Lack of sperm in the semen

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12
Q

What happens to chromosomes with inversions and insertions in meiosis I? (2)

A
  • The chromosomes generate abnormal looped structures in meiosis I which can be sufficient to disrupt spermatogenesis
  • If a crossover occurs within the inverted region then unbalanced gametes may form which leads to karyotypically abnormal conceptions that are likely to spontaneously abort or lead to serious health complications if brought to term
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13
Q

What is the most common balanced chromosomal rearrangement? (2)

A
  • Balanced translocations
  • Roughly 1 in 1000 are carriers
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14
Q

What are the 2 types of balanced translocation in the population?

A
  • Unique/familial translocations
  • Recurrent translocations
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15
Q

How do balanced translocations arise?

A

Illegitimate recombination during spermatogenesis (in contrast to aneuploidy which is largely attributed to maternal meiotic errors)

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16
Q

How is the identity of a chromosome determined?

A

The origin of the centromeric region

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17
Q

What happens to chromosomes with balanced translocations during MI? (2)

A
  • Chromosomes pair up to form a pachytene cross
  • The pachytene cross is susceptible to errors in chromosome segregation
18
Q

What are all the ways in which pachytene crosses can segregate? (4)

A
  • Alternate segregation
  • Adjacent I segregation
  • Adjacent II segregation
  • 3:1 mal-segregation
19
Q

What is alternate segregation? (4)

A
  • Anaphase of meiosis I: alternate centromeres are segregated to the same pole of the cell (both normals go together, both translocated go together)
  • Sister chromatids are then segregated at anaphase of meiosis II into 4 viable gametes
  • Shows that a carrier of a translocation can generate a viable balanced pregnancy
  • If the foetus inherits the translocation they may suffer reduced fertility in later life (especially if male)
20
Q

What is adjacent I segregation? (3)

A
  • Adjacent centromeres are co-segregated either side of the longest synaptic axis (a normal and a translocated go together)
  • Generates 4 unbalanced gametes because fertilisation of all 4 would result in trisomy/monosomy of something
  • Shows that genetically unbalanced pregnancies are possible/more likely for carriers of large structural rearrangements
21
Q

What is adjacent II segregation? (2)

A
  • Adjacent centromeres are co-segregated either side of the shortest synaptic axis (a normal and a translocated go together)
  • Generates 4 unbalanced gametes like in adjacent I segregation
22
Q

What is 3:1 mal-segregation? (4)

A
  • Segregation results in gametes containing 3 or 1 of the chromosomes in the pachytene cross
  • Those with only 1 would not be viable because the imbalance is too massive (monosomy is lethal)
  • Those with 3 would not be affected by monosomy but partial trisomy so may come to term
  • If the baby was born it would be have serious health complications
23
Q

How many clinically recognised pregnancies miscarry?

A

15%

24
Q

What proportion of miscarriages have an abnormal complement of chromosomes?

A

Between 30-50%

25
Q

What is the most common genetic rearrangement in humans?

A
  • Robertsonian translocations
  • Present in around 1 in 1000
26
Q

Which chromosomes are affected by Robertsonian translocations?

A

The acrocentric chromosomes (13, 14, 15, 21, 22)

27
Q

What are Robertsonian translocations? (3)

A
  • Occur between any 2 acrocentric chromosomes and form a dicentric chromosome (only one centromere is thought to be active)
  • Fuses 2 acrocentric long arms
  • Considered to be unbalanced as a small acentric fragment is lost
28
Q

Why are the no adverse clinical consequences to loss of acrocentric p arm material in a Robertsonian translocation?

A

Satellited chromosomal regions are composed of repetitive elements and rDNA genes that are present in the genome in high copy numbers so the losses have negligible impact on cellular function

29
Q

What are the 2 types of Robertsonian translocation?

A
  • Homologous (the 2 fused long arms are derived from homologous chromosomes)
  • Non-homologous (more common)
30
Q

What are the most common Robertsonian translocations? (2)

A
  • t(13;14) about 3/4
  • t(14;21) about 10%
31
Q

What drives the prevalence of the derivatives of Robertsonian translocations? (2)

A
  • The close juxtaposition of acrocentric p arms during the formation of the nucleolus
  • The inverted nature and sequence similarity of satellite DNA located in acrocentric p arms
32
Q

What are the consequences for Robertsonian translocations in meiosis? (5)

A
  • Abnormal synaptic structure form in meiosis I that predispose to mal-segregation and unbalanced gametes that can result in viable pregnancy or genetic disease
  • t(14;21) can generate gametes that are disomic for 21 so the conception will have trisomy 21
  • This could spontaneously abort or result in Down syndrome
  • Monosomy would be lethal
  • t(13;14) increases risk of Patau syndrome
33
Q

What are imprinted chromosomes?

A

When some genes on a chromosome are silenced via methylation and the genes from the other parent are expressed

34
Q

What are the consequences of inheritance of 2 maternal chromosome 15s and no paternal copies?

A

Prader-Willi Syndrome

35
Q

What are the consequences of inheritance of 2 paternal chromosome 15s and no maternal copies?

A

Angelman Syndrome

36
Q

What is UPD?

A

Uniparental disomy

37
Q

What can cause UPD?

A

Mitotic NDJ events

38
Q

What diseases can be caused by UPD? (3)

A
  • Temple syndrome (mat/pat UPD14)
  • Silver-Russell syndrome (mat UPD7)
  • Beckwith-Wiedemann syndrome (pat UPD11)
39
Q

What is the most common human trisomy?

A

Trisomy 16

40
Q

What is illegitimate/non-allelic recombination?

A

Recombination events where the template and repair sites are located at non-equivalent genomic positions

L3 Clinical Genomics (14 decks)

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