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Genetics PMY-3 > Variations In Chromosome Arrangement > Flashcards

Variations In Chromosome Arrangement Flashcards

1
Q

Describe the basic structure of a chromosome

A
  • linear DNA is tightly wound around proteins to allow compaction and condensation into chromosome structure
  • Centromere forms a recognition site for the kinetochore proteins -required for cell division

Repetitive sequences:

  • interspersed throughout chromosome
  • Near centromere and telomeres
  • repetitive regions of DNA comprise more than 50% of the genome
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2
Q

Where are the telomeres located?

A

Telomeres located at both ends and have specialized sequences
-telomeres protect the end of the chromosome and prevent fusion with other chromosomes or DNA

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3
Q

What happens if DNA breaks?

A

-When DNA breaks, the ends are “sticky” and can rejoin other broken ends

  • Consequences in germ cells if the breakage and rejoining does not re-establish the original structure/orientation
    • gametes will contain the structural rearrangement
    • The change will be heritable
    • During synapsis in meiosis, altered chromosomes will pair in characteristic configurations
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4
Q

List the types of chromosome variations. Contrast them

A

Unbalanced-total amount of genetic information in the chromosome changes- change in genetic dosage

Forms- deletions, duplications and Translocations with deletion and of duplication

Balanced- total amount of genetic material might remain the same, but the material will be rearranged

Forms- inversions, translocations( non reciprocal and reciprocal translocations)

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5
Q

What are copy number variants?

A

Copy number variants (CNVs) in the genome describe anything different from 2 copies (1 from each chromosome), whether a gain or a loss

 -recall most genes have 2 copies, one from mom and the other from dad
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6
Q

What are the length of copy number variants?

A

CNVs can be from 50 bp to over 10Mb

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7
Q

Where can copy number variants be found? Express there variation

A

Can be found in coding (genes) and noncoding regions in chromosomes

-CNVs can be normal variation (Polymorphisms) or be associated with disease (intellectual disability syndrome, autism, cancer)

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8
Q

How much deletions and duplications did the human genome project identify?

A

Occupy 5%-10% of genome of normal human population

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9
Q

How can chromosomes gain or lose material?

A

Misalignment of repetitive regions in the genome is a source of structural abnormalities, I.e. if crossover occurs at repetitive sequences, duplications and deletions occur

  • Non-allelic homologous recombination (NAHR)
    • Occurs during meiosis when chromosomes pair
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10
Q

What are the types of deletions?

A

The proportions without a centromere is typically lost
-terminal deletion(near one end)

  • Interstitial/intercalatory deletion (interior of the chromosome)
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11
Q

What is the origin of deletion?

A
  • Chromosome breaks in one or more places
  • missing regions of chromosome
  • The location of the deletion can vary
    • Some chromosomes have regions more likely to break
  • The portion of the chromosome that remains that retains the centromere is maintained through cell division, meiosis or mitosis
  • the portion without a centromere is typically lost
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12
Q

What are the clinical symptoms of Curly calf syndrome /Arthrogryposis multiplex ?

A
  • Curly calf syndrome affecting mainly Angus or Angus related cattle
    • stillborn
    • Bent or Twisted spine
    • Small size and thin appearance
    • Autosomal recessive disorder
    • Chromosomal deletion in the mammal grandshire of a popular sire
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13
Q

Explain the genetics (and secrecy) behind Curly calf syndrome/Arthrogryposis Multiplex

A

An intercalatory deletion
-Bovine genetics are still being worked on, bovinegenome.org

  • Much of what we know is based on linkage analysis using markers and LOD scores
  • Genetic tests for bovine genetic disorders mostly patented
  • Bovine heave 29 autosome pairs and sex determination
  • what is reported is 23,000 bp deletion and my searching suggests that it is chromosome 16
  • Info well-guarded by genetic testing companies
    - YOU CAN TEST FOR IT BUT YOU WILL NOT BE TOLD WHICH CHROMOSOME!
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14
Q

Describe the synapsis for an interstitial deletion

A
  • Synapsis between a chromosome with a large interstitial deletion and a normal complete homolog during meiosis
  • For pairing to occur, the normal homologue must buckle out and form a “deletion loop” or also known as a compensation loop of the unpaired region
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15
Q

What is an example of a deletion syndrome?

A

Cri du Chat syndrome

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16
Q

Explain the genetics of the Cri du Chat syndrome

A
  • “cry of the chat”
  • Terminal deletion of a small part of chromosome 5p
  • The top end of the p-arm is deleted in most cases
  • The length of the deletion varies, individuals with larger deletions are likely to have more severe clinical features
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17
Q

What are the symptoms of Cri du Chat syndrome?

A

Infants exhibit anatomical malformations(affecting a body part, developmental)

  • Microcephaly (small head)
  • intellectual disability, developmental delay
  • Micrognathia(small chin)
  • Language difficulties
    • small larynx and neurological difficulties
    • Affect the way a baby cries
    • Some describe this as the sound of a cat meowing
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18
Q

What syndromes can result from duplications?

A

Human diseases can result from gene duplication

  • Neurodevelopmental syndromes
  • Many cancers associated with gene duplications
    • Myc duplication(amplification) May promote cancer development
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19
Q

What are duplications?

A

Duplications arise from unequal crossing over between synapses chromosomes during meiosis

-One chromatid (3) has a duplication and other chromatid(2) has a deletion

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20
Q

What ca7ses Potocki-Lupski syndrome?

A

Chromosome 17p11.2 duplication

- dup(17)(p11.2) syndrome
- PTLS
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21
Q

What are the symptoms of Potocki-Lupski syndrome ?

A
  • Intellectual disability
  • Speech delay
  • Autism spectrum disorder
  • Behavioral problems
  • Delayed growth, lean body
  • Hyperactivity, ADHD
  • Heart defects
  • Mild craniofacial abnormalities
    • triangular face

-Sleep disturbance with central sleep apnea

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22
Q

What do gene redundancies arise from?

A
  • Gene redundancies arise from gene duplication
    • example: many copies of ribosomal RNA genes(called rDNA) on Acrocentric chromosome stalk regions
      - E. coli haploid genome is 0.7% rDNA
- Drosophilia 0.3% rDNA
- Very important for oocyte’s for use in early development
  • having extra copies of a gene creates altered proteins
    • Various forms for hemoglobin (alpha, beta, delta and gamma)
    • Trypsin and chymotrypsin (digest proteins at different sites
    • Gene families
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23
Q

What are inversions?

A

Rearrangement of linear gene sequence

-May be polymorphic and present in general population

  • No loss of genetic information
    • Mutations May occur at breakpoints
    • Altered arrangements may affect gene expression
    • May have no impact on gene function
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24
Q

What does an inversion do? What is required for this?

A
  • Segment of chromosome turned 180 degrees within chromosome
  • Requires two breaks in chromosome, and rejoining of inverted segment
  • May arise from chromosomal looping
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25
Q

What is a Paracentric inversion?

A
  • Centromere is not part f the inverted sequence

- Does not change lengths of two arms of chromosome

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26
Q

What is pericentric inversion?

A
  • Centromere is part of inverted segment

- May change lengths of arms of chromosome

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27
Q

What happens during meiosis with normal and paracentric homologues? What gametes are produced?

A

Two viable gametes that did not cross over

  • One normal(1)
  • One with inverted sequence

Two non viable gametes

  • One with two centromeres (2) (dicentric)
  • One with no centromeres (4)(acentric)

Reduced fertility

28
Q

What happens during meiosis with normal and pericentric homologues? What gametes are produced?

A

Two viable gametes

  • One normal gamete(1)
  • One inverted gamete(3)

Two other gametes have duplications and deletions and are not viable

  • “Reduced fertility”
  • Possible individuals who are carriers will have children birth defects, malformation, syndrome, etc
29
Q

What are translocations?

A

Movement of a chromosomal segment to new location in the genome

30
Q

What are reciprocal translocations?

A
  • Involves the exchange of segments between two NONHOMOLOGOUS chromosomes
  • Has big implications when it is time to form gametes
31
Q

What are quadrivalents?

A

In reciprocal translocations

Unusual synapsis configuration during meiosis called a quadricalent

32
Q

What are two possible segregation patterns during meiosis?

A

Alternate segregation

Adjacent segregation

33
Q

Explain alternate segregation

A
  • Segregation pattern during at first meiotic division
  • Has complete complement of genetic information
  • Balanced genetic information is these gametes
  • Compatible with life.
34
Q

Explain adjacent segregation

A
  • Leads to gametes containing duplications or deletions
    • reduced fertility
  • If these gametes participate in fertilization in animals, it is typically lethal
    • Offspring do not usually survive
    • Spontaneous abortion
  • carrier of translocation is said to have semisterility
35
Q

Will reciprocal translocations have clinical or phenotypic consequences?

A

-May or may not have a clinical or phenotypic consequence

  • May cause mutation in gene or affect gene transcription at location of breakage and rejoining
    • Can inactivate a gene
    • Can cause gene function
36
Q

How can reciprocal translocations lead to cancer/cancer-related diseases?

A

Example of reciprocal translocation: chromosome 9 and 22 can translocations to form the Philadelphia chromosome t(9;22)(q34;q11)

- results in fusion of two genes BCR and ABL: BCR-ABL1
         - after translocation, the protein is always “on” resulting in altered cell cycle and increased genome instability    - Oncogene

-is a driver of cancer and is often observed in chronic myelogenous leukemia and acute lymphoblastic leukemia

37
Q

What is robertsonian translocation?

A
  • Involves Breaks at ends of short arms of two acrocentric chromosomes
    • in humans, chromosomes 13, 14, and 21
  • Small segments containing the “stalks” are lost
  • A large sub metacentric (or metacentric) chromosome is produced
  • Carriers are typically unaffected
38
Q

What are the effects and results Robertsonian during meiosis?

A

Alternate segregation can result in:

  • Normal gamete(gamete 1)
  • Gamete with the derivative chromosome (gamete 2), that results in a Robertsonian translocation carrier on fertillization

Adjacent segregation can result in:

  • Gamete 3: would result in trisomy 21(Down syndrome) on fertillization
  • Gamete 4: Monosomy 21, lethal
  • Gamete 5: would result in trisomy 14, that is not compatible with survival, and results in spontaneous abortion
  • Gamete 6: Monosomy 14, lethal
39
Q

How much Down syndrome in children does Robertsonian translocation account for?

A

Robertsonian translocation accounts for 2x5%of children with Down syndrome due to carrier parents (these carrier parents themselves are healthy)

40
Q

Describe the karyotype of Down syndrome due to Robertsonian translocation

A

Two chromosome 21 and derivative chromosome 14 has the long arm of chromosome 21

46, XX,der (14;21)(q10;q10), +21

41
Q

What are fragile sites on chromosomes?

A

Karyotype analysis revealed some individuals have sites on the chromosomes where “gaps” appeared

These areas are susceptible to breakage

Most fragile sites not linked to diseases

42
Q

How can gaps/fragile sites be revealed on chromosomes?

A

Culturing lymphocytes for karyotype in a medium limited for folate(folic acid) revealed fragile sites on X chromosome in some individuals
-these individuals had similar facial features and intellectual

  • Named fragile X syndrome
43
Q

What is the most common form of inherited intellectual disability?

A

Fragile X syndrome

44
Q

What are the symptoms of fragile X syndrome in males?

A
  • Long, narrow faces
  • Protruding chin
  • enlarged ears
  • Increased testicular size
45
Q

What 3 abnormalities is prenatal screening used to detect?

A

Trisomy 21-down syndrome

Trisomy 18
-trisomy 13 has similar results to 18 but is about 1/22,700 live births

Neural tube defects

46
Q

What is the frequency of trisomy 21/down syndrome?

A

About 1/830 live births

47
Q

What is the frequency of trisomy 18?

A

About 1/7,500

48
Q

What is the frequency of neural tube defects?

A

About 1/2,000 live births

49
Q

Give the non-invasive tests for prenatal screening and what time span they’re used for?

A

Maternal serum screening -16 weeks optimal

First trimester screen-11-14 weeks+1 day

Second trimester screen- 14 weeks+ 2 days. -20 weeks

Ultrasound (fetal anomaly scan) - 20 weeks optimal time

Nuchal translucency - 11-14 weeks

50
Q

What are the invasive tests for prenatal screening? Give the timeframe each should be used

A

Amniocentesis. 16-20 weeks

Chronic villus sampling 11-14 weeks

51
Q

What tests can be used for Maternal Serum Screening: first trimester tests?

A

First trimester tests: 11-14 weeks + 1 day

Pregnancy. Associated plasma protein-A(PAPP-A)

Human Chorionic gonadotropin (B-hCG)

52
Q

What tests can be used for Maternal Serum Screening: Second trimester tests?

A

14 weeks + 2 days to 20 weeks

Quad test:

  • Inhibin A
  • AFP(alpha fetal protein)-this is a marker in fetal screening
  • Estriol(unconjugated estriol, or uE3)
  • Human chorionic gonadotropin (B-hCG)
53
Q

What is the purpose of maternal serum screening?

A

Provides risk of affected pregnancy

Detection rate:

  • 80% of Down syndrome cases
  • 80% of trisomy 18 cases
  • 80% cases of spina bifida
  • over 90% of cases of anencephaly

Results
-results for trisomy 21 and trisomy 18 are reported as a risk figure

- Not a diagnostic test
     - Other testing required for clarification of screening results
54
Q

What is Non-invasive prenatal screening (NIPS, also called NIPT)?

A

Maternal serum screening

Used to predict for risk of an affected fetus
-requires follow-up prenatal testing to cobfirm any findings

Challenges/complications in testing

  • Young maternal age
  • Twin or other multiples
  • Previous pregnancies
55
Q

What is the main function of NIPS? How does it work?

A

Maternal serum screening

  • detects cell-free DNA(cfDNA) from the fetus in the maternal circulation
    • fetal fraction (amount of fetal DNA in material circulation )
    • Small segments of DNA

Used primarily for detection of aneuploidy
-trisomy 13, 18, 21 or extra or missing Sex chromo

56
Q

What is cell free DNA?

A

Obtain sequence reads from fetal DNA in maternal circulation

-expect to see equal reads from all autosomes(all represented the same; diploids) if trisomy, over represented

If there is trisomy 21, there would be a 3:2 ratio of Ch 21 to other chromosomes

57
Q

Why would ultrasound be used in conjunction with maternal serum screening?

A

Increases the non-invasive prediction of an. Affected pregnancy

58
Q

At 20 weeks what specifically can ultrasonography be used to detect?

A

Different structural abnormalities

59
Q

An ultrasound detects an increase in maternal AFP, what does this detect?

A

Neural tube defects

60
Q

An ultrasound detects micrognathia , what May this suggest?

A

May suggest Cri-du-chat syndrome

61
Q

An ultrasound detects rocker-bottom feet, what does this detect?

A

Trisomy 18, Edwards syndrome

62
Q

What does anencephaly detected by ultrasound suggest?

A

Neural tube defect

63
Q

There is an increase in nuchal translucency suggest?

A

Increased nuchal translucency thickness 11-14 weeks is associated with chromosome a aneuploidy

Trisomies 21, 18,13; triploidy and turns syndrome (45,X)

This is measurement of fluid under skin in back of neck

64
Q

Positive results of a prenatal screening must be …

A

Confirmed by a diagnostic tests

65
Q

What diagnostic tests can be used for confirmation of prenatal screening?

A

Chorionic villus sampling

Amniocentesis

66
Q

Explain chorionic villus sampling

A

11-14 weeks
-removal of fetal cells by aspiration from the inner surface of placents(trans-vaginal)

  • Genome analysis
    • karyotype
    • chromosome microarray analysis
    • direct DNA sequencing

-risk of miscarriage

67
Q

Explain amniocentesis

A

15-18 weeks

10-20mL of amniotic fluid aspirated trans-abdominals guided by ultrasound
-fetal cells are pelleted by centrifugation, cultured

  • Genome analysis
    • karyotype
    • chromosome microarray analysis
    • Direct DNA sequencing/exonerated analysis

Supernatant can be used for AFP. Assay, other tests

Risk of miscarriage

Genetics PMY-3 (27 decks)

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