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GT4300 Advanced Medical Genetics > Overview > Flashcards

Overview Flashcards

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1
Q

Which protein group functions in chromosomal structure, replication, as well as segregation?

A

Nonhistone Proteins

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2
Q

Euchcromatin

A

Contains protein coding DNA

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3
Q

X Chromosome inactivation

A

All daughter cells of a given cell have the same X activated.

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4
Q

A common mechanism by which a full trisomy arises

A

Meiotic Non-Disjunction

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5
Q

If a cell lacks functional Shugoshin, what is the predicted effect on cohesin?

A

Cohesin at the centromeres of sister chromatids will be cleaved during Meiosis I

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6
Q

Turner Syndrome is most commonly observed as a chromosomal aneuploidy of

A

45, X

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7
Q

Example of triploid karyotype

A

69, XXX

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8
Q

Example of a chromosome alteration with phenotypic abnormalities

A

46, XY, der(14;21)(q 10, q10), +21

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9
Q

Intron size?

A

0.5 kb to 30 kb

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10
Q

Average Exon size?

A

150 to 200 bp

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11
Q

mRNA size?

A

2.5 kb

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12
Q

Coding DNA size?

A

1.5 to 1.8 kb

OR

500 to 600 codons

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13
Q

5’UTR size?

3’UTR size?

A

5’UTR - 100 bases

3’UTR - 600 to 800 bases

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14
Q

What is DNA resolution limit when studying chromosomes?

A

The resolution for studying chromosomes has improved from > 5 Mb (metaphase) or 5 million bases.

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15
Q

Define Translocation

A

A change in location, when part of a chromosome is transferred to another chromosome.

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16
Q

Define Inversion

A

A chromosome rearrangement in which a segment of a chromosome is reversed end to end. A single chromosome undergoes breakage and rearrangement within itself.

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17
Q

Paracentric Inversion

A

Paracentric inversions do not include a chromosome’s centromere, and the breaks occur in one arm only.

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18
Q

Pericentric Inversion

A

Pericentric inversions include a chromosome’s centromere, so the breaks occur in both arms.

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19
Q

Define Duplications

A

A type of mutation that involves the production of one or more copies of a gene or region of a chromosome.

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20
Q

Define Additions

A

The gaining of any genetic material through insertion or duplication.

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21
Q

Define Deletions

A

A type of mutation involving the loss of genetic material. It can be small, involving a single missing DNA base pair, or large, involving a piece of a chromosome.

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22
Q

Define Derivatives

A

A structurally rearranged chromosome generated either by a chromosome rearrangement involving two or more chromosomes or by multiple chromosome aberrations within a single chromosome. Can include an inversion and deletion within the same chromosome, or deletions in both arms, etc.

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23
Q

Define Isochromosomes

A

An isochromosome is an unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other. The chromosome consists of two copies of either the long arm or the short arm because isochromosome formation is equivalent to a simultaneous duplication and deletion of genetic material.

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24
Q

Define Dicentrics

A

An abnormal chromosome with two centromeres. It is formed through the fusion of two chromosome segments, each with a centromere, resulting in the loss of acentric fragments.

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25
Q

Intra

A

Insertion within the same chromosome.

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26
Q

Inter

A

Insertion between 2 or more chromosomes

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27
Q

Interstitial

A

A deletion that occurs from the interior of a chromosome.

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28
Q

Composite Karyotype

A

Used to report when there is some variation from cell to cell in the abnormalities present. (Common in oncology.)

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29
Q

What are causes of aneuploidy?

A
  • Meiosis I Errors:
    1. Asynapsis of homologous chromosomes
    2. Recombination failure
    3. Premature homologue separation
    4. True nondisjunction
    5. Premature sister chromatid separation
  • Meiosis II Errors:
    1. Nondisjunction
    2. Premature sister chromatid separation

-Meiosis & Mitosis Error:
Anaphase Lag

30
Q

What is Recombination Failure?

A

When Chiasmata do not form between paired homologues. The synaptonemal complex breaks down, and two homologues segregate randomly and independently.

31
Q

What is True nondisjunction?

A

When the Chiasma is not resolved, and both homologues are pulled to same pole.

32
Q

What is Nondisjunction?

A

When homologous chromosomes or sister chromatids fail to separate during meiosis.

33
Q

What is Anaphase Lag?

A

The delayed movement of homologue or chromatid to one of the poles, resulting in bivalent or chromatid not being included in the nuclear membrane. Eventually the chromatid will be lost during cell division.

34
Q

What are the essential elements of eukaryotic chromosomes?

A
  1. Origins for initiation of DNA replication
  2. The centromere
  3. The two ends, or telomeres
35
Q

What is a chromosome’s composition?

A

One linear molecule of DNA and two classes of proteins collectively called chromatin.

36
Q

What are the 2 classes of proteins that make up a chromosome?

A

Histone:

  • H1
  • H2A
  • H2B
  • H3
  • H4

Nonhistones:

  • Structural
  • DNA replication (DNA polymerase)
  • Chromosome segregation (kinetochore)
  • Gene expression (largest group)
37
Q

What makes up a chromatin?

A

Nucleosome, a histone core with 160 base pairs, a segment of DNA, and 40 base pairs of linker DNA.

38
Q

Which regions codes for rRNA?

A

The nucleolus organizer region (NOR).

39
Q

What are the roles of non-histone proteins on kinetochore?

A

Chromosome segregation, kinetochore participates in the function when a chromosome attaches to spindle apparatus during cell division at it’s centromere.

40
Q

What is the function of nucleosomes?

A

They are the basic packing unit of DNA built from histone proteins around which DNA is coiled. They serve as a scaffold for formation of higher order chromatin structure as well as for a layer of regulatory control of gene expression.

41
Q

What is the DNA replication process?

A
  1. Double Helix unwinds.
  2. DNA polymerase adds new nucleotides
  3. Synthesis occurs from 5’ to 3’

Remember:

  • That each DNA segment has own timing.
  • Telomerase required to complete replication of telomeres at 5’ end
  • DNA replication only one part of process (proteins must also be duplicated)
42
Q

Why do chromatin compaction change?

A

Chromatin structure
is dynamic and can change to allow access of specific
proteins when they need to act. These changes produce
variations in chromatin structure necessary for different chromosomal functions.

43
Q

What is the role of chromosomal origins of replication?

A

A sequence of DNA at which replication is initiated on a chromosome, plasmid, or virus. Mammals have multiples (over 10,000) because with only one starting point replication would take over 800 hours.

44
Q

What is the difference between male and female meiosis?

A

Males:

  • Meiosis occurs in the seminiferous tubules of the testicles
  • Meiosis occurs at puberty
  • Meiosis in males produces four daughter cells that all mature into sperm cell

Females:

  • Meiosis occurs in cells called as oogonia.
  • Meiosis occurs right at birth. -Meiosis in females generates four daughter cells that only yield one mature egg cell
45
Q

Why are centromeres necessary for proper segregation during mitosis and meiosis?

A
  • It is the site at which chromosome attaches to spindle apparatus during cell division.
  • The centromere breaks down to allow separation.
  • Centromere function includes sister chromatid adhesion and separation, microtubule attachment, chromosome movement, establishment of heterochromatin and mitotic checkpoint control.
46
Q

What is the role of telomeres?

A
  • To protect the integrity of the chromosome structure.

- To cap the chromosome ends to minimize the loss of DNA during rounds of cell replication.

47
Q

Describe Klinefelter Syndrome

A

47,XXY

  • 1 in 1,000 newborn males
  • Infertile
  • Taller than normal brothers
  • Hypogonadism (with underdeveloped secondary sex characteristics)
  • IQ within normal range (10 point difference)
  • Risk of learning disabilities and speech delay
48
Q

Describe Turner Syndrome

A

45,X

  • 1 in 4,000 live female births
  • Only viable monosomy
  • 99% miscarry by 28 weeks
  • Short (under 5 ft)
  • Lack of 2nd sex characteristics
  • Cystic hygroma in utero
  • Lymphedema of hands and feet
  • Webbed neck
  • Broad Shield chest
  • Cubitus valgus (angled forearm)
  • 50% cardiac defects
  • 1/3 renal anomalies
  • Learning disabilities may be present
49
Q

How does chromatin packaging influences gene activity?

A
  • In nucleosomes, they are not evenly spaced but placement is crucial to gene function and transcription. Placement is transmitted from parent to daughter cell with high fidelity.
  • It is dynamic because it permits processes such as gene transcription and replication to occur.

-In the Upper panel
Methylation promotes tightly packed nucleosomes, thus transcription factors cannot bind DNA and genes are not expressed.

-In the Lower panel
Acetylation of histones results in loosely packed nucleosomes, thus the transcription factors are able to access DNA and the genes are expressed.

50
Q

What is euchromatin?

A

It is a chromatin that contains protein coding DNA, and the genes are actively transcribed.

51
Q

What is Heterochromatin?

A

A modified or suppressed chromatin with 2 subtypes:

Constitutive:

  • Repetitive DNA sequences
  • Does not contain genes

Facultative:

  • Euchromatin which has been inactivated
  • Genes not transcribed
52
Q

What are the factors that ensures a proper chromosome segregation?

A

Spindle attachment during metaphase via the centromere and the
role tension on kinetochores (a nonhistone) plays ensures proper
chromosome segregation.

53
Q

Explain X chromosome inactivation

A

X-chromosome inactivation occurs randomly for one of the two X chromosomes in female cells during development. Both X are active at conception, but Inactivation occurs when RNA transcribed from the Xist gene on the X chromosome from which it is expressed spreads to coat the whole X chromosome. X-inactivation ensures that females, like males, have one functional copy of the X chromosome in each body cell.

54
Q

What are the causes of Trisomy 21?

A

Down syndrome
47,XY,+21

  • Phenotypic result of three copies of 21.
  • Advancing maternal age increases risk of nondisjunction.
  • Most autosomal aneuploidies result from errors in maternal meiosis
  • Majority are M1 errors
55
Q

How are the different types of chromosomal rearrangements generated?

A

These events are caused by a breakage in the DNA double helices at two different locations, followed by a rejoining of the broken ends to produce a new chromosomal arrangement of genes.

Through deletions, duplications, inversions; and translocations.

56
Q

Explain meiotic pairing

A

‘Pairing’ refers to the juxtaposition of a pair of homologs at meiotic prophase.

57
Q

Explain dynamic mosaicism

A

Triggered by the inner instability concerning the ring structure, thus leading to the establishment of different cell clones with secondary aberrations.

58
Q

What are the factors that influence the phenotypes of a mosaic?

A

They occur when the somatic cells of the body are of more than one genotype. In the more common mosaics, different genotypes arise from a single fertilized egg cell, due to mitotic errors at first or later cleavages.

59
Q

Describe the concept of imprinted genes

A
  • Expression of imprinted gene depends on sex of transmitting parent.
  • For example: In some cases imprinted genes are expressed when the are inherited from the mother
  • Normal growth and development dependent upon correct inheritance of imprinted genes
  • Some imprinted genes must be inherited from the mother
  • Other imprinted genes must be inherited from the father
  • Most genes not imprinted
60
Q

list some diseases associated with gene imprinting

A

Angelman syndrome:
-Loss of proximal 15q inherited from the mother

Prader-Willi syndrome:
-Loss of proximal15q12 inherited from the father

61
Q

Describe Angelman syndrome

A
  • Severe developmental and intellectual impairment
  • Microcephaly (small head)
  • Severe seizures
  • Ataxic gait (uncoordinated)
  • Absence of speech
  • Flapping of hands
  • Inappropriate outbursts of laughter
  • Skin hypopigmentation (discoloration)
62
Q

Describe Prader-Willi Syndrome

A
  • Neonatal hypotonia and feeding difficulties
  • Onset of hyperphagia and food seeking as young child
  • Hyperphagia leads to obesity as child
  • Obesity leads to cardiopulmonary disease and diabetes
  • Short stature
  • Mild to moderate intellectual disability
  • Mean IQ is 60-80
  • Motor and language delay
  • Some behavioral issues
63
Q

Diagnostic resolution of CMA

A

Chromosomal Microarray Analysis (CMA)

Detects:

  • Numerical abnormalities
  • Unbalanced structural abnormalities including ones too small to be seen by conventional karyotyping or FISH
  • Some cases of uniparental disomy if array contains single nucleotide polymorphism SNP probes

-Will not detect balanced structural rearrangements
Cannot determine exact nature of rearrangement

  • Uses extracted DNA to detect copy number abnormalities
  • Patient and control DNA labeled with different color fluorescent dyes
  • Mixed and applied to slide containing hundreds of thousands of DNA probes
  • Laser scanner measures dye intensities of each probe
  • Computer software compares patient and control data
64
Q

Diagnostic resolution of FISH

A

Fluorescent in situ hybridization

  • Can detect numerical and structural abnormalities
  • Applicable to interphase or metaphase cells

Metaphase FISH:
-Detection of deletion too small to be seen by karyotyping
-Green control probe
Red target probe

Example: Patient with 22q11.2 microdeletion syndrome:

  • Typical deletion < 3 Mb
  • DiGeorge syndrome
  • Velocardiofacial syndrome

Interphase FISH:

  • Detection of copy number
  • No information on chromosome structure
  • Detection of gene rearrangements in oncology studies

Advantages:

  • Increased resolution over G-banded analysis
  • Faster TAT for interphase FISH
  • Genetic sex determination in newborn with ambiguous genitalia
  • Rule out lethal trisomy in critically ill newborn
  • Detection of mosaicism missed in dividing cells
  • Archival tissue (formalin fixed paraffin embedded) may be used in some cases

Disadvantages:

  • Only targets specific chromosome region
  • Probes not readily available for all known abnormalities
65
Q

Diagnostic resolution of G-banding

A
  • G bands produced by trypsin pretreatment followed by staining with Giemsa
  • Each autosome pair, X & Y have unique G-banding pattern
  • Requires live cells that can be arrested in metaphase

Used to detect:

  • Numerical abnormalities
  • Balanced Structural -Abnormalities affecting more than 5-10 Mb of DNA
  • Unbalanced Structural Abnormalities affecting more than 5-10 Mb of DNA
66
Q

Describe polyploidy

A

-The gain of haploid or diploid set of chromosomes

x=ploidy level
n=haploid #
formula: xn +/- 11

Tetraploidy :

  • gain of one diploid set
  • 92 chromosomes

Triploidy:

  • gain of one haploid set of chromosomes
  • 69 chromosomes
  • diandry = paternal
  • digyny = maternal
67
Q

Compare and contrast a SNP as it relates to diseases and non-diseases

A

single nucleotide polymorphism

  • Variation in general population at a specific location
  • If a SNP occurs within a gene, then the gene is described as having more than one allele. In these cases, SNPs may lead to variations in the amino acid sequence.
  • Researchers have found SNPs that may help predict an individual’s response to certain drugs, susceptibility to environmental factors such as toxins, and risk of developing particular diseases. SNPs can also be used to track the inheritance of disease genes within families
68
Q

Describe UPD

A

Uniparental Disomy

  • 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. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development.
  • can occur by a variety of mechanisms, either prezygotic (usually errors of meiosis) or postzygotic (errors of mitosis) and can affect whole chromosomes or be segmental
  • uniparental inheritance of an imprinted gene can result in the loss of gene function, which can lead to delayed development, mental retardation, or other medical problems.
69
Q

role of meiotic nondisjunction

A

is responsible for the extra chromosome 21 in trisomy 21 (Down syndrome) and for extra and missing chromosomes that cause other birth defects and many miscarriages.

70
Q

role of mitotic nondisjunction

A

Mitotic nondisjunction: The failure in mitosis for the two members of a chromosome pair to separate (to disjoin) normally

3:1

71
Q

Why aneuploidy of the sex chromosomes is tolerated in humans

A

These aneuploidies are better-tolerated than autosomal ones because human cells have the ability to shut down extra X chromosomes in a process called X-inactivation.

GT4300 Advanced Medical Genetics (4 decks)

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