Variations In Chromosome Arrangement Flashcards
Describe the basic structure of a chromosome
- 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
Where are the telomeres located?
Telomeres located at both ends and have specialized sequences
-telomeres protect the end of the chromosome and prevent fusion with other chromosomes or DNA
What happens if DNA breaks?
-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
List the types of chromosome variations. Contrast them
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)
What are copy number variants?
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
What are the length of copy number variants?
CNVs can be from 50 bp to over 10Mb
Where can copy number variants be found? Express there variation
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)
How much deletions and duplications did the human genome project identify?
Occupy 5%-10% of genome of normal human population
How can chromosomes gain or lose material?
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
What are the types of deletions?
The proportions without a centromere is typically lost
-terminal deletion(near one end)
- Interstitial/intercalatory deletion (interior of the chromosome)
What is the origin of deletion?
- 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
What are the clinical symptoms of Curly calf syndrome /Arthrogryposis multiplex ?
- 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
Explain the genetics (and secrecy) behind Curly calf syndrome/Arthrogryposis Multiplex
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!
Describe the synapsis for an interstitial deletion
- 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
What is an example of a deletion syndrome?
Cri du Chat syndrome
Explain the genetics of the Cri du Chat syndrome
- “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
What are the symptoms of Cri du Chat syndrome?
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
What syndromes can result from duplications?
Human diseases can result from gene duplication
- Neurodevelopmental syndromes
- Many cancers associated with gene duplications
- Myc duplication(amplification) May promote cancer development
What are duplications?
Duplications arise from unequal crossing over between synapses chromosomes during meiosis
-One chromatid (3) has a duplication and other chromatid(2) has a deletion
What ca7ses Potocki-Lupski syndrome?
Chromosome 17p11.2 duplication
- dup(17)(p11.2) syndrome - PTLS
What are the symptoms of Potocki-Lupski syndrome ?
- 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
What do gene redundancies arise from?
- 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
- example: many copies of ribosomal RNA genes(called rDNA) on Acrocentric chromosome stalk regions
- 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
What are inversions?
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
What does an inversion do? What is required for this?
- Segment of chromosome turned 180 degrees within chromosome
- Requires two breaks in chromosome, and rejoining of inverted segment
- May arise from chromosomal looping
What is a Paracentric inversion?
- Centromere is not part f the inverted sequence
- Does not change lengths of two arms of chromosome
What is pericentric inversion?
- Centromere is part of inverted segment
- May change lengths of arms of chromosome
What happens during meiosis with normal and paracentric homologues? What gametes are produced?
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
What happens during meiosis with normal and pericentric homologues? What gametes are produced?
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
What are translocations?
Movement of a chromosomal segment to new location in the genome
What are reciprocal translocations?
- Involves the exchange of segments between two NONHOMOLOGOUS chromosomes
- Has big implications when it is time to form gametes
What are quadrivalents?
In reciprocal translocations
Unusual synapsis configuration during meiosis called a quadricalent
What are two possible segregation patterns during meiosis?
Alternate segregation
Adjacent segregation
Explain alternate segregation
- Segregation pattern during at first meiotic division
- Has complete complement of genetic information
- Balanced genetic information is these gametes
- Compatible with life.
Explain adjacent segregation
- 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
Will reciprocal translocations have clinical or phenotypic consequences?
-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
How can reciprocal translocations lead to cancer/cancer-related diseases?
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
What is robertsonian translocation?
- 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
What are the effects and results Robertsonian during meiosis?
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
How much Down syndrome in children does Robertsonian translocation account for?
Robertsonian translocation accounts for 2x5%of children with Down syndrome due to carrier parents (these carrier parents themselves are healthy)
Describe the karyotype of Down syndrome due to Robertsonian translocation
Two chromosome 21 and derivative chromosome 14 has the long arm of chromosome 21
46, XX,der (14;21)(q10;q10), +21
What are fragile sites on chromosomes?
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
How can gaps/fragile sites be revealed on chromosomes?
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
What is the most common form of inherited intellectual disability?
Fragile X syndrome
What are the symptoms of fragile X syndrome in males?
- Long, narrow faces
- Protruding chin
- enlarged ears
- Increased testicular size
What 3 abnormalities is prenatal screening used to detect?
Trisomy 21-down syndrome
Trisomy 18
-trisomy 13 has similar results to 18 but is about 1/22,700 live births
Neural tube defects
What is the frequency of trisomy 21/down syndrome?
About 1/830 live births
What is the frequency of trisomy 18?
About 1/7,500
What is the frequency of neural tube defects?
About 1/2,000 live births
Give the non-invasive tests for prenatal screening and what time span they’re used for?
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
What are the invasive tests for prenatal screening? Give the timeframe each should be used
Amniocentesis. 16-20 weeks
Chronic villus sampling 11-14 weeks
What tests can be used for Maternal Serum Screening: first trimester tests?
First trimester tests: 11-14 weeks + 1 day
Pregnancy. Associated plasma protein-A(PAPP-A)
Human Chorionic gonadotropin (B-hCG)
What tests can be used for Maternal Serum Screening: Second trimester tests?
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)
What is the purpose of maternal serum screening?
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
What is Non-invasive prenatal screening (NIPS, also called NIPT)?
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
What is the main function of NIPS? How does it work?
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
What is cell free DNA?
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
Why would ultrasound be used in conjunction with maternal serum screening?
Increases the non-invasive prediction of an. Affected pregnancy
At 20 weeks what specifically can ultrasonography be used to detect?
Different structural abnormalities
An ultrasound detects an increase in maternal AFP, what does this detect?
Neural tube defects
An ultrasound detects micrognathia , what May this suggest?
May suggest Cri-du-chat syndrome
An ultrasound detects rocker-bottom feet, what does this detect?
Trisomy 18, Edwards syndrome
What does anencephaly detected by ultrasound suggest?
Neural tube defect
There is an increase in nuchal translucency suggest?
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
Positive results of a prenatal screening must be …
Confirmed by a diagnostic tests
What diagnostic tests can be used for confirmation of prenatal screening?
Chorionic villus sampling
Amniocentesis
Explain chorionic villus sampling
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
Explain amniocentesis
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
