Chromosome Abnormalities, Mutations and Analysis

Question 1

What type of chromosome abnormalities can occur

Answer 1

Numerical
Structural
Mutational

Question 2

What percentage of first trimester miscarriages are due to chromosomal abnormalities

Answer 2

50%

Question 3

What is the main type of chromosomal abnormalities causing first trimester miscarriages

Answer 3

Trisomy

Question 4

What type of abnormality and syndrome does 47, XX+21

Answer 4

Downs syndrome

Means there are 47 chromosomes with the extra chromosome 21

Question 5

How can chromosomal abnormalities arise

Answer 5

From non-disjunction which can occur in meiosis 1 or 2

Question 6

Give examples of autosomal aneuploidy syndromes

Answer 6

Trisomy 21 (Down syndrome)
Trisomy 13 (Patau syndrome)
Trisomy 18 (Edwards syndome)

Question 7

Give examples of sex chromosome aneuploidy syndromes

Answer 7

45, X (Turner syndrome)

47, XXY (Klinefelter syndrome)

Question 8

What is the incidence of trisomy 21

Answer 8

1 in 650 to 1 in 700 (increases with advancing maternal age)

Question 9

Describe the features of trisomy 21

Answer 9

Characteristic facial dysmorphologies
IQ less than 50
Average life expectancy (50-60 years)
Alzheimer’s disease in later life

Question 10

What is the incidence of trisomy 13

Answer 10

1 in 5000

Question 11

Describe the features of trisomy 13 (Patau syndrome)

Answer 11

Multiple dysmorphic features and mental retardation

About 5% die within first month, very few survive beyond first year

Question 12

What is the incidence of trisomy 18

Answer 12

1 in 3000

Question 13

Describe the features of trisomy 18 (Edwards syndrome)

Answer 13

Severe developmental problems

Most patients die within first year, many within first month

Question 14

Describe the features of 45, X (Turner syndrome)

Answer 14

Females of short stature and infertile
Neck webbing and widely spaced nipples
Intelligence and lifespan is normal

Question 15

Describe the features of 47, XXY (Klinefelter syndrome)

Answer 15

Tall stature, long limbs
Male but infertile, small testes, about 50% gynaecomastia
Mild learning difficulties

Question 16

What is gynaecomastia

Answer 16

Abnormal development of breast tissue in male

Question 17

What type of structural abnormalites can occur in chromosomes

Answer 17

Balanced or unbalanced rearrangements
Translocations
Deletions
Insertions
Inversions

Question 18

What type of translocations can occur

Answer 18

Reciprocal

Robertsonian

Question 19

What is a reciprocal translocation

Answer 19

Involves breaks in two chromosomes with the formation of two new derivative chromosomes

Question 20

What is a robertsonian translocation

Answer 20

The fusion of two acrocentric chromosomes (the short arms are lost)
The two chromosomes are fused but no genetic information is lost: other translocations occur but do not lead to a viable fetus

Question 21

What are the outcomes for reciprocal translocation carriers

Answer 21

Partial trisomy and partial monosomy

Partial monosomy and partial trisomy

Question 22

How can an unbalanced translocation occur

Answer 22

From the combination of a normal set of chromosomes which a set of balanced translocation chromosomes

Question 23

What can the robertsonian translocation carriers produce

Answer 23

Trisomy 14
Monosomy 14
Monosomy 21
Trisomy 21

Question 24

What occurs in chromosomal deletions

Answer 24

A break in the chromosome causes genetic material to be deleted

Question 25

What occurs in a paracentric inversion

Answer 25

A break in the chromosome causes DNA to be inverted (switched upside down)

Question 26

What type of inversions are there

Answer 26

Paracentric inversion Pericentric inversion These are balanced rearrangements

Question 27

What occurs in a pericentric inversion

Answer 27

A break in the chromosome which includes the centromere causes DNA to be inverted with the centromere (switched upside down)

Question 28

What kind of genetic mutations can occur

Answer 28

Germline | Somatic - in early development or later

Question 29

What types of genetic mutations can occur

Answer 29

Non-coding - typically has no effect | Coding

Question 30

What type of coding mutations are there

Answer 30

Silent – synonymous e.g. CGA (Arg) to CGC (Arg) Missense e.g. CGA (Arg) to GGA (Gly) Nonsense e.g. CGA (Arg) to TGA (Stop) Frameshift – deletion / insertion e.g. CGA (Arg) to CCGA (Pro, then out-of-frame)

Question 31

What type of point mutations can occur

Answer 31

Transitions | Transversions

Question 32

Give examples of transition mutations

Answer 32

Purine to purine A > G | Pyrimidine to pyrimidine C > T

Question 33

Give examples of transversions mutations

Answer 33

Purine to pyrimidine A > C | Pyrimidine to purine C > G

Question 34

How are mutations named

Answer 34

When labelled above they refer to DNA sequence, below refer to protein sequence

Question 35

How can mutations be detected

Answer 35

Polymerase chain reaction (PCR) Gel electrophoresis Restriction fragment length polymorphism (RFLP) analysis Amplification refractory mutation system (ARMS) DNA sequencing

Question 36

What is required for PCR

Answer 36

``` Sequence information Oligonucleotide primers DNA Nucleotides DNA polymerase ```

Question 37

How does PCR occur

Answer 37

Double stranded DNA is denatured at 93-95oC Then annealed at 50-70oC Then extended at 70-75oC It is then repeated 20-30 times

Question 38

What does gel electrophoresis do

Answer 38

Separate DNA fragments by size for analysis (e.g. the ones from PCR)

Question 39

How does gel electrophoresis work

Answer 39

Apply an electric field DNA is negatively charged Separate through agarose gel matrix Visualise DNA fragments

Question 40

What are the advantages of PCR

Answer 40

Speed Ease of use Sensitive Robust

Question 41

Where can PCR be applyed

Answer 41

``` DNA cloning DNA sequencing In vitro mutagenesis Gene identification Gene expression studies Forensic medicine Typing genetic markers Detection of mutations ```

Question 42

What are the advantages of ARMS

Answer 42

Cheap Labelling not required Electrophoresis required Primer design critical

Question 43

What are the disadvantages of ARMS

Answer 43

Need sequence information Limited amplification size Limited amounts of product Infidelity of DNA replication

Question 44

What are restriction endunucleases

Answer 44

Enzymes from bacterial cells

Question 45

What do restriction endunucleases do

Answer 45

``` That have a protective mechanism They degrade DNA of invading viruses Recognise specific DNA sequences Usually 4-8 bp Always cut DNA at the same site ```

Question 46

What are the advantages and disadvantages of restriction endunucleases

Answer 46

``` Advantages: Simple Cheap Non-radioactive Requires gel electrophoresis Disadvantages: Not always feasible ```

Question 47

What does DNA sequencing use

Answer 47

Chain termination method (Sanger) | Use of dideoxynucleotides

Question 48

What are the advantages of DNA sequencing

Answer 48

Gold standard for mutation detection | Automation and high throughput

Question 49

What are the disadvantages of DNA sequencing

Answer 49

Expensive equipment | Poor quality sequence read (First part of sequence, 15 to 40 bases, Deterioration after 700-900 bases)

Question 50

What should be considered when determining which genetic mutations detecting method should be used

Answer 50

``` Direct test Quick and easy Cheap High Sensitivity High Specificity ```

Question 51

Where is non-disjunction abnormalities more likely to occur

Answer 51

The maternal gamates

Question 52

Which chromosomes are acrocentric chromosomes

Answer 52

``` 13 14 15 21 22 ```

Question 53

When are genetic mutations identified

Answer 53

When they cause gene disruption or are associated with disease

Question 54

What does PCR do

Answer 54

Amplifies DNA

Question 55

What is a new type of sequencing becoming more popular

Answer 55

Next generation sequencing - 18 billion bp in 4 days (about 6 human genomes)