Introduction to Cytogenetics

Question 1

What is cytogenetics the study of?

Answer 1

Chromosomes

Question 2

In humans, how many autosomal and how many sex chromosomes do we have (which ones)?

Answer 2

23 pairs of chromosomes (so 46 in total)
Autosomal= 1-22
Sex= X+Y

Question 3

How are the chromosomes numbered?

Answer 3

In order of size (i.e 1 is the biggest)

Question 4

What do the dark bands on chromosomes signify?

Answer 4

Gene poor areas

Question 5

What do the paler regions of chromosomes signify?

Answer 5

Gene rich areas

Question 6

Which arm of the chromosome is named ‘p’ and ‘q’?

Answer 6

p= petit (the shortest arm)
q= long arm

Question 7

Which phase of the cell cycle are chromosomes most detectable in and therefore used in molecular cytogenetics?

Answer 7

Metaphase

Question 8

Describe the different stages of mitosis.

Answer 8

Interphase= condensation of chromosomes
Prophase= Sister chromatids
Prometaphase= Mitotic spindle start to form
Metaphase= Mitotic spindles attach to centromeres
Anaphase= Sister chromatids pulled apart
Telophase= Membrane starts to separate
Cytokinesis= Separation

Question 9

What is ‘G-banding’?

Answer 9

A technique used to chemically inhibit the continuation of metaphase and staining the chromosomes to produce a clear karyotype- often useful for detecting disease

Question 10

Why is cytogenetics so important- What % of still births, miscarriages and cancers have resulted from genetic disorders?

Answer 10

5% stillbirths
60% miscarriages
40% all conceptions
up to 100% cancers

There are over 140 different known syndromes and genetics has a major contribution to learning difficulties (around 20%)

Question 11

Give 5 ways in which cytogenetic abnormalities produce abnormal phenotypes.

Answer 11

1) Dosage effect (loss or gain- loss is more deleterious than gain)
2) Disruption of a gene (inappropriate activation/inactivation, breakpoint)
3) Effect due to parental origin (Genomic fingerprinting- functional effect such as imprinted regions on chromosome 15)
4) Position effect (A gene in a new position functions inappropriately)
5) Unmasking of recessive disorder

Question 12

The severity of phenotypes resulting from cytogenetic abnormalities varies, Many are lethal in utero. What phenotypes may arise to those who survive to be born?

Answer 12

Organ malformation
Facial dysmorphism
Compromised mental/intellectual functioning

Question 13

Do abnormalities in the sex chromosomes lead to less or more severe phenotypes?

Answer 13

Much less severe than autosomal as they contain fewer genes

Question 14

There can be structural or numerical abnormalities with chromosomes. Focusing on numerical, describe what the following sets are (healthy or abnormal) and what their individual chromosomes are called:
Haploidy
Diploidy
Triploidy
Tetraploidy
Polyploidy

Answer 14

Both of these are normally found in humans:
Haploidy (gametes)= Monosomy
Diploidy= Disomy

The following are abnormalities:
Triploidy (3) = Trisomy (3 chromosomes- Such as in down syndrome)
Tetraploidy (4) = Tetrasomy (4 chromosomes)
Polyploidy (many-general)

Question 15

What is Mosaicism?

Answer 15

Diploidy + aneuploidy at the same time

Question 16

What are the three origins that may give rise to a numerical abnormality?

Answer 16

Gametogenesis
Fertilisation
Early cleavage in post-zygotic non disjunction

Question 17

Gametogenesis can be an origin of numerical errors in chromosomes. As the mother’s age increases, what effect does that have on the chance of aneuploidy (presence of abnormal number of chromosomes in cells) occuring?

Answer 17

It increases, especially around late 40s- 1/3 chance of down syndrome. There is no risk as the father ages though

Question 18

What is Chiasmata?

Answer 18

The process in which chromatids swap bits of DNA with their partners

Question 19

Meiotic errors can lead to numerical errors (part of gametogenesis). Describe how.

Answer 19

Failure of chromosome or chromatid separation. In first stage of meiosis (meiosis 1), chromosome nondisjunction can happen where both chromosomes go into the same gamete instead of splitting, leading to two eggs being disomic and two being nullisomic. Chromatid non disjunction can occur in the second stage of meiosis (meiosis 2) which results in a disomic gamete, a nullisomic gamete and two normal gametes (look at slide if unsure)

Question 20

Why are trisomy 21, 18 and 13 common but other types are not?

Answer 20

These are all survivable whereas others are not. E.g trisomy 19 is lethal as it has many pale parts/ gene rich areas and so is critical

Question 21

What are the common names for trisomy 21, 18 and 13?

Answer 21

21: Down syndrome
18: Edward Syndrome
13: Patau syndrome

Question 22

Trisomy 21: Down syndrome

How many babies are affected?
Which gamete and stage of meiosis causes this?
What percentage spontaneously abort?

Answer 22

1/700
90-95% trisomy 21, 80% maternal meiosis 1
2-5% mosaic - mitotic
2-5% Robertsonian translocation
75% spontaneously abort

Question 23

What are the phenotypic features of trisomy 21 (down syndrome)?

Answer 23

Upslanting eyes
Short neck
Flat face
Protruding tongue
Low-set ears
Sandal gap in toes
Simian crease on hand

Question 24

How does Trisomy 21 affect adults?

Answer 24

Fertility in males (usually infertile)
Average life span 55-68 yrs
Medical problems such as high risk of cancer, alzheimer’s, hypothyroid, obesity/coeliac, arthiritis, diabetes, hearing loss and seizures

Question 25

Trisomy 18: Edward’s syndrome

How many babies are affected?
What causes this? Which stage of which gamete?
What % spontaneously abort?
How many survive to be over 1 yrs?

Answer 25

1/3000
90% trisomy 18. 10% mosaic
97% maternal- 2/3 in stage 2 of meiosis and 1/3 in stage 1
95% spontaneously abort
10% live to reach 1

Question 26

What phenotypic features does a baby with Trisomy 18 display?

Answer 26

Rocker-bottom feet
Clenched fists
Polydactyly (extra fingers)
Short sternum
Scalp defect
Micrognathia
Heart disease
Little chin
Low set ears
Lobe at back of head

Question 27

Trisomy 13: Patau syndrome

How many babies are affected?
What is it caused by?
How many spontaneously abort?

Answer 27

1/5000
75% trisomy 13 (90% maternal, 10% paternal)
5% mosaic
20% Robertsonian translocation
95% spontaneously abort

Question 28

What are the phenotypic features of Trisomy 13 (Patau syndrome)?

Answer 28

Holoprosencephaly (absent forebrain)
Heart defects
Cyclops/aniphthalmia (doesn't divide properly/one closed)
Cleft lip/palate
Sloping forehead
Polydactyly
Rocker-bottom feet

Question 29

Why is there a maternal age effect?

Answer 29

Could be unfavourable chiasmata distribution (e.g pulled to wrong parts of cells or not held together properly) and age- dependent deteriotation of meiotic structures due to hormonal imbalance, irradiation, oral contraceptives, alcohol and perhaps poor diet

Question 30

Describe 4 types of sex chromosome aneuploidy and how many people it affects (remember that these are not as severe. Also, it has been found that there is no age related risk).

Answer 30

Turner syndrome- 45, X Affects= 1/2500
Klinefelter syndrome- 47, XXY Affects=1/1000
47, XYY Affects= 1/1000
47, XXX Affects= 1/1000

Question 31

People suffering Turner syndrome have 45 chromosomes due to only having one ‘X’ sex chromsome. Explain what phenotypes this results in.

Answer 31

Female with sexual development problems- loss of ovarian function, no puberty, gonadal failure, infertility
Lymphatic obstruction- webbed neck and swelling of hands/feet
Skeletal abnormalities- short stature
Coarction of aorta
IQ normal or reduced compared to sibs

Question 32

People suffering from Klinefelter syndrome have 47 chromosomes due to ‘XXY’ sex chromosomes. How does it affect men and when is it diagnosed usually?

Answer 32

It is usually diagnosed when trying to have a baby due to infertility. They may lack secondary sexual characteristics, testicular dysgenesis and 30-50% gynaecomastia (20x risk breast cancer).
Adults have long arms and legs
IQ is normal but may decrease with increased Xs

Question 33

The origin of aneuploidy can be at the fertilisation stage. Triploidy often occurs from this. Which examples are there of this, how many spontaneously abort and how many affect live births?

Answer 33

69 XXY; 69 XYY; 69 XXX
99.9% spontaneously abort
1/57000 live births affected

Question 34

In terms of the origin of triploidy during fertilisation, what is digyny, diplospermy and dispermy? What do the foetus look like if it’s maternal or paternal?

Answer 34

Digyny is when the 2n comes from the mother (an egg has twice number of chromosomes)- v. small placenta and big head (so odd foetus)
Diplospermy is when the 2n comes from one father sperm
Dispermy is when 2 sperm fertlise one egg- Small foetus and placenta often large (so odd placenta)

Question 35

What are molar pregnancies?

Answer 35

When a haploid (normal) sperm fertilises an empty egg, the haploid zygote doubles up to ‘correct’ the lack of chromosomes. This causes a cystic placenta mass which is filled with fluid and bubbles to grow in the uterus and cause disease

Question 36

How can errors at early cleavage cause trisomy?

Answer 36

Division in the second mitotic division can cause a monosomic cell and a trisomic cell and two normal ones. When a trisomic egg splits, there can be ‘trisomic zygote rescue’ in which at least one cell turns out normal in which one chromosome is thrown out, however depending on which is thrown out, this can result in inheriting two chromosomes from the same parents

Question 37

In early miscarriages, how many are caused by chromosomal abnormalities?

Answer 37

60%- abnormal

40% normal