Introduction to Cytogenetics Flashcards
What is cytogenetics the study of?
Chromosomes
In humans, how many autosomal and how many sex chromosomes do we have (which ones)?
23 pairs of chromosomes (so 46 in total)
Autosomal= 1-22
Sex= X+Y
How are the chromosomes numbered?
In order of size (i.e 1 is the biggest)
What do the dark bands on chromosomes signify?
Gene poor areas
What do the paler regions of chromosomes signify?
Gene rich areas
Which arm of the chromosome is named ‘p’ and ‘q’?
p= petit (the shortest arm) q= long arm
Which phase of the cell cycle are chromosomes most detectable in and therefore used in molecular cytogenetics?
Metaphase
Describe the different stages of mitosis.
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
What is ‘G-banding’?
A technique used to chemically inhibit the continuation of metaphase and staining the chromosomes to produce a clear karyotype- often useful for detecting disease
Why is cytogenetics so important- What % of still births, miscarriages and cancers have resulted from genetic disorders?
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%)
Give 5 ways in which cytogenetic abnormalities produce abnormal phenotypes.
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
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?
Organ malformation
Facial dysmorphism
Compromised mental/intellectual functioning
Do abnormalities in the sex chromosomes lead to less or more severe phenotypes?
Much less severe than autosomal as they contain fewer genes
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
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)
What is Mosaicism?
Diploidy + aneuploidy at the same time
What are the three origins that may give rise to a numerical abnormality?
Gametogenesis
Fertilisation
Early cleavage in post-zygotic non disjunction
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?
It increases, especially around late 40s- 1/3 chance of down syndrome. There is no risk as the father ages though
What is Chiasmata?
The process in which chromatids swap bits of DNA with their partners
Meiotic errors can lead to numerical errors (part of gametogenesis). Describe how.
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)
Why are trisomy 21, 18 and 13 common but other types are not?
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
What are the common names for trisomy 21, 18 and 13?
21: Down syndrome
18: Edward Syndrome
13: Patau syndrome
Trisomy 21: Down syndrome
How many babies are affected?
Which gamete and stage of meiosis causes this?
What percentage spontaneously abort?
1/700 90-95% trisomy 21, 80% maternal meiosis 1 2-5% mosaic - mitotic 2-5% Robertsonian translocation 75% spontaneously abort
What are the phenotypic features of trisomy 21 (down syndrome)?
Upslanting eyes Short neck Flat face Protruding tongue Low-set ears Sandal gap in toes Simian crease on hand
How does Trisomy 21 affect adults?
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
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?
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
What phenotypic features does a baby with Trisomy 18 display?
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
Trisomy 13: Patau syndrome
How many babies are affected?
What is it caused by?
How many spontaneously abort?
1/5000 75% trisomy 13 (90% maternal, 10% paternal) 5% mosaic 20% Robertsonian translocation 95% spontaneously abort
What are the phenotypic features of Trisomy 13 (Patau syndrome)?
Holoprosencephaly (absent forebrain) Heart defects Cyclops/aniphthalmia (doesn't divide properly/one closed) Cleft lip/palate Sloping forehead Polydactyly Rocker-bottom feet
Why is there a maternal age effect?
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
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).
Turner syndrome- 45, X Affects= 1/2500
Klinefelter syndrome- 47, XXY Affects=1/1000
47, XYY Affects= 1/1000
47, XXX Affects= 1/1000
People suffering Turner syndrome have 45 chromosomes due to only having one ‘X’ sex chromsome. Explain what phenotypes this results in.
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
People suffering from Klinefelter syndrome have 47 chromosomes due to ‘XXY’ sex chromosomes. How does it affect men and when is it diagnosed usually?
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
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?
69 XXY; 69 XYY; 69 XXX
99.9% spontaneously abort
1/57000 live births affected
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?
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)
What are molar pregnancies?
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
How can errors at early cleavage cause trisomy?
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
In early miscarriages, how many are caused by chromosomal abnormalities?
60%- abnormal
40% normal
