POM - GENETICS - CHROMOSOMAL ABNORMALITIES

Question 1

What is a karyotype and what is it used for?

Answer 1

 A karyotype is an individual’s whole set of chromosomes
 Karyotyping is used to examine a person’s whole set of chromosomes and identify any abnormalities in the chromosome

Question 2

what is a giemsa staining, ideogram and G-banded architecture?

Answer 2

 Giemsa staining has been used to identify individual chromosomes
 Introduces ‘banding’ of light and dark areas
 An ideogram is a schematic used to show the size and banding patterns of the chromosomes.
 The Giemsa staining leaves a recognisable pattern of bands

Question 3

what are band numbers? how do they work?

Answer 3

 Bands are caused by different staining
 Bands were originally identified with low levels of resolution
 There was only a few bands visible per chromosome (1,2,3)
 As technology improved, more bands became visible - they were named as sub-bands ie, 11,12,21,22,23
 Further improvements in resolutions helps identify smaller aberrations (11.1, 11.2 etc)

Question 4

what is currently the most detail we can study chromosomes?

Answer 4

We can now study bphs – bands per haploid set. Bands DON’T REPRESENT GENES OR FAMILIES OF GENES. Regions of different compaction can help identify the number of genes in each band. Dark – heterochromatin – means that it is more compact and there are fewer genes. Light – euchromatin- means that there are more genes.

Question 5

what does the different regions of compaction mean?

Answer 5

Regions of different compaction can help identify the number of genes in each band. Dark – heterochromatin – means that it is more compact and there are fewer genes. Light – euchromatin- means that there are more genes.

Question 6

when is karyotyping most commonly carried out?

Answer 6

Karyotyping is more commonly done in prophase rather than metaphase

Question 7

what is meant by WSG? when is it carried out?

Answer 7

 We are beginning to see genomic medicine due to the human genome project reading the whole human genome
 Cost of WSGs are decreasing
 Babies could have their genomes sequenced from birth
 This is currently done for some types of cancer patients to inform the best treatment
 WSGs are currently done for babies who have a suspected abnormality.

Question 8

what is an aneuploidy

Answer 8

 An aneuploidy is an abnormal number of a chromosome
 2 copies are sufficient, 3 is a trisomy and 1 is an insufficient monosomy

Question 9

what is the ‘normal’ process of meiosis?

Answer 9

 To achieve a reduction from diploid (46) to haploid (23) chromosomes in the cell.
 This ensures genetic variation in the gametes and enables random assortment of homologues and recombination

Question 10

what is non-disjunction? what does it lead to? how does it arise?

Answer 10

 Results in an uneven number of chromosomes in daughter cells
 Occurs in either meiosis I or meiosis II
 In meiosis I = all daughter cells are affected
 In meiosis II = half are affected
 Always results in +1 or -1 chromosomes
 After fertilization this results in a trisomy or monosomy

Question 11

what is sex chromosome anueploidy, how common is it and what is its effects?

Answer 11

 Most common form of aneuploidy
 Affects 1:400 males and 1 in 650 females
 But why is it tolerated? Why doesn’t it result in a non-viable fetus?
 There is X-inactivation of excess X-chromosomes so only 1 X chromosome is active
 The Y chromosome is only 150 genes  low gene content.
 However, the inactive X chromosome still has an effect as both the X and Y chromosome have PAR  psuedo-autosomal region

Question 12

what are the classes of chromosomes?

Answer 12

• meta centric,
• arcocentric
• submetacentric

Question 13

what is targeted fish? what does it pick up?

Answer 13

 If the deletion is too small to detect using standard karyotyping, it can be detected using targeted FISH
 FISH - fluorescent in situ hybridisation, where the lack of elastin on affected chromosome is picked up.

Question 14

what is the effect of 2 chromosomal abnormalities? how does it affect carriers? what could it cause instead?

Answer 14

If the 2 chromosomal abnormalities are balanced, it often does not affect carriers. However, it may cause partial trisomy or monosomy (Cri-du-Chat Syndrome.)
Can occur in somatic cells.

Question 15

what is meant by microscopic?

Answer 15

 Chromosomal deletions are microscopic as they can be deleted easily under a microscope.
 Microdeletion, which is seen in very high resolution banding has 20+ genes deleted

Question 16

what is the inheritance of chromosome abnormalities?

Answer 16

 Many chromosomes abnormalities are de-novo.
 Some people are unidentified carriers who can have offspring which are affected

Question 17

what is mosaicism?

Answer 17

 Presence of two or more populations of cells with different genotypes. X-inactivation results in different mosaic expression
 Mosaicism can arise by non-disjuncture in early development and loss of extra chromosome in early development
 Results in a milder phenotype.
 Some lethal aneuploides are thought to be survivable if mosaic
 Everyone is a mosaic!

Question 18

what is the effect of aneuploidy and pregnancy?

Answer 18

 Aneuploidy sadly accounts for 5% of still births and 50% of spontaneous abortions.
 They accoutn for 5% of all clinically recognised prenancies
 Trisomies of all chromosomes can be detected perenatally
 Monosomy is very poorly tolerated most trisomies (21,18 and 13) are not compatible with life

Question 19

what is the link between maternal age and Downs syndrome? why is oogenesis vulnerable?

Answer 19

 Trisomy 21 = down syndrome, resulting from maternal non-disjunction
 The risk of down-syndrome increases exponentially with maternal age
 This is due to the vulnerability of oogenesis
o Oogenesis is paused in utero in prophase I until puberty
o The secondary oocyte arrests in metaphase II
o It is only completed if it is fertilized
o One primary oocyte yields only one ovum
o There is a finite number of primary oocytes

Question 20

what is the link between maternal age and female non-disjunction? what’s the cause?

Answer 20

 Most aneuploidy caused by non-disjunction arises in oogenesis
 This is due to the degradation of factors holding homologous chromatids together

Question 21

Why is male meiosis still a vulnerable process with age?

Answer 21

 There is no equivalent to oocyte mitotic arrest.
 However, male meiosis is still a vulnerable process as primary spermatocytes undergo 23 mitotic divisions per year and can potentially accumulate age effects.

Question 22

does paternal age affect aneuploidy? what paternal factors do affect aneuploidy? what does paternal age affect?

Answer 22

 Paternal age doesn’t increase the risk of aneuploidy, however it does affect a subset of single gene disorders (Mendelian) caused by point mutations in FGFR2, FGFR3, RET including Apert syndrome, Crouzon syndrome, Pfeiffer syndrome.
 This is enhanced by ‘selfish spermatogonial selection’ leading to an advantage over wild type cells.
 Although paternal age doesn’t increase the risk of aneuploidy, smoking is a risk factor. Eg, 80% of people who are 45 X have fathers who smoked.