Lecture 21: Chromosomal Abnormalities

Question 1

What is the normal human karyotype?

Answer 1

22 pairs of autosomal chromosomes and one pair of sex chromosomes (female, XX and male, XY)
Total of 46 chromosomes

Question 2

In which phase of mitosis are chromosomes karyotyped?

Answer 2

During metaphase - each chromosome comprises 2 chromatids at this point

Question 3

Outline DNA compaction.

Answer 3

• DNA wrapped around histone to form nucleosome
• Nucleosomes coiled into chromatin fibre
• Chromatin is further condensed to form chromosome

Question 4

What does the G-banded architecture of a chromosome show?

Answer 4

G-dark bands show DNA that is tightly bound and less accessible to transcription machinery
G light bands show DNA that is less tightly bound and more accessible to transcription machinery

Question 5

What type of staining leaves a recognizable pattern of bands on a chromosome?

Answer 5

Glemsa staining

Question 6

What are the 2 arms called on a chromosome?

Answer 6

p-arm (petite/shorter arm)

q-arm (longer arm)

Question 7

What is the centromere of a chromosome?

Answer 7

The centromere is the chromosome region that attaches to a spindle fibre at metaphase of mitosis or meiosis and moves to the spindle pole at anaphase, pulling the rest of the chromosome behind it.

Question 8

What are the telomeres of a chromosome?

Answer 8

Telomeres are distinctive structures found at the ends of our chromosomes. They consist of the same short DNA sequence repeated over and over again and protect the ends of the chromosomes

Question 9

What does this mean: 46,XX,t(1;2)(p32;q22) ?

Answer 9

46 chromosomes, female (XX sex chromosomes), with a balanced translocation between chromosomes 1 and 2 with breakpoints in the short arm of chromosome 1 at band 1p32 and the long arm of chromosome 2 at band 2q22.

Question 10

How would you note there’s a deletion in a karyotype?

Answer 10

Using ‘del’ and then the chromosome number and band number

Question 11

How would you note there’s monosomy in a karyotype?

Answer 11

using ‘-‘ and the chromosome number

Question 12

How would you note there’s trisomy in a karyotype?

Answer 12

using ‘+’ and the chromosome number

Question 13

What is a haploinsufficient gene?

Answer 13

Need expression from both alleles to have a normal phenotype

Question 14

What is an imprinted gene?

Answer 14

Imprinted genes are genes whose expression is determined by the parent that contributed them. Only allele from one parent is actually expressed rather than both due to methylation of one of the alleles either in maternal or paternal line.

Question 15

What is a haplosufficient gene?

Answer 15

Only need expression from one allele or the other

Question 16

Gene expression can be…?

Answer 16

• tissue specific
• at a specific time in development
• in response to an event

Question 17

What is the purpose of mitosis?

Answer 17

• to create 2 identical daughter cells
• for growth and repair
• to replace exhausted cells
• 2n –> 2n

Question 18

What is the purpose of meiosis?

Answer 18

• to achieve reduction from diploid to haploid
• to ensure genetic variation in gametes
• to enable random assortment of homologues and recombination

Question 19

What is non-disjunction?

Answer 19

When chromatids don’t split properly
The failure of one or more pairs of homologous chromosomes or sister chromatids to separate normally during nuclear division, usually resulting in an abnormal distribution of chromosomes in the daughter nuclei.

Question 20

What is the result of non-disjunction in Meiosis I?

Answer 20

2 daughter cells with trisomy and 2 daughter cells with monosomy

Question 21

What is the result of non-disjunction in Meiosis II?

Answer 21

2 unaffected daughter cells, 1 daughter cell with trisomy and 1 daughter cell with monosomy

Question 22

Why is female meiosis vulnerable to non-disjunction?

Answer 22

• paused in utero until puberty
• unbalanced division and one primary oocyte yields only one ovum
• finite no. of oocytes

Question 23

Most aneuploidy is caused by what?

Answer 23

Non-disjunction in oogenesis - likely due to degradation of factors which hold homologous chromatids together

Question 24

Does the risk of maternal non-disjunction increase or decrease with age?

Answer 24

Risk increases with age

Question 25

What causes Down’s syndrome?

Answer 25

Trisomy of chromosome 21 (most trisomy 21 arises in maternal non-disjunction)

Question 26

What can quantitative fluorescence PCR (QF-PCR) tell us?

Answer 26

Whether there is trisomy or not.

1: 1 ratio (disomy)
1: 1:1 ratio (meiosis I trisomy)
1: 2 ratio (meiosis II trisomy)

Question 27

Why is sex chromosome imbalance tolerated?

Answer 27

• X inactivation of excess X chromosomes

- low gene content of Y chromosome

Question 28

Describe some reciprocal chromosomal abnormalities?

Answer 28

• translocations ( chromosome breaks and a portion of it reattaches to a different chromosome)
• insertions (insertion of a larger sequence into a chromosome.)
• inversions (chromosome rearrangement in which a segment of a chromosome is reversed end to end. An inversion occurs when a single chromosome undergoes breakage and rearrangement within itself.)

Question 29

What do reciprocal chromosomal abnormalities have in common?

Answer 29

• carriers are usually phenotypically normal
• chromosomes have to contort into unusual figurations to achieve synapsis at mitosis and meiosis
• present a reproductive risk: increased chance of unbalanced gametes

Question 30

In unbalanced chromosomal abnormalities what does the severity of the phenotype depend on?

Answer 30

Gene content of affected segment

Question 31

What type of aneuploidy is usually more tolerated?

Answer 31

Trisomy usually more tolerated over monosomy

Question 32

How else can unbalanced chromosomal abnormalities occur?

Answer 32

May arise de novo (dn) or from a reciprocal parental abnormality

Question 33

What is contiguous gene deletion syndrome?

Answer 33

A contiguous gene syndrome (CGS), also known as a contiguous gene deletion syndrome is a clinical phenotype caused by a chromosomal abnormality, such as a deletion or duplication that removes several genes lying in close proximity to one another on the chromosome.

Question 34

What is Williams syndrome?

Answer 34

WBSCR deletion (7q11.23 deletion) - long philtrum, short upturned nose, arched eyebrows, supravalvular aortic stenosis, absence of social anxiety

Question 35

What are do contiguous gene deletion/duplication syndromes have in common?

Answer 35

• have common breakpoints
• mediated by low copy repeats (LCR)
• risk of non-allelic homologous recombination (NAHR) may be increased by parental LCR inversions

Question 36

What happens with 7q11.23 duplication syndrome?

Answer 36

Delayed speech development, autistic behaviours affecting social interaction and communication, dilatation of aorta, flat eyebrows, broad nose and short philtrum

Question 37

Do duplications or deletions have milder phenotypes?

Answer 37

Duplications usually have a milder phenotype than the reciprocal deletion

Question 38

What can point mutations and small insertions/deletions potentially do?

Answer 38

Completely ablate or alter the function of a gene

Question 39

How is male meiosis vulnerable?

Answer 39

• no equivalent to menopausal limit on reproductive span

- primary spermatocytes undergo approx. 23 mitotic divisions per year and potentially accumulate defects

Question 40

Where is the paternal age effect particularly apparent?

Answer 40

In subset of single gene disorders caused by point mutations in FGFR2, FGFR3 and RET including:

• apert syndrome
• crouzon syndrome
• Pfeiffer syndrome

Question 41

How is the paternal age effect enhanced?

Answer 41

By ‘selfish spermatogonial selection’ resulting from a selective advantage over neighbouring wild type cells