Lecture 21: Chromosomal Abnormalities Flashcards
What is the normal human karyotype?
22 pairs of autosomal chromosomes and one pair of sex chromosomes (female, XX and male, XY)
Total of 46 chromosomes
In which phase of mitosis are chromosomes karyotyped?
During metaphase - each chromosome comprises 2 chromatids at this point
Outline DNA compaction.
- DNA wrapped around histone to form nucleosome
- Nucleosomes coiled into chromatin fibre
- Chromatin is further condensed to form chromosome
What does the G-banded architecture of a chromosome show?
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
What type of staining leaves a recognizable pattern of bands on a chromosome?
Glemsa staining
What are the 2 arms called on a chromosome?
p-arm (petite/shorter arm)
q-arm (longer arm)
What is the centromere of a chromosome?
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.
What are the telomeres of a chromosome?
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
What does this mean: 46,XX,t(1;2)(p32;q22) ?
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.
How would you note there’s a deletion in a karyotype?
Using ‘del’ and then the chromosome number and band number
How would you note there’s monosomy in a karyotype?
using ‘-‘ and the chromosome number
How would you note there’s trisomy in a karyotype?
using ‘+’ and the chromosome number
What is a haploinsufficient gene?
Need expression from both alleles to have a normal phenotype
What is an imprinted gene?
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.
What is a haplosufficient gene?
Only need expression from one allele or the other
Gene expression can be…?
- tissue specific
- at a specific time in development
- in response to an event
What is the purpose of mitosis?
- to create 2 identical daughter cells
- for growth and repair
- to replace exhausted cells
- 2n –> 2n
What is the purpose of meiosis?
- to achieve reduction from diploid to haploid
- to ensure genetic variation in gametes
- to enable random assortment of homologues and recombination
What is non-disjunction?
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.
What is the result of non-disjunction in Meiosis I?
2 daughter cells with trisomy and 2 daughter cells with monosomy
What is the result of non-disjunction in Meiosis II?
2 unaffected daughter cells, 1 daughter cell with trisomy and 1 daughter cell with monosomy
Why is female meiosis vulnerable to non-disjunction?
- paused in utero until puberty
- unbalanced division and one primary oocyte yields only one ovum
- finite no. of oocytes
Most aneuploidy is caused by what?
Non-disjunction in oogenesis - likely due to degradation of factors which hold homologous chromatids together
Does the risk of maternal non-disjunction increase or decrease with age?
Risk increases with age
What causes Down’s syndrome?
Trisomy of chromosome 21 (most trisomy 21 arises in maternal non-disjunction)
What can quantitative fluorescence PCR (QF-PCR) tell us?
Whether there is trisomy or not.
1: 1 ratio (disomy)
1: 1:1 ratio (meiosis I trisomy)
1: 2 ratio (meiosis II trisomy)
Why is sex chromosome imbalance tolerated?
- X inactivation of excess X chromosomes
- low gene content of Y chromosome
Describe some reciprocal chromosomal abnormalities?
- 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.)
What do reciprocal chromosomal abnormalities have in common?
- 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
In unbalanced chromosomal abnormalities what does the severity of the phenotype depend on?
Gene content of affected segment
What type of aneuploidy is usually more tolerated?
Trisomy usually more tolerated over monosomy
How else can unbalanced chromosomal abnormalities occur?
May arise de novo (dn) or from a reciprocal parental abnormality
What is contiguous gene deletion syndrome?
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.
What is Williams syndrome?
WBSCR deletion (7q11.23 deletion) - long philtrum, short upturned nose, arched eyebrows, supravalvular aortic stenosis, absence of social anxiety
What are do contiguous gene deletion/duplication syndromes have in common?
- have common breakpoints
- mediated by low copy repeats (LCR)
- risk of non-allelic homologous recombination (NAHR) may be increased by parental LCR inversions
What happens with 7q11.23 duplication syndrome?
Delayed speech development, autistic behaviours affecting social interaction and communication, dilatation of aorta, flat eyebrows, broad nose and short philtrum
Do duplications or deletions have milder phenotypes?
Duplications usually have a milder phenotype than the reciprocal deletion
What can point mutations and small insertions/deletions potentially do?
Completely ablate or alter the function of a gene
How is male meiosis vulnerable?
- no equivalent to menopausal limit on reproductive span
- primary spermatocytes undergo approx. 23 mitotic divisions per year and potentially accumulate defects
Where is the paternal age effect particularly apparent?
In subset of single gene disorders caused by point mutations in FGFR2, FGFR3 and RET including:
- apert syndrome
- crouzon syndrome
- Pfeiffer syndrome
How is the paternal age effect enhanced?
By ‘selfish spermatogonial selection’ resulting from a selective advantage over neighbouring wild type cells
