Numerical Abnormalities Flashcards
What are histones?
Histones are highly positively charged proteins that are attracted to the negative charge of DNA. Imagine this like coiling a garden hose up; in takes up less room to store than if you leave the garden hose out stretched. But it requires energy to coil that hose up and essentially that is what histones supply. They give the DNA a support to wrap around
A chromosome is an organized package of DNA found in the nucleus of the cell. Different organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes–22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes, X and Y. Each parent contributes one chromosome to each pair so that offspring get half of their chromosomes from their mother and half from their father.
Describe the structure of a chromosome
What is euchomatin and hetrochromatin?
How is DNA usually packed?
What is chromatin?
o Chromosomes usually exists as chromatin
- DNA double helix bounds to histones
- Octamer of histones form nucleosome
o Euchromatin – open - Extended state, dispersed through nucleus
- Allows gene expression
o Heterochormatin – highly condensed - Highly condensed, genes not expressed
o DNA usually loosely packed, except during cell division when DNA is complexed with various proteins and undergoes several levels of compaction through coiling and supercoiling.
o Nucleosome is fundamental unit of DNA – eight histones and two turns of DNA
o DNA + Proteins = Chromatins
o Exist in homologous pairs
o Two copies of each chromosome maternal and paternal copies
o The homologues have the same genes on them (the autosomes) but they may have different allelic forms
o Same loci on each chromosome.
Why are chromosomes sometimes shown with a single chromatid?
Like in interphase
• Why are chromosomes sometimes shown with two sister chromatids?
Replication
Describe the phases of the cell cycle
o G1 - Cell makes a variety of proteins needed for DNA replication
o S - synthesis; chromosomes are replicated so that each chromosome now consists of two sister, identical chromatids
o G2 - synthesis of proteins especially microtubules, error checks wrt the chromosomes.
o Some cells don’t replicate; some are senescent.
o Our cells are mostly quiescent single chromatids at this point
o The cell cycle only begins when we need new cells
o S phase is where DNA duplicates so there are exact copies of the single chromatids
Go from a single chromatid to two identical chromatids being attached
This is necessary to produce the daughter cells
What is metacentric, submetacentric and acrocentric
o Metacentric
- p & q arms even length
- 1-3, 16-18 o Submetacentric - p arm shorter than q - 4-12, 19-20, X o Acrocentric - Long q, small p - p contains no unique DNA - 13-15, 21-22, Y
What chromosomal changes can happen and how are they detected?
o Numerical – can be detected through traditional karyotyping, FISH, QF-PCR, NGS
o Structural - can detect through traditional karyotyping, FISH
o These techniques are good for visualising big changes to the genome – and those big changes fall into these two categories.
o Numerical and structural.
An give me an example of a numerical change?
Down’s syndrome
What’s the genetic change which causes Down’s syndrome?
Trisomy 21
Define haploid, diploid, polyploid and aneuploid
o HAPLOID - one set of chromosomes (n=23) as in a normal gamete.
o DIPLOID - somatic cells, cell contains two sets of chromosomes (2n=46; normal in human)
o POLYPLOID - extra sets of chromosomes rare
- multiple of the haploid number (e.g. 4n=92)
- STERILE
o ANEUPLOID - chromosome number which is not an exact multiple of haploid number - due to extra or missing chromosome(s) (e.g. 2n+1=47 or -1=45)
- Downs, Patau, Edward syndrome
o Trisomy
o Monosomy
o Mosaicism – a mixed collection of cells. Some could be trisomic others normal
Have a look at mitosis and meiosis
On image
How does aneuploidy arise?
o If non-disjunction occurs in meiosis I the two homologues both go into a single cell. So you end up with two copies of the chromosome in the same cell and none in another
o In Meiosis II disjunction happens appropriately and pulls the chromatids apart and distributes them into the resulting gametes but we now have two copies of that chromosome in that gamete known as being DISOMIC
o No copies NULLISOMIC
o Alternatively we could see that disjunction happens appropriately in meiosis I but then in meiosis II two of the single chromatids have ended up in the same gamete DISOMIC
o Gametes should be MONOSOMIC
Describe non-disjunction
Pulling apart chromosomes at centromere= disjunction. Improper disjunction= nondisjunction (e.g. trisomy, monosomy). Main cause of aneuploidy.
What is mosaicism?
What causes it?
What is anaphase lag?
- Presence of two or more genetically different cell lines derived from a single zygote. E.g. disomy 21, trisomy 21 and monosomy 21- mosaic blastocyte.
- Mechanisms- post-zygote non-disjunction (mitotic non-disjunction after fertilisation).
- Anaphase lag- where one homologous chromosome in meiosis or one chromatid in mitosis fails to connect to the spindle apparatus or is tardily drawn to its pole and fails to be included in the reforming nucleus. Forms micronucleus in cytoplasm and lost from cell.
- The lagging chromosome is not incorporated into the nucleus of one of the daughter cells, resulting in one normal daughter cell and one with monosomy.
- Common cause of aneuploidy and mosaicism.
- Can result in trisomic rescue if daughter cell was originally trisomy.
- Clinical relevance- less severe. Difficult to assess due to proportions and tissues affected. E.g. Down’s/Klinefelter’s/Turner’s.
Define Monosomy
o Autosomal are very very rare, found one case report from 1967
o Relatively common sex chromosome monosomy = Turner’s
o Full monosomy arise by NDJ
o Partial monosomy (microdeletion syndromes) far more common – mechanism different
- Only a chunk of the second X chromosome is missing
- Rarely autosomal.
- Common sex chromosome monosomy is Turner’s syndrome.
- Full monosomy arising from nondisjunction.
- Partial monosomy far more common, due to microdeletions.
- Nullisomic gametes (no X) fertilised with Y chromosome is lethal- YO. XO is not lethal- female presenting.
How does Turner’s (45,X) arise?
o Blue = Maternal sex chromosome; black = paternal sex chromosome
o Nullisomic gametes fertilised with a sperm carrying an X chromosome will be XO (Turners)
o Nullisomic gametes fertilised with a sperm carrying a Y chromosome will be YO
o Disomic gametes can be
