Chromosomal abnormalities I Flashcards
what are histones?
highly positively charged proteins that are attracted to the negative charge of DNA
-give the DNA a support to wrap around
what is a chromosome?
an organized package of DNA found in the nucleus of the cell
- half of your chromosomes come from your mother and half from your father
- Different organisms have different numbers of chromosomes
- exist in homologous pairs
how do chromosome usually exist?
as chromatin (hetero/euchromatin)
- DNA double helix bounds to histones
- Octamer of histones form a nucleosome
what is a nucleosome?
a fundamental unit of DNA – eight histones and two turns of DNA
2 forms of chromatin?
Euchromatin -Extended state, dispersed through nucleus Allows gene expression -Transcriptionally activate -Loosely packed
Heterochormatin
Highly condensed, genes not expressed
what is a locus?
location of a particular gene on a chromosome
at each locus, an individual has 2 alleles, one on each chromosome - they can be heterozygous or homozygous dominant/recessive
cell cycle phases
G1 - cellular contents excluding chromosomes are duplicated
S - synthesis, each of the 46 chromosomes are duplicated so that each chromosome now consists of 2 identical sister chromatids
G2 - synthesis of proteins (microtubules), error checks made in respect to the duplicated chromosomes, repair if needed
M - mitosis
G0 = resting phase, cells not dividing nor preparing to divide
how many pairs of chromosomes do humans have?
23
22 pairs of autosomes
1 pair of sex chromosomes (XX or XY)
what keeps the sister chromatids separate?
the centromere
name some classifications of chromosomes based on the centromere position?
Metacentric
p & q arms even length
Submetacentric
p arm shorter than q
Acrocentric
long q, small p
p contains no unique DNA
13-15, 21-22, Y
what are some types of chromosomal changes and how can they be detected?
numerical and structural
numerical can be detected by traditional karyotyping, FISH, QF-PCR, NGS
eg. Down’s (trisomy 21)
structural can be detected by raditional karyotyping, FISH
definitions of numerical abnormalities:
haploid
diploid
polyploid
aneuploid
HAPLOID:
one set of chromosomes (n=23) as in a normal gamete
DIPLOID:
cell contains two sets of chromosomes (2n=46, normal in human)
POLYPLOID:
multiple of the haploid number (e.g. 4n=92)
ANEUPLOID:
chromosome number which is not an exact multiple of haploid number - due to extra or missing chromosome(s) (e.g. 2n+1=47
forms of aneuploidy?
Trisomy - a type of aneuploidy in which there are three instances of a particular chromosome, instead of the normal two, eg. downs
Monosomy - a form of aneuploidy with the presence of only one chromosome from a pair, eg. turners syndrome
Mosaicism and its importance
SLIDE 20 diagram
mixed group of cells, some haploid, some diploid
Mosaicism is important wrt clinical presentation, for examples downs syndrome
-Down’s can have varying levels of severity depending on how many of the cells are trisomic for ch 21
examples of trisomy
3 copies of the chromosome (13, 18, 21)
pateu’s, edward’s and down’s respectively
disjunction
Pulling apart at anaphase
with non-dysjunction, what is the result?
with mitotic cell divisions you can have a non dysjunction occurring
-the daughter cells will not have identical copies of chromosomes, instead they will have three copies or one which, leading to trisomic and monosomic cells
monosomic cells break down but trisomic remain, so you get the formation of a mosaic blastocyst
2 causes of numerical abnormalities
Post-zygotic nondisjunction, i.e. mitotic non-disjunction = All 2n to mixture of 2n and 2n+1
Anaphase lag, i.e. trisomic rescue = All 2n+1 to mixture of 2n+1 and 2n. Anaphase lag can also cause aneuploidy.
explain anaphase lag
process gets paused and doesn’t work properly
meiotic non dysjunction, generating a cell that is 100% trisomic wrt ch 21.
post zygotic proliferation with occur, and anaphase lag occurs, and one of those 3 chromosomes gets pocketed off into a vesicle and kicked out of the cell, resulting in 2 chromosmes remaining
all daughter cells after that will be disomic, but in the cells where that didn’t happen they will be trisomic
Sex chromosomes abnormalities vs autosome chromosomal abnormalities - which are more severe?
autosomal chromosomal abnormalities are far more severe
which type of abnormalities are very very rare?
Autosomal monosomy - 1 copy of the chromosome, and partial monosomies are far more common
Relatively common sex chromosome monosomy = Turner’s
possible combination for nullisomic gametes?
Nullisomic gametes fertilised with a sperm carrying an X chromosome will be XO (Turners)
Nullisomic gametes fertilised with a sperm carrying a Y chromosome will be YO - this is in-utero lethal
possible combination for disomic gametes?
XX
+ X chr = XXX = triple X syndrome
+ Y chr = XXY = Klinefelter’s (physically male)
XY
+ X chr = XXY = Klinefelter’s
+Y chr = XYY = XYY syndrome
Summary of numerical abnormalities
Types (all can be mosaic) Autosomal Trisomy 13, 18, 21 Sex chromosomes XO, XXY, XYY
Mechanism
Nondisjunction
Anaphase lag
