Adam - prenatal Flashcards
how do gross structural chromosome abnormalities come about?
typically what problems do they cause?
- they are catalysed by DNA damage. recombination/repair? occurs between homologues sequences in a non-allelic manner. that is, normally the template used for repair is the sister chromatid (during mitosis) and the homolog (in meiosis). when the template used is located in a non-allelic position you can get gross structural abnormalities
- they predispose cells to mal segregation in meiosis, increasing chances of pregnancy loss, still birth and genetic disease in offspring. (balanced) rearrangements are often undetected until adulthood when infertility becomes an issue
what are pericentric inversions and what can you look out for to spot them?
what are paracentric inversions?
pericentric inversions are when the breakpoints are on opposite arms of the chromosome - i.e. the centromere is included in the segment being inverted
this means you can look out for a change in chromosome morphology, as in the centromere will be in a different location/the two arms change lengths
AND changes in banding
paracentric inversions are when the breakpoints don’t flank the centromere, they are harder to spot as the only changes are in the banding structure (not the chromosome morphology)
what impact do inversions have on people carrying them and why?
carriers are often not identified until adulthood. The main reason for the “late” detection of such abnormalities is because the inversions tend not to disrupt gene function or expression (possibly the regions near to the centromere tend to be heterochromatin/not expressed?), so the patient is essentially “normal”.
Inversions do create abnormal chromosome structures during meiosis and these can be problematic and disruptive to spermatogenesis (resulting in male infertility or reduced fertility), and can increase the risk of unbalanced gamete formation
what are insertions and why are they rare?
two breakpoints in one chromosome (marking the section that’s gonna be taken out and…) another breakpoint in a different chromosome where the fragment will be inserted. they often occur in cancer cells and are typically sub-microscopic/too small to identify.
note - can be intrachromosomal or intrachromosomal
rarer than inversions, because more events need to take place at the same time in the same space (thus lower probability).
explain how and why carriers of structural rearrangements are infertile/exhibit low fertility (like the whole process, specifically pericentric inversions).
in meiosis, specifically in prophase and metaphase I when homologous chromosomes are paired, the pairing structures formed by rearranged chromosomes are abnormal.
they cant align side-by-side because the homologous regions wont align (as one Chr has an inverted segment), so they form an abnormal loop structure.
if crossing over occurs within the inversion, the result is two unbalanced (and two balanced chromatids).
the loop structures are enough to disrupt spermatogenesis, resulting in oligospermia, low sperm count, or azoospermia, lack of sperm in semen, and/or reduced motility. oogenesis is a more robust/resilient process, and the gametes typically survive the rearrangements and still form, however the unbalanced chromatids are not viable.
the balanced chromosomes are…
what is meant by recurrent translocations/rearrangements? why are they recurrent?
the derivative chromosomes are observed in the general population – in unrelated families. This is because there are known non-allelic homologous repeat sequences that are brought together in the genome at defined times – and these are particularly vulnerable to illegitimate recombination events. Perhaps the best example of this is the recurrent translocation that is observed between chromosomes 11 and 22
if a balanced inversion was identified in a newborn/prenatally etc…, where is it likely to have come from and what must be done?
the formation of the abnormal loop structures often disrupt spermatogenesis and the gametes don’t form, oogenesis is more robust and is more likely to still complete - the two balanced chromatids can be passed on to children, so a balanced inversion likely came from mum…
the normal development of that foetus or child was in question – then further investigations would need to be conducted to exclude the possibility that the rearrangement was linked to the abnormal clinical phenotype i.e. via a change to the expression or function of genes in the vicinity of the breakpoints. Logically the first thing to check is whether the abnormality occurred de-novo – or if it was inherited. If inherited from a parent who is apparently normal – then the assumption is that the inversion does not disrupt gene function and is therefore thought to be benign
(this is probably overkill but) assuming crossing over occurred within the inversion, what four chromatids do you get with a pericentric inversion? with a paracentric?
- One normal chromatid: No crossing over, remains unaffected.
- One inverted chromatid: No crossing over, carries the inversion but has all genetic material.
- One recombinant chromatid with duplications and deletions: Crossing over results in parts of the chromosome being duplicated and others deleted.
- Another recombinant chromatid with reciprocal duplications and deletions: Complementary to the other recombinant chromatid.
Key Consequence:
Gametes with recombinant chromatids are typically inviable due to imbalanced genetic material (duplications and deletions)
paracentric -
One normal chromatid: No crossing over, remains unaffected.
One inverted chromatid: No crossing over, carries the inversion but has all genetic material.
One recombinant chromatid with no centromere (acentric fragment): Lacks a centromere and is lost during cell division.
One recombinant chromatid with two centromeres (dicentric chromatid): Contains two centromeres, leading to instability during cell division as it is pulled in two directions, often causing breakage.
Key Consequence:
Recombinant chromatids (acentric and dicentric) are typically non-functional, leading to reduced fertility. Only gametes with normal or inverted chromatids are viable
what are balanced translocations?
while pointing out the difference between familial and recurrent translocations, explain how translocations come about.
Balanced = no gain or loss of genetic material. (in some cases you can get small deletions near breakpoints but this is still not imbalanced (does not typically have a clinical implication as most cases the breakpoints in translocation events occur in non-coding regions, and are detected in the normal adult population if someone is trying and struggling to start a family)
some chromosomes with homologous regions on a different numbered chromosome. This doesn’t happen super often because of ‘territories’ - chromosomes are dynamic but occupy certain areas, and diff. Number chromosomes with areas of homology are kept apart by these territories. Familial ones are so unlikely, seeing it again must be in someone of the same family.
Ones we se recurrently must occur from regions of the genome that are homologous come together a little more often - the system isn’t perfect. The territories transiently overlap
what is meant by a derivative?
what kind of issues do translocations (balanced) cause in men?
the term used to describe a chromosome that has been generated (derived) from abnormal events. The identity of a chromosome is determined by the origin of the centromeric region
balanced translocations are likely to cause abnormal structures during MI, and these would likely be disruptive to spermatogenesis (oligospermia, azoospermia, recurrent miscarriage - 3 or more spontaneous loss of pregnancy)
in homologous recombination, what happens if a balanced translocation is present and why?
because of the translocation, if the homologous chromosomes aligned linearly in a bivalent, regions of the chromosomes would not all align. so like how inversions form abnormal loops, translocations form something called a pachytene cross.
however this cross is susceptible to (but not guaranteed to have) errors in chromosome segregation…
explain the steps of chromosome segregation of a pachytene cross that results in four viable gametes
clarify the end results
known as MI alternate segregation…
anaphase of MI: alternate centromeres are segregated to the same pole. Meaning that to one pole moves the two normal chromosomes, and to the other pole moves the two derivatives/abnormal chromosomes that balance each other.
Sister chromatids are then segregated at anaphase in meiosis II into 4 gametes
this shows carriers of translocation can generate a viable, balanced pregnancy.
the first pole describes results in 2 gametes with normal chromosomes, so fusion with another normal gamete would yield a chromosomally normal conceptus.
Gametes from the second pole described have a full complement of chromosomes, just mixed up, so would generate a viable and chromosomally balanced conceptus - the foetus would carry the translocation in these cases. In all likelihood the foetus would develop normally, but would perhaps suffer reduced fertility later in life, particularly if male
another way the pachytene cross can segregate is ‘MI adjacent I segregation.
describe what happens here, making sure to explain the end results
‘adjacent centromeres are co-segregated’ as in centromeres next to each other in the cross go together to the same pole (in this case, when you split the cross along the ‘long axis’)
so one of the normal Chrs goes to one pole, with an abnormal Chr involved in the translocation, and the other normal chromosome goes to the other pole with the other abnormal chromosome.
FOUR UNBALANCED GAMETES
so each gamete receives one normal chromosome and one translocated chromosome from the involved pair.
These gametes are unbalanced because the translocation causes duplications and deletions of genetic material
so each gamete would have partial trisomy of the normal chromosome it got (because the abnormal one was involved in a translocation and has a bit more of that number chromosome stuck on), as well as partial monosomy of the abnormal chromosome (that had been swapped for the extra of the other causing said trisomy^)
would almost certainly result in an inviable pregnancy
bit wordy but just so you get it
another option at segregation for the pachytene cross (balanced/reciprocal translocation has occurred) is the MI adjacent II segregation.
describe what happens here, making sure to explain the end results
the cross is split along the short axis, and adjacent centromeres (the opposite pairing to MI adjacent I segregation) go to the same pole.
in this case, the normal chromosome is paired with the abnormal chromosome that is very similar to it, i.e. normal Chr 11 goes with the derivative from the translocation that is mostly Chr 11 with a little bit missing replaced with a small chunk of 14 or something (and vice versa)
similarly, you’d have partial trisomy and partial monosomy in every gamete, all likely to result in non-viable pregnancies.
there’s been a balanced translocation, and a pachytene cross has formed.
what kind of segregation can result in a relatively small imbalance that could result in a viable pregnancy?
3:1 mal segregation
occurs when there is another ‘long axis’ for the cell to choose from, present when one of the chromosomes created in the translocation is very long (has a big chunk of the original Chr, plus a big chunk of the slapped on translocated Chr)
this long Chr goes to one pole alone, and the other three Chrs go to the other pole together.
at the pole with three Chrs you get partial trisomy, but not monosomy for wither Chr, so t’s quite possible for the pregnancy to come to term – and if it did, the the baby would be affected by serious conditions and morphological features
the other pole produces two gametes with partial monosomy of both Chr numbers involved, aren’t viable, likely to abort before the pregnancy is clinically recognised.
what are acrocentric chromosomes?
when the p arm is very short, and composed of repetitive DNA sequences and rDNA genes
in humans they are Chrs 13, 14, 15, 21 and 22
what are Robertsonian translocations?
chromosomal rearrangement where the long arms (q arms) of two acrocentric chromosomes fuse at their centromeres, forming a single large dicentric chromosome (tho only one centromere is thought to be active). The short arms (p arms) form an accentric fragment that is typically lost, as they contain non-essential repetitive rRNA genes
They are considered to be unbalanced as a small acentric fragment consisting of satellited p arm material is lost
why are robertsonian translocations common-ish?
1 in 1000, because all these acrocentric chromosomes are involved in formation of the nucleolus, coming together at the end of telophase, to bring the rDNA genes together and enable efficient expression - so if there’s a DNA break there’s a chance you’ll get a translocation between them due to close juxtaposition, and…
The inverted nature and sequence similarity of satellite DNA located in acrocentric p arms
explain the outcomes, in terms of gametes, for Robertsonian translocations (lets say Chr 21 and 14, tho most common is 13 and 14 btw)
as we know, translocation occurs so that the long arm of 21 and 14 combine, and the short arms also combine. This results in a long chromosome carrying most of the genetic information from Chr 21 and Chr 14, and a short chromosome carrying few genes from Chr 21 and 14 - this short chromosome is usually lost in meiosis
the long chromosome can kind of be considered as a Chr 14 and Chr 21 in one (but I don’t think I’d say this is the exam)
down one route, you can get two gametes with trisomy 21 - when the normal Chr 21 is paired with the long chromosome made up of Chr 21 and 14’s long arms (counting as a copy of Chr 21 and a copy of Chr 14) so when a sperm brings along it’s single copy of Chr 21 the resulting zygote has three Chromosome 21s (albeit one of which is missing the short arm). the other two gametes have no Chr 21as the short arm is lost (so zygotes would be monosomic for Chr 21
reverse can happen with trisomy 14 and monosomy 14
or you can have the normal 21 and 14 pair, giving two normal gametes, and the other two gametes have the long chromosome kind of functioning as a 21 and a 14, so are ‘balanced carriers’
