Cytogenetics II   Chromosome Translocations

Cytogenetics II Chromosome Translocations


Our final podcast in our series on
cytogenetics is going to deal with chromosomal translocations. Abnormal
chromosome structure can result from translocations that are either
unbalanced or balanced. Unbalanced would be rearrangement that causes gain or loss
of chromosomal material. This can produce serious consequences to individuals or
to offspring. On the other hand, balanced rearrangements do not cause gain a loss
of chromosomal material. Those would usually have minor health consequences.
And let’s assume that these are occurring in gametes for our discussion.
So, what is a translocation? A translocation is the transfer of one
part of a chromosome to another part of the same or a different chromosome. It
results in rearrangement of genes. If we think about translocations occurring on
the same chromosome, that’s a good thing in a sense that that’s what homologous
recombination does during meiosis. If the translocation is occurring
between different chromosomes, that you might think of could be not so good a
thing, because that might lead to genetic consequences. Most translocations occur
on the autosomes. Before we talk about those let’s talk about sex chromosomes
and pseudo autosomal regions. The pseudo autosomal regions are regions on the X
and Y chromosome. There’s two or three regions that share homology with each
other and undergo very high levels of recombination. And recombination is
actually absolutely important for chromosomes to pair so that they can
segregate properly during meiosis 1. So, the X and Y chromosome have to pair
during meiosis 1 so they can segregate. Now, there’s a pseudo autosomal region
one that’s at the distal end of the X and Y chromosome. On the short arms, there’s
an obligatory crossover point in a 2.6 megabase region that’s required for
proper segregation of X and Y. Now, it turns out that the SRY
gene is just proximal to the pseudo autosomal region and the Y chromosome.
An unequal crossing over in this pseudo autosomal region between X and Y can
lead to XX males and XY females. This is just a hypothetical example of what
could occur. So, it’s showing crossing over leading to an XX male or an XY
female. The pseudo autosomal region acts like an autosome with as exchanges on
the XP region with X and Y. The SRY gene, as you may remember, is the
sex-determining region on the Y chromosome. It’s expressed during
embryonic development and encodes a product that interacts with other genes
to initiate development of an undifferentiated embryo into a male. This
is the example of showing the balanced chromosome rearrangements between the
homologous chromosome regions, the pseudo autosomal regions of X and Y
cross over in meiosis. The SRY region contains the test of determining factor
and it normally resides on the short arm of the Y chromosome. The gene product as
we said determines if the embryo is male. Translocation of the SRY gene, as we said,
can lead to XX males or XY females or even two hermaphrodites.
So, here showing normal crossing over between X and Y with the SRY region
maintained on the Y chromosome. Here showing crossing over that would occur
below the SRY region so that gets translocated onto the X and you’d have
XX male and then an XY female. And this is rather interesting, this type of crossover or it occurs below the SRY gene may occur in one in
20,000 live births. That might suggest that they may be something like if
15,000 individuals in the United States that have this unusual
translocation. There may be up to three babies a year that are born in Tennessee
with this translocation. The pseudo autosomal region 1 on X and Y chromosome also contain genes called the SHOX genes. The SHOX genes stand for Short Stature
Homeobox Genes . So, there’s the SHOX genes on the X chromosome and there’s the SHOX Y gene on the Y chromosome. And this just shows the chromosomal locus. You need to have
two functional copies of the SHOX genes for normal height. So, might ask how would
this relate to short stature in Turner syndrome? Turner you have 45X, so you
only have one copy of the SHOX gene, you’re missing the other SHOX or the
SHOX Y gene. There’s also a condition called Langer mesomelic dysplasia and Leri-Weill syndrome that result from SHOX mutations. These behave like
mutations on autosomes. Genes located on the pseudo autosomal two regions of the
X and Y chromosome are necessary for vesicle fusion and they code for
proteins related to interleukin receptors. There is no known function for
genes that are on the pseudo autosomal three regions of the X and Y chromosome.
Rearrangements of translocation between homologous chromosomes on the autosomes generally may have no genetic consequences. You might ask, why is that
the case? It’s because you’re exchanging material
on the same homologous chromosomes, but what would happen if there’s a
rearrangement between non homologous chromosomes? Here’s an example that shows a reciprocal balanced translocation between chromosome 6 and chromosome 3. So, these are derivative chromosomes, has a derivative chromosome 3 with a little
bit of chromosome 6 on it, and a derivative chromosome 6 with a little
bit of chromosome 3 on it. The offspring here, this
child receives a derivative chromosome 3 and a normal chromosome 6 from
the carrier parent and normal chromosomes from the other parent and
we’ll come back to this. Reciprocal translocations are caused by breaks on
non homologous chromosomes. So, there’ll be exchange of genetic material. Carriers of
balanced reciprocal translocations usually have normal phenotypes but the
offspring may have a partial trisomy or a partial monosome and an abnormal
phenotype. So, the previous example showed an a partial trisomy for chromosome 6.
So, here, you see the partial trisomy for chromosome 6. You should also see that
this child is a partial monosome for chromosome 3, because here is the
derivative chromosome 3 it shows this chromosome 3 but it’s missing
the other region of chromosome 3, so it’s a partial monosome for that
region of chromosome 3. Reciprocal translocations are usually balanced and
they don’t carry a risk for disease to a carrier unless one of the breakpoints
interrupts gene function, and that actually may be maybe a 5% chance that
that can occur. Reciprocal translocations can cause problems in meiosis because of
segregation meiosis one may lead to gametes with unbalanced chromosome
complements and genetic disease in an individual. Here’s a normal individual, here’s
an individual with the reciprocal balanced translocation. When these pair during
meiosis, you can see that you may get unusual segregation. So, here is an
example of normal segregation, whereas this chromosome segregates with that
chromosome. Here is a balanced segregation where this one segregates with that one. But then, you can see the unbalanced ones,
where this will segregate with that, or this one will segregate with that one. Another series of unbalanced
segregations, this one segregates with this one, or this one
segregates with that one. Here’s an example of a Robertsonian
translocation and these occur when the long arms of acrocentric chromosomes
fuse at the centromere. So, in humans, Robertsonian translocations can only
occur between chromosomes 13, 14, 15, 21, and 22. In the case shown here, the long
arms of chromosome 13 and 14 have fused. There’s usually no genetic consequences
because the individual has the full information on chromosomes 13 and 14,
maybe has lost a little bit of the short arms. This individual, the karyotype would be designated 2N=45, translocation
13, 14. The individual with this balanced translocation doesn’t have any genetic
consequences because they may have lost a little bit of the ribosomal genes, but
remember, the ribosomal genes are repetitive. Robertsonian translocations
are responsible for small percentage of Down syndrome phenotypes and we’ll ask
you to think about that. Here is the translocation between chromosome 21 and chromosome 14, for example. This individual is 2N= 45, translocation
21, 14, has a normal phenotype but the offspring could have problems as a
result of pairing at meiosis one. This shows the individuals
with Robertsonian and translocations. They have normal phenotypes and snow genetic
material is lost, but since they have only 45 chromosomes, pairing and
segregation at meiosis one can lead to potential problems.
This shows possible chromosome combinations and gametes that are going
to be transmitted to offspring. Here, you can see this one will segregate with
that one, normally like that, or you may have that one segregating. This could
segregate normally like that, or that one can segregate. This one can segregate
normally with that, or that one can segregate. So, you look at those gametes
being fertilized with gametes from a normal parent and you can see the types
of combinations that you’ll get. Possible combinations of gametes and the
offspring of normal parents and the translocated carrier parent. And I’m
gonna bring this to the next slide just to make it a little bit easier to see. So,
here, would be the gametes that are normal and the translocated parents with the possible combination of
offspring. These individuals, you’ll have a monosome, a trisomy, a monosome. And
in these individuals normal a balanced translocation and a translocated down
syndrome. These individuals, the monosomic 21, the trisomic 14, and the monosomic 14 don’t survive to term. Now, you might expect equal frequencies of normal
individuals, balanced translocation individuals, and individuals the Down
syndrome. But, it turns out, that if mothers have this translocation 10% of the births will be Down syndrome,
if fathers have the translocation 2% of the births will be what
Down syndrome. That’s a lot higher than 1 in 800, which is the typical
frequency of babies born with Down syndrome. Abnormal chromosomes may come about from deletions. You may have microscopically observable deletions. So,
you may have a terminal break. In this case, a hypothetical sequence. If you have a terminal break here, you’ll have a deletion like that. You may have an
interstitial deletion, so you may have a break here and a break here will result
in something for the deletion like that. Cri-du-chat syndrome is caused by a
deletion in the short arm of chromosome 5. Williams syndrome is caused by a
deletion in the long arm of chromosome 7. So, you might represent the karyotype 46
XY with a deletion in the long arm. Various micro deletion syndromes can be
recognized with high-resolution chromosome banding and fluorescence in
situ hybridization. I’m not going to ask you to memorize these for an exam, they are just here to give you some examples. More chromosomal abnormalities can get
duplications with as unequal crossing over or offspring of reciprocal
translocations, usually the consequences are not severe. Inversions, there may be
two breaks and reinsertion of a fragment at the original site but in an inverted
order. So, you can have pericentric inversions, which include the centromere.
Pericentric inversions do not include the centromere. Inversions usually do not
produce disease in the carrier but there may be problems in meiosis and disease
in the offspring and you can have ring chromosomes. Here’s an example of a
pericentric inversion where the inversion involves the centromere region. Here’s an
example of a paracentric inversion where the inversion is just on the long
arm of the chromosome. Here’s an example of a ring chromosome that’s formed where
the two little pieces is a loss and the remaining chromosome forms a ring.
Chromosomal anomalies that can relate to development and intellectual disability. There may be alterations and facial morphogenesis.
There can be growth delay, short stature, poor weight gain. There can be congenital
malformations, especially, heart defects because many genes can be affected. And
finally, chromosome rearrangements in relation to somatic cells can cause
cancers. For example, chronic myelogenous leukemia is a reciprocal translocation
between chromosome 9 and 22 and that’s shown here. The derivative chromosome 22 is called the Philadelphia chromosome. There is a case where the able-proto-oncogene is moved to the long arm of chromosome 22. Reciprocal
translocations between chromosome 8 and 14 can cause Burkitt lymphoma. A deletion
in the long arm of chromosome 13, for example, can cause retinoblastoma. Here’s
the example of the reciprocal translocation B chromosome 9 and 22
causing chronic myelogenous leukemia. Here’s an example of that condition with
fluorescence and situ hybridization and here is showing the Philadelphia
chromosome with the fused able-oncogene product. Basically, part of the breakpoint
cluster region from chromosome 22 is fused with part of the able-proto-oncogene
on chromosome 9. That fused BCR abel-oncogene product codes for constitutively
active tyrosine kinase. That activates many cell cycle proteins, leads to
uncontrolled cell division, may inhibit DNA repair and apoptosis. Additional
mutations occur like that and that will tip the balance. Some of these additional
mutations may be in the RAS genes and in the p53 tumor suppressor genes.

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