This podcast will focus on abnormal chromosome number. Abnormalities of
chromosome number, you can consider cells that have multiples of 23 would be
haploid and diploid and these would be considered euploid. Other cells that have
multiples of 23 because it had polyploid. A triploid individual 3N = 69, a
tetraploid individual 4N = 92. Turns out that maybe one in ten thousand
live births can be triploid, few tetraploid live
births have ever been recorded. Most polyploid conceptions are
spontaneously aborted and indeed they may account for 25% of
chromosomal abnormalities at conception. Polyploid conception are all
incompatible with long term survival. So, how does a polyploid conceptus arise?
Well, potentially by polyspermy. You may have mitotic failure in oocytes or
spermatocytes. Why would tetraploid he be much less common? Well, you'd have to
think about it and say: you've got two independent abnormalities occurring, both
on the male side and the female side. So, it's really very, very rare. Polyploidy in
most human somatic cells is not common, but it does occur regularly in cells of
some tissues and organs. So, remember that in the epithelial cells that line the
urinary tract, you can have polyploid cells you can even have cells that are 2
nuclei. So, polyploidy is common in epithelium lining the urinary tract.
Polyploidy is also common in human liver cells. Here, you can see some liver cells
that are very large nuclei, for example. An aneuploid cell is not an even
multiple of 23 chromosomes. There's a missing chromosome or an extra
chromosome. Aneuploidy, usually but not always, involves one chromosome. Autosomal
aneuploid are clinically important. They usually arise by mitotic nondisjunction.
Autosomal monosomes rarely reached term. As you'll come to appreciate,
autosomal trisomies can be fairly common. How do you wind up getting aneuploid
individuals? Well, you may have nondisjunction that can occur at meiosis
one or nondisjunction that can occur at meiosis two. The diagram on the Left
shows nondisjunction at meiosis one. After the first meiotic
division, you've got cells that have two copies of a particular chromosome and
cells with no copies of that chromosome. So, if these were the developing sperm
and then you consider what would happen with a fertilized egg, here would be two
conceptuses that are trisomic for this particular chromosome, and two conspectuses
that are monosomic for this particular chromosome here they're
presumably getting the chromosome only from the maternal side. So, this would be
nondisjunction at meiosis one. The issue would be that all of the conspectuses
would be abnormal. 50% of the conceptuses would be trisomic and 50% of the
conceptuses would be monosomic. On the other hand, if nondisjunction is
occurring at meiosis 2, and again, you look at the percentage of conceptuses,
50% of the conceptuses would be normal-ploidy, 25% of the conceptuses would be
trisomic, and 25% of the conceptuses would be monosomic. Now, remember, we're
looking at the percentage of conceptuses that are normal, we'e not looking at
the percentages of live births that are normal, because that would be an entirely
different question. From this example shown on the right, what we can say with
general certainty is that monosomic conceptuses don't reach term. So, in
this case, two-thirds of the live births would be normal,
one third would be trisomic, because the monosomic conceptuses would almost
absolutely be lost. Now, again, you don't know the question to ask,
because in many cases even the trisomic conceptuses would be lost.
So, really, you might say that in this case, a hundred percent of the live
births would be normal but there may be a lot of pregnancy loss. Here is a
karyotype with trisomy 21 so called Down Syndrome. It's represented as 47 XY,
because it's a male with an additional chromosome 21 shown there on the
karyotype. Trisomic 21 is the most common aneuploid that's compatible with
survival to term. It occurs in about one in 800 live births. You should appreciate
that 3/4 of trisomic 21 conceptuses are lost spontaneously. Down Syndrome. 95%
of Down Syndrome is a result of nondisjunction during gamete formation. A
small percentage of trisomic 21 is due to mosaicisms and/or translocations.
Mosaic trisomy results from a random error during embryonic cell division
such that some cells have two copies of a given chromosome and some cells have
three copies of a given chromosome, and we'll show more about that later.
Trisomic 18is so called Edwards Syndrome could be represented as 47 XY.
In this case, +18 for an extra 18. It's the second most common autosomal
trisomy 1 in 6,000 live births. It's the most common chromosomal
abnormality and stillbirths. Individuals born with trisomic 18 usually don't live
beyond about a year, and there's no preference as far as whether the trisomic
18s are males or females. Trisomic 13 here represented 47 XX, because it was
female +13 Patau Syndrome, usually one in ten thousand live births. Again,
usually not able to survive beyond 24 months. Something you have to be careful
about, because you'll see examples on YouTube of some of these different
trisomies and they can be very compelling and they can really evoke a
lot of empathy as you look at them, but understand that some of these trisomics
may be results of mosaic individuals, not trisomies in every cell
in the body. And some of those mosaics have better odds of surviving than the
ones that are full trisomics in every cell. But, you also need to understand
that even though they show those images on YouTube and they can be very
compelling, you've got to understand that some of these trisomies can result in
significant burdens on a family. Now, here's an interesting chart and I think
people are familiar with this and it indicates the number of Down Syndrome
cases per thousand live births and it shows the Down Syndrome cases increasing
with maternal age. And indeed, autosomal trisomy tend to increase with maternal
age because of mitotic nondisjunction. And Down Syndrome, there's not much
evidence for paternal age effect. So, why would maternal age be critical? It may be
because the gametes are staying for sometimes decades arrested in meiosis
one and so there's a greater chance of nondisjunction. Understand that the
number of Down Syndrome cases increases with maternal age, but this is sometimes
misleading because there are very many more individuals born with Down Syndrome
to younger women than to older women and that's simply because more younger women
are conceiving than older women. So, you have to be careful what the statistics
tell you. And that's what I mean by saying that these data relate to risk
but not absolute number. Aging men pass great in numbers of genetic mutations to
their children, while women intend to pass a fixed number regardless of their
age. And this is a set of data that was actually published in the popular press
in Time magazine and it's showing the number of mutations that accumulate in
sperm increases with age, whereas the number of mutations that accumulate in
eggs stay relatively the same. And one probably can relate this to the fact
that meiosis is occurring in men throughout reproductive life, so there's
greater chances that there may be errors in the replication machinery or the DNA
repair machinery compared to what occurs in women. Children from older men may
have a relatively lower birth weight, there may be more still births, and there
are more psychiatric issues, especially with issues like autism or schizophrenia.
And again, if we you think about why that's the case it's most likely because
there's greater likelihood for breakdown in the molecular mechanisms like DNA
repair or replication, because gametogenesis is occurring throughout a
man's reproductive life, whereas gametogenesis occurs early and fetal
life in females and is arrested for most of a woman's reproductive life. We
can also talk about sex chromosome aneuploidy. So, we talked about X
chromosome trisomy or even more x chromosomes. These individuals are
overtly female. There may be some intellectual disability. You'll see
borrow body variations and/or drumstick variations. We can also talk about XYY
chromosome trisomy. Here, individuals are male, they may be taller than average.
There may be some minor behavioral issues, but generally, XYY males have a
normal IQ. Klinefelter individuals are individuals with multiple X
chromosomes but with the Y chromosome. They are very tall individuals. They may
have a lower but normal IQ range. Now, we want to be careful because sometimes
people used to talk about XYY and even XXY individuals that may have been
prone to criminal behavior. This was postulated because when the studies were
first done they looked at individuals that were in prison and obviously, if
people are in prison, they have criminal behavior.
Well, when studies were done in the general population, one found that they
really weren't any differences in these sex chromosome aneuploidies in the
general population. So, have to be careful with how data is interpreted. There's
another X chromosome aneuploidy, Turner's Syndrome is 45X. This is the only monosome
that's compatible with life. But, it turns out that 98% of the fetuses that
are 45X are spontaneously aborted. Turner Syndrome individuals have a very
characteristic phenotype with a certain array of malformations. Their IQ range,
however, is perfectly normal and Turner individuals, 45X, that do survive
function and lead a normal life. Y-chromosome monosome is an absolutely
lethal condition. You have to have at least one X chromosome to have a
conceptus that's compatible with life. I think we showed you this slide in a
previous podcast showing cells from normal females, XX, showing an individual
with two Barr bodies, XX, and then with three Barr bodies XXX. So, the
karyotype here would be 47 XXX. The karyotype here would be 48 XXXX with 3 of
the X chromosomes being present as Barra bodies. Here's an individual
that would be XY, no Barr bodies. This individual could also be XO of Turner
Syndrome. Here's an individual with the drumstick appendages in neutrophils
3 X chromosomes, so the individual would be 47 XXX. Here's a normal female
46 XX.