Biology concepts – chimeras, twins, immune tolerance, ABO
blood groups, random assortment
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The latest Wrath of the Titans movie had a chimera
as one of
the monsters that had to be
defeated. It had two lion heads,
breathed fire, wings, and a
tail that was the head of a snake.
Those aren’t the chimeras
we’re talking about today.
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The partner was indeed the father, but something about Lydia
was funky. Was she trying to game the system? Had she secretly been a surrogate
mother? At the birth of the third child, the judge ordered an immediate genetic
test for the newborn and the mother, just as she delivered. Once again, the
test determined that she wasn’t the genetic
mother. Certainly she was the gestational mother, the baby had just come out of
her!
On a tip from another lawyer, her attorney asked that other
cells be tested. They looked at several cell types, and those from Lydia’s
thyroid and cervical smear demonstrated maternity for all three children. She
wasn’t a surrogate, she hadn’t stolen embryos; she was their mother.
Lydia was a chimera;
she had two populations of cells in her body, each with a different set of
chromosomes. Most likely she had started out as a dizygotic (DZ) twin and there
was a fusion or exchange event. In fact, Lydia recalled that she had a twin
brother who died in infancy. We’ll talk about that possibility, but we’ll also
discuss how it could have come from something much weirder.
There are a couple of ways to end up a chimeric twin; blood group chimerism and tetragametic
chimerism. Blood chimerism is slightly simpler so let’s talk about it first.
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People who get organ
transplants are iatrogenic (medicine-
induced) chimeras because
they now have two populations
of cells with different
genetic profiles. If you get a blood
transfusion, you will
transiently be a chimeric, but you’ll
soon be your old self. What
if a chimeric
donated blood for you?
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When you receive blood in a transfusion, it is important
that you receive blood that doesn't contain antibodies to the antigens on your
RBCs. For instance, a type A person can’t use type B blood because it has
anti-A immunoglobulin in the serum. Type O is the universal donor, while type
AB is the universal recipient – can you explain why?
Apparently, it’s much more common than previously thought that
DZ twins will mix blood systems, including hematopoietic
(blood making) stem cells. This can occur in monochorionic twins (one placenta, see this post) where the
placental vessels of each twin have a common portion where the blood can mix.
Each twin has their own tissue cells and bone marrow cells, but they also have
some bone marrow cells from their twin. The weird part? A case from 2013 and one from 2014 show
that one placenta is possible and not uncommon for dizygotic twins.
It’s estimated that 8% of DZ twins are blood chimeras, and the actual number may be much higher. With the incidence of DZ
twins increasing (see last week’s post) so will the number of blood group
chimeras.
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Science depends on accurate
definitions, so we all know
exactly what we’re
discussing. This makes it hard because
so many people use chimera
and mosaic incorrectly. A
chimera comes from two
zygotes (even if from different times)
while a mosaic results from
genetic changes in a single zygote.
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This is exactly what is believed to have happened in the
first example of blood group chimerism investigated, in 1953. A woman tested
for both blood type O and blood type A. Sixty percent of her cells were O, and
her cheek cells didn’t have A antigen, so O was her blood type and A was the
type of her twin, who had died in infancy – same as Lydia Fairchild's twin brother.
This chimerism is usually of little importance, but in the
1953 case, a benefit was possible. While her own immune system didn’t attack O
cells because they were self, it also didn’t attack A type cells because it had
become tolerized to them (saw them as self). So the adult female could use type
A blood and even receive transplants from a type A donor. The tolerance of one
set of cells for another of different genetic profile is the subject of much
study now (we’ll see why next week). Can you think of a case where it would be
harmful to be a blood group chimera?
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We don’t know how embryos
fuse to become a chimera. It
must happen early, but
wouldn’t they still be surrounded
by the zona pellucida before
they hatch (see this
post)? You figure that one out for a Nobel
Prize.
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Tetra- means four
and -gametic means from gamete cells.
To get four of them, imagine two oocytes fertilized by two male gamete cells –
DZ twins. But in this case, the two embryos fuse; just the opposite of MZ twins
where one embryo splits. The result is one developing fetus made of two
genetically different populations of cells.
Why do they have two different chromosomal profile cells if
come from just one mom and one dad? It goes back to meiosis and random
assortment. When replicated chromosomes (two chromatids each) line up in
meiosis I, they arrange themselves as pairs – but mom’s can be on the right or
the left.
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Random assortment ensures
that all eggs (and all male gametes)
will have different genetic
profiles – or will they? There is a 1 in
4 million chance that two
eggs will have the same random
assortment patter, same for
male gametes. That means a 1in 16
million chance that two
identical eggs could be fertilized by
identical male gametes. But
they would have to occur in the
same cycle – now we’re
getting into really large numbers.
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The picture (right) shows six
possibilities if we only had two pairs of chromosomes, but we have 23! What are
the chances of two eggs with exactly the same random assortment being
fertilized by two male gametes that also just happened to have the exact same random
assortment? Pretty low, so any fusion event is going to produce a chimeric individual.
It’s possible to get a blood group-confined chimera via
embryonic fusion; in fact there was a case of it described in China in 2011. The baby was type AB, but formation of antigen-antibody complexes (agglutination) was mixed. Looked at parents blood types – AB
and O. They assumed there was a parentage issue – why? Why can’t an AB and an O
have an AB baby? Molecular cloning showed that the baby's hematopoietic cells were AO
and BO, and other sites showed the same allele patterning, so the baby was a
definite tetragametic chimera, but the mixed cells were confined to the blood
compartment.
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A chimera might show subtle
signs, depending on where the two
populations of cells land and
starting propagating. A shaft of
curly hair on a straight
haired girl – maybe a chimera. Max
Scherzer of the Detroit
Tigers might be a chimeric or a
mosaic –
you can see it in his eyes - but there many other ways to end up
with two different colored
irises.
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It wouldn’t have to be just right versus
left; consider the Fairchild case. Blood cells and at least some of her cheek
cells were from here twin, while her thyroid cells and her ovarian and cervical
cells were her own. You can’t predict where the chimeric cells will end up
because you don’t know how many cells fused and what positions they were
originally in.
You usually don’t see the effects of tetragametic chimerism
phenotypically, the two versions of mom’s chromosomes and the two versions of
dad’s are usually close enough that the fused embryo fetus looks like a normal
kid. But there could be indications – one ear lobe that hangs down and one that
doesn’t - one big thumb (it’s genetic, ask my wife) and one thin thumb - patchy
color of skin, eyes, or hair (heterochromia).
If the two twins were of different sexes, then where the XX cells and the XY
cells end up in the reproductive tissue will determine the sex of the baby -
the offspring could be male, female, or intersex (true hermaphrodite).
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Lines of Blaschko follow the
same pattern in everyone. The bottom
right image of dermatitis is
following the lines because the cells of
each patch are slightly
different and may react to an allergen or
infection differently. In a
chimeric, you might be able to see a
difference in the skin cells
under UV light, or if the pigmentation
expression is very different,
with the naked eye (top right).
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In tetragametic chimeras, there may be small differences in
the pigmentation of the cells of the different areas, so a UV light can
illuminate the patterns. If the genetic pigmentation expression is very
different, you can see them easily.
Next week – it’s highly possible that we’re all chimeras. Maybe not
twins, but it is likely that we all carry cells from our mom and she has some
cells from us. You might even have cells from your older sister living inside
you – oh yuck!
For more information or
classroom activities, see:
Chimeras –
Blood groups –
i n t e r e s t i n g
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