We usually assign heredity to the mating of an egg and a
sperm cell resulting in a set of chromosomes that will determine the
characteristics of the resultant child.
But that simple picture does not explain how one goes from a fertilized
ovum to producing a viable infant constructed from numerous specialized cells. Somehow a single cell must be able to produce
progeny that become muscle tissue, blood cells, lungs, brains, and so on. There must exist some path by which this
transformation can occur. Early
researchers, who did not have the benefit of modern technologies, struggled
with understanding this and assumed there must be another form of heredity, “internal
heredity,” that “assigned” cells the means of becoming a specific type of cell. Thinking in terms of a form of heredity
seemed appropriate because once an assignment was given, the cell and all its
progeny would forever more be of the same type.
Carl Zimmer provides his readers with some fascinating insight into this
process, and many other biological wonders, in his fact-filled book She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity.
Thinking in terms of internal heredity leads to the
notion that some sort of mutation must have taken place to convert one type of
cell into another. We now know that the
process is more complicated. One might
describe it as exquisitely complicated.
The basic genetic information in our cells is maintained through cell
division and diversification. What
changes are the sections of our chromosomes that are allowed to remain active.
“The DNA that encodes someone’s
genes is replicated in full each time a cell divides. What makes a sweat gland cell different from
a taste bud cell is the combination of genes that are active in each of them,
as well as the combination that is silent.
And that difference can be passed down from mother cells to daughter
cells.”
“It’s an inheritance, but not of
some particular mutation. It’s the
inheritance of a state, a configuration of life’s network. And the first glimpse of how that network is
configured came to a woman whose day job was to prepare for the apocalypse.”
Zimmer is referring to Mary Lyon whose interest was in
genetics. Early experience with nuclear
explosions made it clear that the radiation generated could cause damage to the
genetic information stored in our cells.
There was great concern on the part of the British to learn more about
how serious this might be, both because of the nuclear testing taking place,
and because nuclear war seemed a distinct possibility at the time. In 1955, Lyon was hired to work in the
Radiobiological Research Unit of the Medical Research Council. Her background and interests were in the genetics
of mice. Somehow, she managed to
continue work in that area and from that would come the insight that would stimulate
generations of researchers.
Lyon had access to a strain of mice that had a genetic defect. The result for females was that they would develop
a mottled coat of hair with randomly located patches of an abnormal color. The males, on the other hand, would either
have a normal coat or they would die before birth. Since females have two X chromosomes and
males have one X and one Y, this would be consistent with a defect on one X
chromosome. If the male inherited that
mutation on its X it would die, if not, it would be normal. The puzzling thing was the effect of two X
chromosomes on the female. Why did two
healthy Xs not produce twice as many proteins as the single of the male and
thus cause some form of disfunction? And
what caused the mottled appearance of the female coats?
Lyon’s insight was prompted by an observation published
years before that cells in female cats indicated that one X chromosome was
always open for business while the other appeared as a balled-up mass. If only one X chromosome was active in
females that would explain the normal functioning of females with two Xs. But the females of the strain she was
studying didn’t die so they either had to always choose to keep the nonmutated
X active or something else was going on.
And the single X being operative did not explain the mottled coat of the
females. For Lyon, the only explanation
that explained everything was that the females had both X chromosomes active,
just not in the same cell. At some point
in its development, the females’ cells were deciding which of the Xs would be
operative and which would be shut down. Further
assuming that the cells would be half one X and half the other, would explain
how the females could produce enough of the needed molecules to survive the
effect of the mutated gene on the one X chromosome. The appearance of discolored patches on the
female’s coat suggested that the decision of which X to utilize was made early
in the development of the embryo, and that once made, all daughter cells propagated
that decision so that clusters of similar cells would evolve. Also, the fact that the coat patterns were
random from female to female suggested that the selection of which X chromosome
to deactivate was random.
When Lyon published her hypothesis, the general response
was along the lines of “that makes sense, why didn’t I think of that?” The goal then became to prove she was correct
and to understand the mechanisms by which such genetic manipulation was
accomplished.
“The random silencing of X
chromosomes came to be known as ‘lyonization’—although Lyon herself disapproved
of the name.”
It was relatively simple to determine that the picture
proposed by Lyon was correct. In 1963 a
researcher named Ronald Davidson studied a blood disease caused by a defect on
the X chromosome. Looking at skin cells
from women who carried the defect he determined that half the cells had
silenced the defective chromosome and half the functional one.
More complex is the understanding of how the manipulation
of the chromosomes occurred. That would
take some time, but the understanding came.
Here is Zimmer’s description of what occurs when a cell decides which X
to disable.
“A number of scientists have
dedicated their careers to finding the molecules that shut down X
chromosomes. Their search has led them
to one stretch of DNA on the X chromosome, dubbed Xic, where several crucial
genes reside. Early in the development
of a female embryo, the two X chromosomes in each cell are guided toward each
other, their Xic regions lining up neatly.
A flock of molecules descends on the pair of Xic regions, drifting
between them in what is essentially a molecular version of
eenie-meenie-minie-moe. Eventually they
settle on one of the two Xic regions, where they will switch on genes that will
shut down the entire X chromosome.”
“One of the genes they switch on
is called Xist. The cell uses Xist to
manufacture long, snakelike RNA molecules.
They slither along the X chromosome, finding a place where they can take
hold. While one end of an Xist molecule
grips the X chromosome, the other end snags proteins passing by to help
it. Together, they twist and coil the X
chromosome, until it has shrunk down to a compact nugget of DNA. The other X chromosome remains active by
keeping its own copy of the Xist gene silent.”
Once the selection is made the decision is permanent. When it is time for the cell to divide, the
twisted chromosome must be untwisted for the division process and then, in each
daughter cell, the same X chromosome must then be again compressed into an
inactive state.
This X chromosome manipulation provides an example of how
what was described as internal heredity takes place. The collection of molecules in a cell play a
role in determining the functioning of a chromosome’s genes—and thus the
functioning of a given cell.
“These molecules—a combination
of proteins and RNA molecules—control which genes become active and which
remain silent. Some silence genes by
winding stretches of DNA up tightly around spools. Others unwind it, allowing gene-reading
molecules to reach the exposed DNA. Some
proteins clamp down on a gene, shutting it down until they fall off. Since each cell can make many copies of a
silencing protein, another will soon take its place. Cells can also shut down genes for the
long-term by coating them with durable molecular shields. This shielding—called methylation—lasts
beyond the life of a cell. When the cell
divides, its two daughter cells build new shields to match the original
pattern.”
It would seem that women, with their two X chromosomes,
have gained an evolutionary advantage over men.
Diseases linked to the Y chromosome are clearly not a problem for them,
and they are protected from most X chromosome diseases by the lyonization effect. Males, however, have no natural recourse from
defective X chromosomes which they inherit from their mothers.
The male’s Y chromosome is mostly involved in making
males masculine. The X chromosome, on
the other hand, has much more genetic activity.
Zimmer and others also entertain the notion that lyonization provides a
more subtle advantage to females, one not easy to detect.
“It may expand the scope of
heredity for women. In the brain [for
example], some neurons may inherit an active X chromosome that guides them to
sprout branches in one pattern, while other neurons branch in another. The power of the human brain comes from its
diversity—from different kinds of neurons, from different kinds of circuits,
from different types of chemicals for communication. Lyonization may make women’s brains
inherently more diverse.”
The interested reader might find the following articles
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