Wednesday, January 30, 2019

Internal Heredity and Mary Lyon’s Contribution: A Female Advantage?


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.”


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