Embryology   Biology 441   Spring 2011   Albert Harris


HOX Logic?


What functional sense does it make for Hox gene transcription to be colinear?

Developing embryos transcribe "Hox genes" in geometric patterns (spatial co-linearity) (and also in time sequences = "temporal colinearity") that match the relative locations of the Hox genes on the chromosomes (with the genes toward the 3-prime end being transcribed nearest the head)

By far the most popular theory for explaining formation of this pattern is that there is/are concentration gradient(s) of some very permeable substance(s) [suspected to be retinoic acid, which is hydrophobic enough to go through membranes, and which also induces serious birth defects], and that the local concentration of this "morphogen") controls which Hox genes are "turned on" and which are turned off.


  Almost no consideration has been given to entirely different kinds of explanation.

Here are examples of two alternatives: (see if you can invent more; or disprove these)
Suppose that each cell can detect which Hox genes are being transcribed by the other cells closest to it (that are touching it) and compare the Hox genes transcribed by their neighbors with those transcribed by themselves.

Two alternative versions: #1) Each cell changes which Hox genes it transcribes to become whichever Hox gene is located half way in between (the locations on their chromosomes) the Hox genes transcribed by their neighboring cells. For example, if one side of a cell were touching another cell that was transcribing Hox gene A3, and the other side of this same cell was touching a cell that was transcribing Hox gene A5, then this in-between cell would be stimulated to transcribe Hox gene A4.
The end result would be colinearity, A1 A2 A3 A4 A5 A6 etc., as the net result of neighbor-neighbor stimuli, instead of diffusion gradients.

#2) Also based on responses of each cell to comparing which Hox genes are being expressed by nearby cells, and comparing which Hox genes each cell is itself transcribing, as compared with which Hox genes are being transcribed by nearby cells. However, instead of averaging, this alternative mechanism works by cells detecting the size of the difference (meaning the distance apart of the Hox genes on their chromosome. When they are more than one gene apart, then they change expression in the direction of decreasing this distance. For example, if a cell detects that it is transcribing Hox gene 4 and an adjacent cell is expressing Hox gene 9, then one or both cells would change transcription, with one cell switching from 4 to 5, and/or the neighboring cell switching from 9 to 8. The following diagrams are meant to illustrate how the net effect of repeated responses to neighbors would produce colinearity.



111111199 111111299 111111399 111112499 111113599 111124699 111135799 111246899 111357899 112467899 113567899 123567899 124567899 134567899 123456789

111111119 AAAAAAAAI 111111129 AAAAAAABI 111111139 AAAAAAACI 111111249 AAAAAABDI 111111359 AAAAAACEI 111112469 AAAAABDFI 111113579 AAAAACEGI 111124689 AAAABDAHI 111135789 AAAACEGHI 111246789 AAABDFGHI 111356789 AAABCFGHI 112356789 AABCEFGHI 112456789 AABDEFGHI 113456789 AACDEFGHI 123456789 ABCDEFGHI

Historically, progress in genetics has been accomplished by noticing abstract patterns in data, and then inventing several alternative mechanisms that would be capable of generating these observed patterns. Human nature tends to cling to some favorite concept, instead of trying to invent as many alternative possibilities as possible, as a step toward inventing further experiments or observations by which you could disprove all but one of the alternative theories.

I believe that most current embryologists are "locked in" to the idea of concentration gradients of diffusing chemicals as if that were the only way to create and repair (regulate) consistent spatial patterns. They believe that unknown diffusion gradients stimulate which Hox genes will be transcribed, and that the Hox gene proteins then control which differentiated cell types will form at each location.

Nobody considers whether interactions between Hox genes might themselves be creating the spatial patterns, by means of repeated close-range interactions.


  I only ask that you consider these alternative possibilities. I also hope that you will try to invent other possibilities, and hope that you will also try to analyze internal consistencies of the different kinds of explanations that I suggest. For example, if you can tell me on an exam that "your theory #1 couldn't be true because...etc." Or explain why theory #2 would lead to certain further predictions that I haven't noticed, then your criticisms and predictions will earn my highest respect and highest grades. (But don't worry if new ideas or disproofs don't occur to you! Grades of A can also be earned just by knowing the facts.)

In 1952, "Chargaff's Laws" were right there in journal articles, for anyone to read. 99.99% of scientists either could not, or did not, perceive that A=T, C=G makes sense in terms of chemical structures in which A pairs with T and C pairs with G, and that selective pairing is a good way to duplicate and encode genetic information.

In 2011, the data on Hox gene co-linearity is right there in journal articles, for you to read.

Nobody has grasped why co-linearity is a good way to control formation of anatomy. Everyone tries to fit it into pre-existing theories of diffusion gradients. Maybe that's all there is to it?

Maybe you will invent some other way of thinking about co-linearity, that will be as big an AHA! Eureka! as base pairing was. Probably, neither you nor I will invent such a gigantic breakthrough idea. Probably not; but our chances aren't zero.

Unless we just passively accept what's already in the books: because that acceptance really will reduce our chances to zero.



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