Tuesday, September 1, 2009

Complexity Associated Protein Sectors (CAPS), new evidence for the MGD hypothesis

A Cell paper two weeks ago reports an important and beautiful result on protein sequence conservation and evolution (1) (free open access http://www.cell.com/fulltext/S0092-8674(09)00963-5) The result contradicts the modern evolution theory but is a precise prediction of the more complete evolution theory, the maximum genetic diversity hypothesis (MGD) (2, 3).

The modern evolution theory mainly consists of natural selection of Darwinism and random drift of the neutral theory. The theory makes no distinction between microevolution and macroevolution and was originally a theory of microevolution or population genetics. It was invented by population geneticists based on a complete ignorance of epigenetics, the other half of heredity equally important if not more important for determining heritable phenotypes. A factual observation is explained either by natural selection or its negation (random drift) depending on which one works better. The reason why a negation of Darwinian natural selection can be accorded equal weight in the modern evolution theory is because natural selection is largely irrelevant to or contradicted by molecular evolution for which the clock/neutral theory seems to superficially work if one overlooks the numerous contradictions of its own. No evolution biologist has ever claimed that the modern evolution theory has no factual contradictions. In truth, however, all the contradictions are about macroevolution. The theory essentially has no contradiction for the domain of microevolution or population genetics for which it was originally invented and should never have been allowed to apply outside of it.

An obvious difference between microevolution and macroevolution is that the latter involves a change in organismal or epigenetic complexity as roughly defined by the number of cell types or the number of epigenetic molecules. With microevolution only, bacteria would stay forever as bacteria, and would never be able to evolve into complex multicellular organisms.

As reported by the Cell paper, one portion of a protein of S1A family protease, termed the blue sector (arbitrary color to be different from two other sectors of red and green), is much more conserved in vertebrates than in invertebrates (Figure 6B of the Cell paper) and is not related to enzyme activity. It represents a domain specific to vertebrates. The existence of sectors in a protein, the blue sector in this case, that can differentiate complex vertebrates from simple invertebrates cannot be explained by the modern evolution theory. Thus the paper made no attempt to discuss the blue sector in connection with any evolution theory, perhaps in order not to openly embarrass the paradigm and thus have a chance to pass the peer censorship of Cell. Here is why. To explain the blue sector by natural selection, one must invoke that vertebrates as a whole encounter an entirely different natural environment from that of invertebrates, which is simply not the case. Even if so, it needs one additional wild ad hoc speculation that natural selection only acts on vertebrates but not on invertebrates, which is unlikely and inconsistent with Darwinism. To explain the blue sector by random drift would require neutrality for most of the amino acid positions in this sector, which is also simply not the case. Because if it is, the blue sector would never have been discovered in the first place as a group of correlated amino acids.

So what does the blue sector say about actual evolutionary mechanisms? A key question that should be discussed by the Cell paper but was unfortunately not. First, it adds one more outstanding fact to the long list of facts that contradict the modern evolution theory. Second, every fact that contradicts the modern evolution theory has been automatically found to be evidence for the MGD and the new result of the Cell paper is no exception. The MGD treats the modern evolution theory as true only for microevolution and suggests that macroevolution is distinctly different and involves a change in epigenetic complexity. One is mostly about pure genetic changes such as point mutations whereas the other is mostly about epigenetic changes, e.g., rearrangement of large segments of chromatin and gene expression patterns.

A good analogy is house building or any kind of man-made construction. We need both bricks/building blocks and architecture plan/map. Microevolution is about changing brick types, like from clay to rock. Macroevolution is about changing architecture plans, like from 1 story to 100 story buildings. And there is a self-evident inverse relationship between plan and bricks: the more complex the building plan, the more restriction on the variation in building blocks. It is always a sign of great science if one can express it in terms of common sense language, as well put by Einstein: “Most of the fundamental ideas of science are essentially simple, and may, as a rule, be expressed in a language comprehensible to anyone.” It is obviously non-sensible to ordinary people for any theory to be equivalent to saying that changing brick type alone can change the architectural style of buildings.

An increase in epigenetic complexity will lead to a decrease in genetic diversity as measured by point mutations due to a self-evident inverse relationship between genetic diversity and epigenetic complexity (2, 3). A gene in complex organisms encounters more epigenetic constraint than in simple organisms and is thus less tolerant of point mutations. Macroevolution towards higher epigenetic complexity involves a suppression of point mutations, and in this sense is the exact opposite of microevolution (ref 2-5). Thus the MGD predicts that protein or DNA sequence sectors that are non-constrained in simple organisms would become constrained in complex organisms even though such sectors may play no role in enzyme function. The blue sector of S1A protease is the first example of such Complexity-Associated-Protein-Sector (CAPS) or more generally Complexity-Associated-Sequence-Sectors (CASS) to also include DNA. Epigenetic complexity puts maximum CAPS on sequence divergence.

Finally, a simple thought experiment on how the blue sector may illustrate the distinction between micro and macro evolution. A common ancestor gave rise to two invertebrate species A and B and a vertebrate species C within a couple of million years during the Cambrian period. After 550 million years of evolution, A and B are 40% non identical in a trypsin of 240 aa. Most of the blue sector residues are located in the non-identical regions. Both A and B contributed equally to the non-identity between them because they are similar in complexity or in their tolerance level to point mutations. On the other hand, C and A or C and B are also 40% non-identical. Most of the blue sector residues of C are also located in the non-identical region. However, mutations in the blue sector are not neutral to C (while neutral to A and B) because C is more complex, and so have happened much less frequently than the corresponding positions of A or B. Thus, while the mutation rate of A or B can be calculated as is done by the modern evolution theory as 40% x 240/2/550 = 0.087 aa per million year, the same cannot and should not be done for C.

Unfortunately, the same has in fact been done and is being done daily for C under the existing paradigm in the past 46 years, resulting in numerous contradictions with the facts of macroevolution in term of both the fossil record and the DNA record such as the genetic equidistance result of Margoliash in 1963 (6), the most remarkable result of molecular evolution. The molecular clock/neutral theory was invented to account for the numerical feature of this result but should never have been invented in the first place and lasted as long as it has been if another feature, the overlap feature, of this result had been appreciated 46 years ago rather than just now as a direct result of inventing the MGD. As things stand today, we either have no theory to explain the overlap feature of the equidistance result as well as numerous other facts such as CAPS or we have a perfect one in the MGD.


1. Halabi, N., Rivoire, O., Leibler, S., and Ranganathan, R. (2009). Protein sectors: evolutionary units of three-dimensional structure. Cell 138, 774-786.

2. Huang, S. (2008) Histone methylation and the initiation of cancer. Cancer Epigenetics, Ed. Tollefsbol, T., CRC Books.

3. Huang, S. (2009) Inverse relationship between genetic diversity and epigenetic complexity, Submitted. Preprint available, http://precedings.nature.com/documents/1751/version/2

4. Gago, S., et al., (2009) Extremely high mutation rate of a hammerhead viroid. Science 323: 1308

5. Zimmer, C. (2009) Fast-mutating viroids hold clues to early life. Science magazine blog, http://blogs.sciencemag.org/origins/2009/03/fast-mutating-viroids-hold-clu.html

6. Margoliash, E. (1963) Primary structure and evolution of cytochrome C. PNAS, 50:672-679

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