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What makes us human? Or why aren't we mice?

Posted by EricWerner on 27 May 2009 at 12:27 GMT

Eric Werner
University of Oxford

Certainly some biologists will breathe a sigh of relief at the discovery that there are genetic differences between mice and men. However this respite may be short lived. Ever since the discovery that many of our genes are shared with the “lower” animals the puzzle has been to account for the differences.
The article by Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, et al. 2009 Lineage-Specific Biology Revealed by a Finished Genome Assembly of the Mouse. PLoS Biol 7(5): e1000112. doi:10.1371/journal.pbio.1000112, states that not only are there more genes in the mouse (over a thousand) but many are different (1,259 mouse-specific genes). Can these quantitative and qualitative differences in genes explain why we are different from mice? I will argue that they cannot. Consider the chimp which really started people wondering if genes can account for the difference between humans and animals.

Since the genes of chimps and humans being 98.8% identical, the differences between chimps and humans cannot be the result of the information that is in those genes. However, just as two buildings can be made of the same parts and materials and yet be totally different in their form and architecture, so too the humans, chimps and mice are very different even if made of the many of the same parts and materials. In the case of a building, the information for its construction and its structure lies not in the information that describes the parts that are used to construct it, rather it is in an architectural plan that is used by agents to construct the building. For humans and in fact any multi cellular organism the information used to construct it resides in the genome, but not in the genes. Rather it is in the network architecture that consists of coding and non coding areas that determine the timing and spatial patterning of cells that ultimately results in the development of the organism. In other words, the linear information in a genome is interpreted by the host cells resulting in actions (communication, movement, cellular division) that generate the four dimensional event that is the development of the organism.

Mendel found that certain traits are inherited and he posited theoretical units or objects that are the ultimate cause of the properties or traits of the developed organism. Many traits that are observed are the result of the mutation of genes. However, since most genes are instructions (or templates) for building parts, a mutation in a gene results in a change of a part. If, for example, we change the properties of a brick so that it is twice as large, then the building constructed with those bricks will be bigger and perhaps distorted. If we change the properties of the cement or iron bars that support a bridge, the bridge may collapse or be stronger than before. However, the overall architecture, its topology is not necessarily changed. So too a mutation in a gene may have a radical effect on the development and final properties of an organism. It may result in what is termed a genetic disease. However, analogous to the case of the parts of a building, a change in a gene for parts used in the construction of the body of an organism usually will not change the overall architecture or topology of the form of an organism. The information in the form is not in the parts-genes. It is in the control architecture -the regulatory networks of control units, most likely in the vast non parts coding regions of the genome.

Some Definitions. Let as call these control networks cenes for control genes. Cenes can be very basic units of control, such as protein activators, or cell directives, but they can combine to form networks of cooperative, conditional control. Such larger control networks can in turn be linked to form yet larger cenes. Indeed evolution most likely proceeded by way of cene construction in cooperation with the cell’s system that interprets and executes the control strategies or cenes in the genome. We call it the interpretive-executive system or IES. The overall control network that guides the development of an organism will be called its cenome.

Changing a control network is like changing a road map that indicates where roads are to be constructed as opposed to changing properties of the cement or materials used to build the roads. The map of the road does not change if different cement is used, or if the cement is replaced by stones or gravel. The information in the map that describes paths of the roads is not contained in information in the materials used to build those roads. This seems to be straight forward. However, many biologists have consistently confused the genes used to build the parts with the road map used to build the organism. It is this mistake that is behind the confusion and the question about what makes us different from mice, chimps, flies or worms when our genes are similar and the gene number is very close.

The question of how complex organisms can develop when their gene count is so small, assumes that it is the genes that must be the cause of our complexity. It confuses the parts with the plan or map. Another example is a computer program. A programming language has very few basis commands. All the complexity of the software that is built with the programming language is not reducible to the information in the commands. Rather it is the arrangement of those commands in their repeated use that makes up the program. It is the cause of the complexity of properties of the running program.

The length of the program is a measure of the complexity of the output, not the length or number of the basic commands of the programming language. The genes are more like the basic commands of a programming language. The actual program in the genome results by a repeated use of those part-genes to construct an organism. Thus the size of the genome is a better measure of complexity than the number of genes. Of course evolution and viruses and such may leave large areas of a genome that is without function. That part of the genome that is not used in some way in the development of the organism cannot contribute to its complexity. So the true measure of complexity of an organism is the length of the minimal genome that is necessary to construct the organism.

The point is that the number of genes has little to do with the complexity organism or the constitutive information required to form the organism. Many who have failed to see the fundamental difference between genes and their arrangement in a network of program (genome architecture) feel forced to try to increase gene size indirectly through combinatorics such as gene splicing. So it is argued that there are many more possible proteins from a small set of genes when we realize we can splice those genes and each spliced copy makes a different protein with a presumably useful function. However , once it is fully realized that gene number has very little to do with organismal form or complexity, the need to find more protein generating sequences (genes) ceases to be of great importance. The problem no longer is relevant.

The dominance of the one gene one phenomenological property hypothesis is based on the fundamental confusion of form and content, of building architecture and bricks, of organism and the materials used to build it, of a computer language and its use in programs. The genome contains the program of development as well as the instructions for making the parts used to build the organism.

Computer modeling and simulation of multicellular development sheds light on this fundamental confusion. By modeling multicellular development on a computer, it became evident that same genes can be used over and over again but arranged in different ways to make very different organisms. Thus the architecture of the genome contains the information for the form of the organism not the individual genes. The genes are identical. The forms can vary infinitely different ways.

This changed fundamentally my conception of what a gene is. There are genes for parts and there are genes (or cenes) that function as commands. They regulate the use of the parts-genes and they meta-regulate other command genes.

Another surprise was that cell physics plays a fundamental role in the actual output of a developmental program. If one changes the physics, one changes the resulting form and properties of the development of that form. The cell is then an interpreter of the genome, an agent that uses the genome to guide its behavior. However, the physical context in which it acts fundamentally influences the result. For instance, changing a parts-gene can have radical consequences for the physics of cells and their parts. Hence, such parts-genes mutations can be debilitating and obvious in their developmental consequences. Moreover, physics can also effect developmental timing. One explanation of why some cancers develop so slowly may ultimately be the result of the physics that prevent cells from growing and moving more quickly.

Given this view of genes, one can see the very question: "What genetic changes made us human?" is wrong. Genetic changes are not the cause of our humanity. Genes are parts and regulators they contain no information that is relevant to our humanity. It is the organized genome gradually built up by evolution that made use human. It differentiates us from the mouse, the chimp, the fly and the worm.

Thus, genetics is to a large extent irrelevant to questions of our nature and of our evolution. Genes are essential as the bricks are to a building. Neither genes nor bricks have any information that would help in developing an organism or building a house. Biologists who experiment with non regulatory genes will gain no information about the informational conditions required to form an organism.

As a consequence we see that this will not be the century of the gene. It will be the century of the genome and its regulatory architecture, the cenome.

No competing interests declared.

RE: What makes us human? Or why aren't we mice?

ShiHuang replied to EricWerner on 17 Aug 2010 at 01:49 GMT

Your point is obviously sound and is in fact well appreciated by many before, perhaps first by Claire-King and Wilson in 1975. But even earlier pioneers in this thought may include old time epigenetists such as Soren Lovtrup and others. Epigenetics is of course about plans on how to use the parts/bricks/genes, which may be only partly encoded by the genome. And importantly for evolution, it is inheritable.

However what is not appreciated is an intuitive inverse relationship between the bricks and the architecture plan: the more complex the plan, the more restriction on the variation in building blocks. 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, which I termed the First Axiom of Biology (1, 2). From this inverse relationship, we can now study change in epigenetic plans by studying its inverse mirror image, genetic diversity, which I have done in several of my papers. The more complex the organism, the more the functional bases, and the less the neutral bases/random noises/entropy. All major facts of macroevolution can be explained by this relationship and many can only be explained by it. New evidence for more functional bases in complex organisms is emerging constantly (3, 4).

Again, the importance of the architecture/epigenetic plan in macroevolution has long been appreciated by many. But no one has found a practical way to quantify/study it until now with the First Axiom of Biology.

1. Huang, S.(2009) Inverse relationship between genetic diversity and epigenetic complexity. Preprint available, Nature Precedings;

2. Huang, S. (2010) The overlap feature of the genetic equidistance result, a
fundamental biological phenomenon overlooked for nearly half of a century.
Biological Theory, 5: 40-52.

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

4. Meader, S., Ponting, C.P., and Lunter, G. Massive Turnover of Functional Sequence in Human and Other Mammalian Genomes, (2010) Genome Research. Published on line August 6, 2010.

No competing interests declared.