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genome topology, lecture one

In the earlier lecture on molecular biology genes were introduced as "beads on a string".

Chromosomes are the long strings of DNA in this picture, and from time to time along these strings the sequence of DNA has a particular function and is called a gene. Genes make up 1-2% of the length of a chromosome.

In humans, for example, the cell nucleus contains 23 pairs of chromosomes, each 1.5 to 8.5 cm long and each partially wrapped around proteins. The total length of the human chromosomes if they were placed end to end is a little over two meters.

At various points along these chromosomes are the 20,000-25,000 human genes.

The average cell nucleus is about 0.000006 meters (6 micrometers) in diameter. So, the chromosomes are about 300,000 times longer than the space into which they must fit.

The one dimensional "beads on a string model" is useful, but not accurate.

Chromosomes must be folded in order to fit into the nucleus.

Chromosomes are found in the nuclei of animal and plant cells. They are entwined, or wrapped up in and with, proteins called histones.

introduction



Genome topology (GT) is the study of the three dimensional structure of chromosomes over time. It is particularly interested in the surface of this structure, and in the changes in this surface over evolutionary, and within individual lifespan,timeframes.

There are three central tenets of genome topology. They are

1.In general, the genome is divided into two regions. Those genes which are on the surface (directly exposed to contents of the nucleus other than DNA and nuclear proteins) are available for transcription. These are the only genes that can be expressed. The interior region of the genome consists of the lengths of DNA that are buried, surrounded by nuclear proteins and DNA and therefore inaccessible to RNA polymerase. Topology is the primary mechanism of gene regulation.

2.Genome topology is unstable. At an individual level the genome topology of the early embryo 'rolls' in various ways When this happens some genes that were on the surface may finish up in the interior of the genome-histone complex. The genes that accompany those sections of the protein are no longer able to be expressed. Other sections of the protein may move, as part of the refolding, from the interior to the surface and the genes associated with those sections are now able to be expressed. These 'rolls' result in the various cell types; skin, muscle, neural, and so on. At an evolutionary level rolls in the genome are a major cause of both speciation and macroevolution. During life, there are further local foldings in genome topology resulting in different genes being expressed, in response to nuclear contents, at different times for different periods of time.

3. Genome topology is mediated by epenes or epi-genetic factors. Nuclear peptides are possible candidate epenes. Epenes are of two types. First, there are 'extrinsic' (i.e originating from outside the cell) epenes, which would generally be induced by either the environment or by acquired characteristics. Then there are intrinsic epenes (of which histones are the largest and most obvious example). There is the possibility that mRNA itself or peptides produced by the expression of partial or short genes could alter genome topology.

Genome topology determines which gene complexes are available for expression when and for how long.

Genome topology is a different way of thinking. In this theory the genome, in humans this is about 20,000 genes, is analogous to a garage full of tools. However, any one cell at any one time must use a toolbox, a selection of perhaps 2,000 of the possible tools. GT determines which tools are in the toolbox of a particular cell at a particular time. There are a number of possible toolboxes (but perhaps not that huge a number, possibly even less than 1,000 in humans) and it is possible by the interaction of epenes with the genome surface to 'swap out' a number of tools in any one toolbox.

Some tools (the 'housekeeping' or metabolic genes required to keep any human cell alive) must be present in every toolbox, and this may be why there are multiple copies of many housekeeping genes in the human genome.

Two further concepts in this model are helpful.

Conformation refers to the three dimensional structure of the genome interior (the buried portion of the genome). The relationship between the buried and surface portions of the genome is many to many - many conformations are consistent with a single surface, and a single conformation can support many surfaces.

This second relationship, that a single conformation can support many surfaces, arises because genome surfaces are loosely bound. A surface length of DNA can itself be folded or refolded while remaining on the surface, as can a portion of a histone exposed to the general nuclear contents.

Sensitivity to initial conditions. Small differences in the starting conformation and surface compound.

All early stage chordate (animal with a spinal cord) embryos, including human embryos, look very similar and go through very similar changes. Small differences compound. The genome rolls differently. Small differences result in different proteins being produced in different places, at different times for different lengths of time, and the differences between species become apparent.

All cells in an early human embryo (say 8 cell total size) are identical, or nearly so. Small differences compound to become differences in genome topology that make a difference. They lead to cells becoming differentiated as muscle cells, nervous system cells, and so on.

Since the middle of last century molecular and evolutionary biology have been dominated by the idea that the genome is just 'beads on a string'. In the 'beads on a string' model every gene in every cell is always available for expression. It's just that only a minority are 'switched on'. GT challenges the belief that every gene is always available for expression. It claims that in any one cell at any one time the vast majority (say 90%) of genes just are not available for expression because they are buried, when only genes on the surface of the genome-histone complex are available for expression.

In humans, for example, the cell nucleus contains 23 pairs of chromosomes, each 1.5 to 8.5 cm long and each partially wrapped around proteins. The total length of the human chromosomes if they were placed end to end is a little over two meters. The average cell nucleus is about 0.000006 meters (6 micrometers) in diameter. So, the chromosomes are about 300,000 times longer than the space into which they must fit. They are folded and wrapped in order to fit into the nucleus. At various points along these chromosomes are the 20,000-25,000 human genes. As well as its applications to our understanding of ontogeny, evolution, and cell biology, GT has potentially important applications in medicine (topology medicine). The central idea is that 'bad' genes may be able to be buried, and 'good' genes that are inactive (non-penetrant) becuase they are buried might be brought to the surface.

This last idea is the basis for the engineering applications of GT. If body shape, strength, or intelligence are the result of a particualr toplogy at a partcular time, then perhaps that can be influenced.

The theory rests on the discovery of more epenes. Histones are extreme examples of intrinsic epenes.

The surface of planet Earth, part water and part land is an analogy to the surface of the genome-histone complex in the cell nucleus. Protein and DNA are entwined, and the result is that in some regions the surface is part of a protein, in other regions the surface is one or more lengths, perhaps a tangle of such lengths, of DNA.

If the genome-histone complex were sliced, the cut surface would, in some regions be protein, in others it would be DNA.

Although the human genome is believed to contain 20,000 – 25,000 genes in any one cell most of these are buried within the genome-histone structure and cannot be reached by the RNA polymerase protein. These genes are not available for transcription. They cannot be expressed while they lie within the interior of the genome-histone complex.

However, genes can be relocated from the interior to the surface. This occurs when a histone changes shape (is refolded).

The topology of the genome determines, in any cell, which genes can be expressed, when, and for how long.

The second central tenet of this model of genome topology is that chemicals or structures in the nucleus can interact with histones to change their shape. When this happens some sections of the protein that were on the surface may finish up in the interior of the genome-histone complex. The genes that accompany those sections of the protein are no longer able to be expressed. Other sections of the protein may move, as part of the refolding, from the interior to the surface and the genes associated with those sections are now able to be expressed.

These chemicals or structures which can fold parts of the genome-histone complex are grouped together as epigenetic factors, or epenes for short.

This course considers four of many areas in which this model of genome topology has applications. They are human evolution, human development (from baby to child to adult to elderly), medicine, and genome engineering

Two further concepts are helpful, and are introduced at this stage.

Conformation refers to the three dimensional structure of the genome interior (the buried portion of the genome). The relationship between the buried and surface portions of the genome is many to many - many conformations are consistent with a single surface, and a single conformation can support many surfaces.

This second relationship, that a single conformation can support many surfaces, arises because genome surfaces are loosely bound. A surface length of DNA can itself be folded or refolded while remaining on the surface, as can a portion of a histone exposed to the general nuclear contents.

Sensitivity to environmental conditions. Both the genome surface (directly) and the genome conformation (indirectly) interact with, and can be changed by, chemical and physical changes in their local environment.

All early stage chordate (animal with a spinal cord) embryos, including human embryos, look very similar and go through very similar changes. Small differences compound. The genome rolls differently. Small differences in genes result in different proteins being produced in different places, at different times for different lengths of time, and the differences between species become apparent.

All cells in an early human embryo (say 8 cell total size) are identical, or nearly so. Small differences compound to become differences in genome topology that make a difference. They lead to cells becoming differentiated as muscle cells, nervous system cells, and so on.

epenes

Epenes or epigenetic factors are chemical products of acquired characteristics which control genome topology.

Because they control genome topology epenes are primary determinants of which genes are available for expression, when, and for how long.

areas for research

higher resolution less destructive imaging technologies

The nuclear membrane exists for a reason. One obvious reason is to provide the nucleosome with an environment not available to it in the cytoplasm. Unfortunately, there are at present no preparation techniques which preserve the nuclear membrane. Then there is the problem of resolution.

evidence supporting the multi-regional hypothesis

With more 'digs' occurring in Asia, more early primate and even ape fossils are being discovered there. The scientists involved are becoming less and less willing to accept the "out of Africa" theory of human evolution

There is a developing "out of Asia into Africa and back to Asia" theory, but more interesting is the limited (so far) fossil evidence that humans evolved independently at multiple sites.

That is, there is evidence that primate evolution took place wherever there were primates and the descendants retained the ability to mate successfully with primates from other areas.

mathematical modelling of genome rolling

Thus far, our study of evolution has focussed on what we have called 'inherited characteristics'. The term refers to proteins that are free to vary in form between individuals. Sometimes that variation is associated with relative reproductive success and that protein increases in incidence within the population.

However this is not the whole story. There are a number of genes or inherited characterisitcs that are not permitted to vary much, if at all, as such variation is fatal to offspring and fatal before offspring are capable of reaching reproductive age.

Genes that code for proteins essential to development (developmental genes) and genes that code for proteins essential for cell metabolism (metabolic genes) are essentially fixed.

The genes that are free to vary, and upon which natural selection acts, I am going to refer to as 'adaptation genes'.

This classification allows us to begin to contruct the 'animation' of genome topology. At all stages a copy of every metabolic gene must be on the surface of the genome. During embryonic development the required developmental genes must be on the surface of the genome. In differentiated cells the required adaptation genes must be on the surface of the genome.

It is always possible for a topology to reach a reduced or 'mitotic' topology

empirical study of candidate epenes

A variety of different chemicals are likely to function as epenes. Peptides are obvious candidates. The trick is to discover which have an effect under what circumstances

readings

www.genometopology.com