9.0: Introduction

In which we consider how DNA molecules, and the genes that reside within them, are organized, how genes are recognized, and how their expression is controlled to form regulatory networks.

An important part of our approach to biology is to think concretely about the molecules we are considering. Nowhere is this more important than with DNA. DNA molecules are very long and cells, even the largest cells, are small. A typicalcylindrical bacterium (↓) is ~2 μm in length and ~1 μm in circumference. Based on the structure of DNA, each base pair is ~0.34 nm in length. A region of DNA that is 1000 (10³) base pairs long is therefore ~0.34 µm in length. A bacterium, like E. coli, has ~3 x 10⁶ base pairs of DNA – that’s a DNA molecule almost a millimeter in length or about 500 times the length of the cell in which it finds itself, and of course there are two of them after DNA replication. That implies that at the very least the DNA has to be folded back on itself many times (←). A human cell has ~6000 times more DNA, resulting in a total length of greater than 2 meters of DNA per cell (before DNA replication). These DNA molecules have to fit into a nucleus that is typically ~10 µm in diameter. In both cases, the DNA has to be packaged in ways that allow it to fit within the cell or nucleus and still be accessible to the various proteins involved in the regulation of gene expression and DNA replication. To accomplish this, the DNA molecule is associated with specific proteins; the resulting DNA:protein complex is known as chromatin.

How DNA structure is regulated and how the information stored in DNA is used is the general topic of epigenetics (on top of genetics). Genetics refers to the information itself, encoded in the sequence of DNA molecules. A mutation will effect the sequence of DNA, it may or may not effect a gene, what a gene encodes and/or its expression. For a particular gene to be expressed, transcription factors must be able to find (by diffusion) and bind, through various intermolecular interactions, to specific nucleotide sequences within the gene’s regulatory region(s). But the way the DNA is organized into chromatin, particularly in eukaryotic cells, can dramatically influence the ability of transcription factors to interact with and bind to their regulatory sequences. For example, if a gene’s regulatory regions are inaccessible to protein binding because of the structure of the chromatin, the gene will be “off” (unexpressed) even if the transcription factors that would normally turn it on are present and active. As with essentially all biological systems, the interactions between DNA and various proteins can be regulated. It is also worth remembering that there are typically one to two copies of a particular gene within a cell. so there may be stochastic effects to consider.

Different types of cells can often have their DNA organized differently; different chromosomal regions may be open(accessible) or closed (inaccessible)(→). Accessible means that proteins, and various molecular machines, can diffuse into and interact with specific regions of the DNA. Accessible, transcriptionally active regions of DNA are known as euchromatin. DNA packaged so as to be inaccessible to regulatory factors is known as heterochromatin. Given that only so many RNA polymerase complexes can move along a DNA molecule at a time; each ribosome assembles a single polypeptide as it moves along an mRNA molecule.

An example of the impact of gene copy number involves sex-determination. In most mammals, and humans, wild type females have two copies of the X chromosome, one from Mom and one from Dad.^[365] Males are XY - with a maternal X and a paternal Y. The genes on the X and Y. chromosomes are different from one another. The X chromosome contains ~1,000 genes, the Y chromosome contains ~80 genes.^[366] There are number of plausible mechanisms by which expression of genes on the X could be the same or similar in males and females. The one used in most mammals is the random (stochastic) transformation, early in embryonic development, of one of the two X chromosomes in each cell into a heterochromatic state, known as a Barr body. The genes on this chromosome are no longer expressed. X-activation is a inheritable event; the epigenetic changes found in the inactivated X persist through DNA replication and cell division. The X chromosome inactivation event is inherited vertically.^[367] The result is that XX females are epigenetic mosaics composed of distinct clones of cells in which either one or the other of their X chromosomes have been inactivated. There is the possibility of evolutionary selection if the expression of one X chromosome leads to a reproductive advantage for one clone over the other. A particular tissue may end up preferentially expressing genes on the maternal or the paternal X chromosome.

An analogous process involving differential DNA (chromatin) accessibility is what is known as monoallelic gene expression, in which only one or the other of the two genes present in a diploid cell (on other chromosomes) is expressed. Monoallelic expression can lead to phenotypic differences between cells.^[368] A question remains whether epigenetic states can be transmitted through the generation of sperm and egg and into the next generation.^[369] Most epigenetic information appears to be reset during the process of gamete (sperm and egg) formation and embryonic development.

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