The Cell Level Simulation

To model larger numbers of cells in a reasonable time requires a change in the level of the simulation. Details at the DNA molecule level must be sacrificed to allow the simulation to extend to higher levels of organization (see Table 48.2). For this we have designed simulations where the lowest level of detail represented is the level of a single cell (Capps et al., 2003; Rajasimha et al., 2004). In the most basic form of this model each simulated cell, is now represented by just two integer values. W is the number of wild-type mtDNA molecules in the cell, and M is the number of mutant mtDNA. Over a time step At the changes in the values W and M are given by the following integer difference equations.

The number of wild-type and mutant mtDNA lost to degradation is calculated from the following equations.

Acquired mutations are represented by decreasing W and increasing M. For example, if the probability of de novo mutation within a time step At is set at Pmut, then mutation terms are added to Eq. 8 to give the following.

This description of the Cell Level simulation lumps all mutant mtDNA together in a single category. To follow different mutations separately is more complicated in the Cell Level simulation than it was in the mtDNA Molecule Level model. To include more than one mutation type we must extend the basic data structure to W(t), Mj(t), M2(t), ..., Mn(t). Each variable Mi(t) represents the number of mtDNA molecules with a specific mutation. The simulation may be set up to represent a set of predefined mutations, or each new mutation event may define a new mutation type. In the latter case, since we expect most mutations to appear only transiently in the cell before being lost to random drift, it is best to remove any data structure Mi(t) that falls to zero and reuse that data structure for the next new mutation to occur. Otherwise you will end up with a large number of empty data structures. From our experimental and simulation work on human colon crypt cells we found that some crypt cells contained three mtDNA mutations at detectable levels (Taylor et al., 2003), and most crypt cells contained fewer than three different mutations. These experimental results indicate that only a few different mutation data structures would be needed to simulate the range of mtDNA mutations found in a single aging human cell.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook


Post a comment