Point accepted mutation

A point accepted mutation — also known as a PAM — is the replacement of a single amino acid in the primary structure of a protein with another single amino acid, which is accepted by the processes of natural selection.

The genetic instructions of every replicating cell in a living organism are contained within its DNA.

At the molecular level, there are regulatory systems that correct most — but not all — of these changes to the DNA before it is replicated.

[5] Conversely, the change may allow the cell to continue functioning albeit differently, and the mutation can be passed on to the organism's offspring.

If this change does not result in any significant physical disadvantage to the offspring, the possibility exists that this mutation will persist within the population.

In either case, while being subjected to the processes of natural selection, the point mutation has been accepted into the genetic pool.

The 20 amino acids translated by the genetic code vary greatly by the physical and chemical properties of their side chains.

The PAM matrices are a mathematical tool that account for these varying rates of acceptance when evaluating the similarity of proteins during alignment.

However, the acronym PAM was preferred over APM due to readability, and so the term point accepted mutation is used more regularly.

However, 'PAM matrix' refers to one of a family of matrices which contain scores representing the likelihood of two amino acids being aligned due to a series of mutation events, rather than due to random chance.

[7] The calculation of these matrices was based on 1572 observed mutations in the phylogenetic trees of 71 families of closely related proteins.

Since the vast majority of protein samples come from organisms that are alive today (extant species), the 'direction' of a mutation cannot be determined.

In addition to these counts, data on the mutability and the frequency of the amino acids was obtained.

vary as some unknown function of the amount of time that a protein sequence is allowed to mutate for.

By using only alignments of proteins that had at least 85% similarity, it could be reasonably assumed that the mutations observed were direct, without any intermediate states.

units, and so the total number of conserved amino acids is The value of

by the simple relationship The PAMn matrix is constructed from the ratio of the probability of point accepted mutations replacing the

represents the number of mutations that occur per 100 amino acids, however this value is rarely accessible and often estimated.

, an assumption that can be reasonably made for typical proteins, this expression is approximately equal to The validity of these estimates can be verified by counting the number of amino acids that remain unchanged under the action of the matrix

The total number of unchanged amino acids for the time interval of the PAMn matrix is and so the proportion of unchanged amino acids is A PAM250 is a commonly used scoring matrix for sequence comparison.

Only the lower half of the matrix needs to be computed, since by their construction, PAM matrices are required to be symmetric.

[13] This suggests that the number of mutations per amino acid in a protein increases approximately linearly with time.

Fossil records are often used to establish the position of events on the timeline of the Earth's evolutionary history, but the application of this source is limited.

However, if the rate at which the molecular clock of protein family ticks — that is, the rate at which the number of mutations per amino acid increases — is known, then knowing this number of mutations would allow the date of divergence to be found.

Suppose the date of divergence for two related proteins, taken from organisms living today, is sought.

in the PAMn matrix which results in the best score is most likely to correspond to the mutations per amino acid separating the two proteins.

This form of scoring system is utilized by a wide range of alignment software including BLAST.

Although both matrices produce similar scoring outcomes they were generated using differing methodologies.

The BLOSUM matrices were generated directly from the amino acid differences in aligned blocks that have diverged to varying degrees the PAM matrices reflect the extrapolation of evolutionary information based on closely related sequences to longer timescales.

[17] However, all amino acid substitution matrices can be compared in an information theoretic framework[18] using their relative entropy.