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Another possible cause of rate acceleration is an increase in mutation rate [ 58].
This was suggested as a cause of rate variation in non-coding DNA in the Lentibulareaceae [ 9].
The multiple site model was again proposed by Pingitore and Eastman (1986) as a possible cause of rate effect on Sr partitioning.
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Because positive Darwinian selection often acts on a small number of amino acid sites in a short period of evolutionary time, it is difficult to detect it and such type of adaptive evolution might be the cause of rate-acceleration in some of the genes.
Accurate estimates of rate variation, and thus accurate inferences regarding the causes of rate variation, depend on accurate estimates of substitution rates.
The rate of molecular evolution is known to vary in three predominant ways (changes in: mutation rate, population size, and selection coefficients; [1]), but in practice, the specific causes of rate variation are difficult to isolate [2], [3].
Unfortunately, causes of rate variation for insertions/deletions beyond the difference between informational genes and operational genes still remain unclear.
A useful method for distinguishing among the potential causes of rate variation is to separately examine nonsynonymous rates (r N ) and synonymous rates (r S ).
Two intrinsic biological variables, generation time and metabolic rate, have been interpreted as causes of rate variations in other organisms [ 60, 61, 65- 68].
Understanding the causes of rate variation in protein evolution is central for many fields including molecular evolution, comparative genomics and structural biology.
Identifying causes of rate heterogeneity as well as specific variables that affect underlying mutation and substitution rates is fundamental to understanding the mechanisms that cause evolution of DNA sequences (reviewed in [ 7]).
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