Rates of synonymous and non-synonymous substitution

By using a modification of the simple Jukes-Cantor model we encountered before, it is possible make separate estimates of the number of synonymous substitutions and of the number of non-synonymous substitutions that have occurred since two sequences diverged from a common ancestor. If we combine an estimate of the number of differences with an estimate of the time of divergence we can estimate the rates of synonymous and non-synonymous substitution (number/time). Table 3 shows some representative estimates for the rates of synonymous and non-synonymous substitution in different genes studied in mammals.

Table 3: Representative rates of synonymous and non-synonymous substitution in mammalian genes (from [1]). Rates are expressed as the number of substitutions per $10^9$ years.

Locus	Non-synonymous rate	Synonymous rate
Histone
H4	0.00	3.94
H2	0.00	4.52
Ribosomal proteins
S17	0.06	2.69
S14	0.02	2.16
Hemoglobins & myoglobin
$\alpha$-globin	0.56	4.38
$\beta$-globin	0.78	2.58
Myoglobin	0.57	4.10
Interferons
$\gamma$	3.06	5.50
$\alpha$1	1.47	3.24
$\beta$1	2.38	5.33

Two very important observations emerge after you've looked at this table for awhile. The first won't come as any shock. The rate of non-synonymous substitution is generally lower than the rate of synonymous substitution. This is a result of what you might call the ``sledgehammer principle.'' Mutations that change the amino acid sequence of a protein are more likely to reduce that protein's functionality than to increase it. As a result, they are likely to lower the fitness of individuals carrying them, and they will have a lower probability of being fixed than those mutations that do not change the amino acid sequence.

The second observation is more subtle. Rates of non-synonymous substitution vary by more than two orders of magnitude: 0.02 substitutions per nucleotide per billion years in ribosomal protein S14 to 3.06 substitutions per nucleotide per billion years in $\gamma$-interferon, while rates of synonymous substitution vary only by a factor of two (2.16 in ribosomal protein S14 to 4.52 in histone H2). If synonymous substitutions are neutral, as they probably are to a first approximation,³then the rate of synonymous substitution should equal the mutation rate. Thus, the rate of synonymous substitution should be approximately the same at every locus, which is roughly what we observe. But proteins differ in the degree to which their physiological function affects the performance and fitness of the organisms that carry them. Some, like histones and ribosomal proteins, are intimately involved with chromatin or translation of messenger RNA into protein. It's easy to imagine that just about any change in the amino acid sequence of such proteins will have a detrimental effect on its function. Others, like interferons, are involved in responses to viral or bacterial pathogens. It's easy to imagine not only that the selection on these proteins might be less intense, but that some amino acid substitutions might actually be favored by natural selection because they enhance resistance to certain strains of pathogens. Thus, the probability that a non-synonymous substitution will be fixed is likely to vary substantially among genes, just as we observe.