On 2015 Jun 26, Donald Forsdyke commented:

The review covers a field that has occupied geneticist Jianzhi Zhang and colleagues for many years. Their publications are in journals that have usually not permitted direct commenting. The present new PubMed facility allows the release of past comments on their work that previously had only limited circulation (see Yang JR, 2012, Lin F, 2012, Park C, 2013). There are also comments on a paper in PLOS Biology that are accessible at http://www.plosbiology.org/annotation/listThread.action?root=81241.

The review considers the scope of negative selection, which usually associates with low evolutionary rates and, following Hurst and Smith (1999), only briefly alludes to positive selection, which usually associates with high evolutionary rates. In so doing, the review seems to exclude evidence from studies of positive selection that might reflect on its thesis (see comment on Park C, 2013). Indeed, biochemists have long known that some proteins that are deemed “important” for their host organism evolve slowly under negative selection. Other “important” proteins evolve rapidly under positive selection. Within this broad negative-to-positive range are scattered many other “important” or “essential” or “non-dispensable” proteins. Thus, the review correctly concludes that “the functional importance of a protein only has a weak impact on its evolutionary rate,” and “the evolutionary rate of a protein is predominantly influenced by its expression level rather than functional importance.”

However, the latter statement can be interpreted as implying that, above a certain minimum, expression level and function are not connected. This misinterpretation could be compounded by (i) the narrow range of papers considered the “foundations in the field,” and (ii) frequent allusions to the functional importance (note singular) of a protein, and (iii) focusing too closely on recently acquired genomic datasets (important as they are).

There is extensive literature showing that collective functions of proteins, which are dependent on expression level, can underlie biological phenomena (e.g. the Donnan equilibrium; Donnan FG, 1927). Thus, a protein can have both specific (e.g. enzymic) and general functions (1). The discovery of X chromosome dosage compensation (reviewed by Muller in 1948; see http://post.queensu.ca/~forsdyke/xchromos.htm) gave an early indication of the importance of the general role.

Since many proteins contribute to collective functions, the loss of an individual protein type is more likely to affect its specific function than its contribution to collective functions. Depending on the collective function, some proteins have properties (e.g. size) that would better support that function than other proteins. Thus, there can be degrees of specificity.

And long ago (McConkey EH, 1982) attention was drawn to the importance of functional constraints due to “quinary” interactions between proteins in the crowded intracellular environment. This referred to “macromolecular interactions that are transient in vivo” which should “constitute an important source of constraints on changes in primary structure” (see also Monteith WB, 2015). The E-R anticorrelation, and selection to avoid protein misinteractions, are further considered in a recent review. A cell mutation that may be deemed as imposing a “gain-in-toxicity,” may function to alert an organism’s cytotoxic T cells that the mutant cell should be destroyed before becoming cancerous. We neglect the immunological concomitants of mutation at our peril (Forsdyke DR, 2015).

(1)Forsdyke DR (2012) Functional constraint and molecular evolution. In: Encyclopedia of Life Sciences. Chichester: John Wiley.

On 2015 Jun 26, Donald Forsdyke commented:

The review covers a field that has occupied geneticist Jianzhi Zhang and colleagues for many years. Their publications are in journals that have usually not permitted direct commenting. The present new PubMed facility allows the release of past comments on their work that previously had only limited circulation (see Yang JR, 2012, Lin F, 2012, Park C, 2013). There are also comments on a paper in PLOS Biology that are accessible at http://www.plosbiology.org/annotation/listThread.action?root=81241.

The review considers the scope of negative selection, which usually associates with low evolutionary rates and, following Hurst and Smith (1999), only briefly alludes to positive selection, which usually associates with high evolutionary rates. In so doing, the review seems to exclude evidence from studies of positive selection that might reflect on its thesis (see comment on Park C, 2013). Indeed, biochemists have long known that some proteins that are deemed “important” for their host organism evolve slowly under negative selection. Other “important” proteins evolve rapidly under positive selection. Within this broad negative-to-positive range are scattered many other “important” or “essential” or “non-dispensable” proteins. Thus, the review correctly concludes that “the functional importance of a protein only has a weak impact on its evolutionary rate,” and “the evolutionary rate of a protein is predominantly influenced by its expression level rather than functional importance.”

However, the latter statement can be interpreted as implying that, above a certain minimum, expression level and function are not connected. This misinterpretation could be compounded by (i) the narrow range of papers considered the “foundations in the field,” and (ii) frequent allusions to the functional importance (note singular) of a protein, and (iii) focusing too closely on recently acquired genomic datasets (important as they are).

There is extensive literature showing that collective functions of proteins, which are dependent on expression level, can underlie biological phenomena (e.g. the Donnan equilibrium; Donnan FG, 1927). Thus, a protein can have both specific (e.g. enzymic) and general functions (1). The discovery of X chromosome dosage compensation (reviewed by Muller in 1948; see http://post.queensu.ca/~forsdyke/xchromos.htm) gave an early indication of the importance of the general role.

Since many proteins contribute to collective functions, the loss of an individual protein type is more likely to affect its specific function than its contribution to collective functions. Depending on the collective function, some proteins have properties (e.g. size) that would better support that function than other proteins. Thus, there can be degrees of specificity.

And long ago (McConkey EH, 1982) attention was drawn to the importance of functional constraints due to “quinary” interactions between proteins in the crowded intracellular environment. This referred to “macromolecular interactions that are transient in vivo” which should “constitute an important source of constraints on changes in primary structure” (see also Monteith WB, 2015). The E-R anticorrelation, and selection to avoid protein misinteractions, are further considered in a recent review. A cell mutation that may be deemed as imposing a “gain-in-toxicity,” may function to alert an organism’s cytotoxic T cells that the mutant cell should be destroyed before becoming cancerous. We neglect the immunological concomitants of mutation at our peril (Forsdyke DR, 2015).

(1)Forsdyke DR (2012) Functional constraint and molecular evolution. In: Encyclopedia of Life Sciences. Chichester: John Wiley.