AICS Research

sci.bio.evolution, 1997, July 9

WHAT IS PLEIOTROPY?

Wirt Atmar

AICS Research, PO Box 4691,
University Park, NM 88003 USA


INTRODUCTION


Zia Khan writes:

>might someone define the term "pleiotropy"?

Literally, pleiotropy means "at more than one turn." In that, every engineer deeply knows the meaning of pleiotropy (although very few actually know it by that name).

What the word means in common terms (to both biologists and engineers) is: "Change one a single item (a gene, a bit of code in a software program, the placement of a mechanical strut) and other subsystems may be affected in wholly unexpected manners."

In politics, the effect is known as "the law of unintended consequences," and that too is the same thing. Pleiotropy is an inevitable consequence of all complex systems, whether the system be ecological, social, mechanical, or genetic.

The twin effects of pleiotropy (where one gene affects many "traits") and polygeny (where one "trait" is the product of many genes) work to create a complex web of genotype-phenotype interactions that renders any simple causative analysis fruitless. But that fruitlessness is equally part and parcel of all complex systems.

The thread that has been proceeding in this newsgroup for some time now concerning the nature of complexity has always been of great interest to engineers, especially those engineers that design very complex systems. The notions of complexity and pleiotropy are intimately intertwined. In order to bring some sense of analytical order to the subject within engineering, the definitions of complexity are generally broken into two parts: explicit and implicit complexities.


EXPLICIT OR APPARENT COMPLEXITY


Integrated circuits are now approaching ten million transistors on a single chip (Pentium Pro processors already have 2 million transistors). Although such a parts count begins to approach a human incomprehensibility, a simple parts count cannot be used as a reliable measure of complexity.

The notion of apparent or explicit complexity depends strongly on the language (or notation) that is used to describe a complex system. Repetitions, symmetries, and other similar regularities quite obviously tend to work to minimize the apparent complexity of a structure. A memory chip with several million transistors is intuitively not as "complex" as a microprocessor with only a few thousand transistors, thus engineers and mathematicians have a tendency to speak of minimum description length (MDL) notations. An MDL captures, generally without loss of information, the "essence" of a complex structure – and thus by itself becomes a metric of the explicit complexity of the structure.


IMPLICIT COMPLEXITY


D.V. Steward wrote in 1981 in an engineering text that "[Implicit] complexity is how much more the whole is than just the sum of its parts." While that definition may seem unusually vague for engineering, and without calculable value, Steward's definition is nonetheless commonly used and often quoted.

Engineers who work on very complex systems tend to define two additional qualities as attributes of complexity: "coupling" and "cohesion." Cohesion is a measure (somehow calculated) of how closely the internal parts that make up a module belong together when seen from different perspectives.

Coupling, in contrast, measures how much the submodules interact. Good structuring and clever systems design works to partition complex systems into minimally interacting modules by reducing the implicit complexity (that complexity over and above the MDL) by minimizing pleiotropic interactions between the subparts.


COMPLEXITY AND PLEIOTROPY


Pleiotropic effects – in any complex system – are intrinsically minimized by modular partitioning of the subprocesses. And evolution, as an adaptive process, has clearly discovered the values attendant to modular code and partitioned behaviors. Indeed, such structural partitioning is the mechanism that allows the common phenomenon of "mosaic evolution," an evolutionary process where one part of the body (such as mandibular morphologies or gut chemistries) are allowed to rapidly change in response to new evolutionary pressures while other organs (such as the eyes or feet) remain relatively unmodified.

Nevertheless, no complex system exists without extensive pleiotropy – nor can it be designed out of a system, no matter how extensive the effort. The best that can be done is to attempt to minimize its effects, but even in that effort, total success is unachievable.

It is possible to obtain a crude measure of the extent of the pleiotropy that permeates a specific design. Such a technique is called "sensitivity analysis" in engineering. Each component in the system is slightly varied. The extent of the change that ripples throughout the system is then measured in every subsystem.

Occasionally, a sensitivity analysis becomes a failure analysis. In the case the Space Shuttle Challenger, the partial failure of a single o-ring gasket shut down the Challenger's on-board telemetry – along with every other subsystem. The Challenger didn't "explode." It suffered a deflagration event (which in engineering terms, means that it suffered an overpressure wave that basically tore it apart at its seams). Each major structural subsystem (the wings, the crew cabin, the main engines) remained more or less intact after the event. It's just that as a collection of subsystems moving at high speed, the Challenger lost "integrity," no longer capable of functioning competitively as a unit whole.

And that's very much the point that Mayr has been trying to make for the last fifty years when he speaks of the "unity of the genotype." The genotype can only be assessed and evaluated as a unit whole – if for no other reason than because that was the context in which the genotype was evolved and optimized.


POLYGENY AND PLEIOTROPY


Five thousand to 50,000 actively translated gene products are characteristic of metazoan genome sizes. On average, 10-50% of the active genome appears to be translated in any one cell type. Constituent code representing basal cellular metabolism (commonly called "housekeeping code") appears to represent 50-75% of the code translated within all cells (10,000-20,000 gene functions in Deuterostomes). Much of this basal constituent code is presumed to be not characteristic of the species, but of the phylum, or higher, indicative of the antiquity of its origin. Tissue-specific code (another 10,000 to 20,000 gene functions in mammals and birds; often called "luxury code") is evolved hierarchically on top of the basal genetic platform.

Nonetheless, the complexity of a metazoan phenotype appears to be far greater than the complexity of its genome. The simple mechanism that permits such excess complexity to be evolved is the re-use of code.

The construction of all complex, well-conserved structures (an eye, a heart, or stereotypical behaviors) result from the polygenic expression, directly or indirectly, of virtually all of the translated genome. To speak of a "gene" for a complex behavior such as altruism, monogamy, or "uncapping" is simply nonsense and cannot be justified even as a verbal shorthand. It is, at its core, completely misleading.

The first to clearly demonstrate the implicit pleiotropy associated with code re-use was Hans Gruneberg. Gruneberg, a geneticist who did the majority of his work in the 1930's, used the phrase "spurious pleiotropy" to describe those pleiotropic effects that permeate much of the phenotype due to the obvious re-use of code. Gruneberg found that a single mutation in the rat caused thickened ribs, a narrowing of the lumen of the trachea, emphysema of the lungs, hypertropy of the heart, blocked nostrils, blunt snout, and low viability. Congenital medical "syndromes" (literally: symptoms that "run together") such as these are virtually always the pleiotropic effects of a single gene's mutation – and hundreds of similar conditions for humans are now well known.

Sewall Wright preferred the term "universal pleiotropy," to especially emphasize the same point that Mayr makes. Change any one gene – and if that change is expressed – then that change will almost certainly have effects that resonate throughout the phenome. Essentially all modern evidence suggests that Wright was correct: all expressed genes tend to be universally pleiotropic. Non-pleiotropic gene products simply don't exist. But that moral is just as prevalent from all engineering experience, also.

As a simple and more subtle example, consider the genetics that encodes the mammalian hair protein rope. The hair coat in mammals is used (among other uses) as: (i) a thermoregulatory blanket, (ii) an armoring coat, (iii) a mechanism of crypsis, (iv) a conspecific recognitiion mechanism, (v) a water shedding surface, (vi) an ectoparasite defense mechanism, (vii) as part of an antifungal, antibacterial mechanism, (viii) an auxiliary mechanical structure, (ix) as weaponry, and (x) as a pheromone dispersant. If a change should occur in the code such that a significantly modified protein rope were manufactured, several (or perhaps all) of these attributes would be affected. Although this would be a far milder form of pleiotropy than Gruneberg's example of physiological impairment, it is nonetheless an example of the same code re-appearing in a dozen or so distinctly differently evolved behaviors, and thus of pleiotropy.


EVOLUTIONARY INERTIA AND PLEIOTROPY


Ultimately, however, the effects of pleiotropy on the evolutionary process itself are more subtle and fundamental than merely these simpler effects. Unchecked pleiotropy within a design has extremely deleterious effects on the ability of a complex system to be continuously evolved over time. Indeed, massively pleiotropic systems can't be modified at all – merely because the fitness value of the integral whole would be so degraded by the smallest change. A system that is massively pleiotropic has become a house of cards and has been made extremely sensitive to change (fragile) as a result.

Thus, the discovery of benefits of modularization, in both code and behavior, is thermodynamically inevitable, for both engineers and their coding practices as well as for natural evolutionary processes. Complex systems cannot be evolved to points of high optimality – and then re-evolved yet again under changing circumstances – if pleiotropic effects aren't suppressed to the greatest degree possible.

The corollary to this statement is perhaps somewhat surprising: the minimization of pleiotropic effects through increasing modularizations of code and behavior operates to greatly accelerate the rate at which evolutionary optimizations may be achieved, and therefore work to greatly increase the competitiveness of a phyletic lineage. This single evolutionary advantage of increased speed attendant to the minimization of pleiotropy may underlie the totality of the reason for the existence and initial appearance of distinct organs within multicellular biota, a design schema where such distinctive organs operate as a complex, co-ordinated unit whole, yet remain substantially isolated in their behaviors. Such a design plan seemingly permits the evolution of extremely complex, autopoetic organizations, far more so than would otherwise be allowed, that can be evolved at much higher rates than would otherwise be permitted.


HIERARCHY AND PLEIOTROPY


There is a secondary attribute of all complex systems that guarantees pleiotropic interactions. Pleiotropy is intrinsic to the nature of all hierarchically layered coding structures, even if code segments (genes, microsubroutines) remain unreused. All complex systems that were evolved over time are inevitably hierarchically structured.

Modifications to the root code in such a hierarchy are inherently highly pleiotropic, simply because the basal code has come, through time, to have a great many subprocesses be dependent upon its reliable execution. Any modification to code at the root of the tree shakes the entire dependency tree. The inevitable result is that the system (the phenotype) is moved off of its previous point of optimization and its fitness value significantly degraded.

Terminal modifications (modifications to code and behavior that have no dependencies) are the only portions of code that can be changed without expectations of explicit pleiotropic effects. The only question that remains: can any behavior be truly imagined or designed so that it is absent of all pleiotropic effects, and thus be truly terminal?

Wirt Atmar


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