EVOLUTION & DEVELOPMENT

2:5, 238–240 (2000)

©

BLACKWELL SCIENCE, INC.

238

What constitutes a ‘large’ mutational change in phenotype?

Bryan Clarke,

a

and Wallace Arthur

b,*

a

Department of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK;

b

Ecology Centre, School of Sciences, University of Sunderland, Sunderland SR1 3SD, UK

*Author for correspondence (email: wallace.arthur@sunderland.ac.uk)

INTRODUCTION

Mutational effects on the phenotype range widely in magni-tude. Despite the widespread use of the convenient labels“micromutation” and “macromutation,” neither is a clear-cutcategory; rather, there is a continuum from one extreme to theother. The evolutionary relevance of this continuum is of con-siderable interest. A key question is: What is the frequencydistribution of mutational effects on the phenotype amongthe allelic fixations that occur during evolutionary change?

MODELS AND MEASURES

Fisher’s (1930) argument, based on an abstract geometricalanalogy, was that the bigger the phenotypic effect of a muta-tion, the lower its probability of being selectively advanta-geous. Kimura (1983) refined this picture by investigatingthe probability of fixation. He noted that among mutationswith advantageous effects those where the advantage wassmall would have a greater chance of being lost throughdrift. He therefore envisaged a skewed distribution, with thelikelihood of contributing to evolutionary change first risingsteeply, then falling more slowly, as the magnitude of effecton the phenotype increases. Recently, Orr (1998) extendedthe scope of Kimura’s model to consider the sequence ofsteps occurring as an adaptive optimum is approached. Heconcluded that the shape of the distribution envisaged byKimura remains the same, but reduces in scale, as the differ-ence between actual and optimum phenotypes declines.

We suspect that this picture of mutations with relativelysmall effects being the predominant, but not exclusive, contrib-utors to evolutionary change is broadly correct. However, theapproaches taken by Orr (1998) and his predecessors presentdifficulties because of their use of a very general and abstractconcept of “magnitude” of phenotypic change. Here, we ques-tion whether this magnitude can be measured, and argue that a

less abstract approach, including reference to different types ofmutational effects on the phenotype, should be considered.

The method used by Fisher (1930), Kimura (1983), andOrr (1998) is to start with standard physical units of mea-surement (e.g., cm for body size), and to relate a mutant in-fluencing these to the distance from the adaptive optimum(

d

) and the number of independent (“orthogonal”) pheno-typic dimensions (

n

) which the mutation may alter (see Orr2000). So the standardized measure of the magnitude of aphenotypic change becomes , where

r

is the ini-tial “raw” value. Since

r

and

d

have the same units, the stan-dardized measure is unit-free. Importantly, many of the pre-dictions of theoretical work on this issue are based on valuesof

x

, yet in practice

x

is never truly measurable.

EXAMPLES: BODY SIZE CHANGES, CHIRALITY REVERSALS

Let us consider first a relatively simple example: changes inbody size in a directly developing animal such as a mammal.Here,

r

is measurable, and

d

at least may be measurable,though there need not necessarily be a single adaptive opti-mum. The problem in this case is that there is no way to mea-sure

n

, the number of independent phenotypic dimensions inwhich a gene influencing body size may act. Indeed, it willbe necessary to know much more about the genetics of de-velopment before patterns of independence and non-inde-pendence among different characters are known in enoughdetail to come up with a figure for

n

for any specific case.However, some of the theoretical predictions are indepen-dent of

n

, and may perhaps be valid in this unusually simpleexample. The quantitative trait loci (QTLs) responsible forthe typical normal distribution of variation in body size prob-ably provide most or all of the mutational basis for evolu-tionary changes. Large-effect mutations producing dwarf orgiant phenotypes are usually detrimental. However, the pat-

x r n d⁄=

Clarke and Arthur

Mutational change in phenotype

239

tern within QTLs remains undetermined, and is of great in-terest because it is now clear that QTLs are more heteroge-neous than had been supposed (Doebley and Stec 1991).

We now turn to a more complex example: switches inleft–right asymmetry. These have been particularly wellstudied from an evolutionary perspective in gastropods. Re-versals of chirality from dextral to sinistral and vice versahave occurred relatively often during gastropod evolution.Robertson’s (1993) broad taxonomic survey shows many su-perfamilies with both sinistral and dextral species, and sug-gests that switches in chirality have occurred several hun-dred times. But although such switches are thus relativelycommon in gastropod evolution, they happen in only a smallminority of speciation events in this group, given that theGastropoda includes more than 50,000 species, the great ma-jority of which are dextral. The genetic basis of chiralityswitches has been determined from three species that haveintraspecific variation in this character:

Lymnaea peregra

(Boycott and Diver 1923, Sturtevant 1923, Freeman andLundelius 1982),

Laciniaria biplicata

(Degner 1952), and

Partula suturalis

(Murray and Clarke 1966; see also reviewby Johnson et al. 1993). In each case, a single locus with amaternal effect is involved, though the dominance of thegene for dextrality or sinistrality varies between species.

Are switches in chirality “large” or “small” phenotypicchanges? Here, the difficulties in a generalized notion of “mag-nitude” become conspicuous. None of the parameters used inOrr’s (1998) model can be measured. In some respects, a switchin chirality is a very large change. The positions of many struc-tures, including the aperture of the shell, the anus, and the respi-ratory and reproductive openings, have all been shifted to theopposite side of the animal. However, a single small shift in thepattern of cell proliferation – the orientation of the first cleavagein the egg – is sufficient to produce all the subsequent larger-scale changes. So, classification by origin or by consequencesresults in opposite conclusions. Also, while changes of coilmay affect mating success in mixed populations, pure popula-tions of dextrals or sinistrals seem equally able to survive.

One thing that must be avoided here (as elsewhere) is a cir-cular argument. If the aim is to predict, through models or oth-erwise, the probability of mutational effects on the phenotypebeing selectively advantageous from considerations of theirmagnitude, then while the measure of magnitude used may in-clude such features as numbers of cells whose fate is altered,it must clearly exclude fitness. There is a weakness in Orr’s(1998) approach when he states: “A large mutation . . . issimply one that has a small chance of being favorable and asmall mutation one that has a greater chance of being favor-able. . . . No other usage seems particularly meaningful.”

In relation to this point, it is instructive to consider the rel-ative frequency of reversals in left–right asymmetry in gas-tropods and mammals. As already noted, such reversals havebeen common in gastropod evolution. In contrast, mammals

are very uniform both within and among species in the hand-edness of their internal organs (Brown et al. 1991). Althoughoccasional reversals are known in isolated individuals (“

situsinversus”

), we are not aware of any cases of such reversalsaccompanying mammalian speciation.

What is the reason for this contrast between gastropodsand mammals? Can it be predicted from considerations ofmagnitude? We think not. Both taxa have extensive left–right asymmetry of multiple structures superimposed on a bi-laterally-symmetrical body plan. In gastropods, the asymme-try appears more extensive, as it involves both internal andexternal structures, and has an effect on reproductive com-patibility (Asami et al. 1998), which its mammalian equiv-alent does not. Such considerations should lead to a pre-diction that chirality switches are rarer in gastropods thanmammals—the reverse of what is observed. Given this situ-ation, we conclude that it is necessary to know more aboutthe developmental processes involved in both systems be-fore making progress in understanding their evolution. Arbi-trarily labeling the mammalian switches as “larger” simplybecause they contribute less often (if at all) to evolution doesnot help.

TYPE VERSUS MAGNITUDE OF EFFECT

All this argues that evolutionary biologists need to take ac-count of types, as well as magnitudes, of mutational effectson the phenotype. The point has been well made by Dawkins(1986), who distinguishes between two types of macromuta-tions: “stretched DC8” mutations which cause a large elon-gation (or other scale change) of an existing design, and “747mutations” which in one step create an entirely new design.Although both are large in some respects, the former type ofmutation is more likely to contribute to evolutionary changethan the latter. Increases in segment number in centipedes pro-vide a good example of the stretched DC8 (Arthur and Farrow1999). Homeotic mutations of

Drosophila

, which appear not tocontribute to evolution (Akam 1998) despite earlier claims tothe contrary (Goldschmidt 1952, Whiting and Wheeler 1994),exemplify the 747, or at least a step in that direction.

These thoughts on types of effect are themselves rather ab-stract, however, and little can be gained by moving from an ab-stract concept of magnitude to an equally abstract concept oftype. To make progress, it will be necessary to develop a de-tailed classification of types of mutational effect on develop-ment—that is, a classification of types of “developmental re-programming.” So far, only rather broad classifications havebeen attempted, e.g., the split between heterochrony, hetero-topy, heterotypy, and heterometry (Arthur 2000), which can beapplied at any level from gene expression patterns to large-scalephenotypic changes. A more refined version of such classifica-

240 EVOLUTION & DEVELOPMENT

Vol. 2, No. 5, September–October 2000

tions is an obvious goal for future work, and will help to com-bine ongoing empirical findings produced through evo-devocase-studies with general evolutionary theories.

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