The theory of facilitated variation
John Gerhart*†and Marc Kirschner‡
*Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; and‡Department of Systems Biology,
Harvard Medical School, Boston, MA 02115
This theory concerns the means by which animals generate phe-
notypic variation from genetic change. Most anatomical and phys-
iological traits that have evolved since the Cambrian are, we
propose, the result of regulatory changes in the usage of various
in development and physiology. Genetic change of the DNA
sequences for regulatory elements of DNA, RNAs, and proteins
leads to heritable regulatory change, which specifies new combi-
nations of core components, operating in new amounts and states
at new times and places in the animal. These new configurations
of components comprise new traits. The number and kinds of
regulatory changes needed for viable phenotypic variation are
determined by the properties of the developmental and physio-
logical processes in which core components serve, in particular by
the processes’ modularity, robustness, adaptability, capacity to
engage in weak regulatory linkage, and exploratory behavior.
These properties reduce the number of regulatory changes needed
to generate viable selectable phenotypic variation, increase the
variety of regulatory targets, reduce the lethality of genetic
change, and increase the amount of genetic variation retained by
a population. By such reductions and increases, the conserved core
processes facilitate the generation of phenotypic variation, which
the population. Thus, we call it a theory of facilitated phenotypic
conserved genes ? phenotypic variation ? physiological adaptability ?
brian times. In the course of their descent from a common
ancestor, animals have diverged in their anatomy and physiology
by the gradual accumulation of selected heritable modifications,
their phenotypic variations. Although such variation is indis-
pensable to evolution, Darwin conceded that ‘‘our ignorance of
the laws of variation is profound’’ (1), and 150 years later the
mode of its generation remains largely unknown. Phenotypic
variation is thought to affect all aspects of an animal’s phenotype
and to be ‘‘copious in amount, small in extent, and undirected’’
with regard to selective conditions (2). Most of these character-
izations go back to Darwin himself. As Gould has noted (2), they
accord well with selection’s primacy as the creative force in
evolution, refining chaotic, profligate variation into exquisite
adaptations. However, they afford little insight into the gener-
copious, small, and undirected variation really is. Although small
in extent, heritable phenotypic variations need be significant
enough to be selected, and, if complex change entails numerous
sequential phenotypic variations, evolution may be impeded. An
example we will pursue later is that of the species of Darwin’s
finches that diverged in the Galapagos from a common ancestor.
The beaks of some species are large and nutcracker-like, and
those of others are small and forceps-like. As Darwin did, we too
might imagine that many small heritable beak variations accrued
slowly in the different species to create large observable differ-
ences. Small variations are arguably the only viable and select-
able ones, because they would allow the upper and lower beaks,
the adjacent skull bones, and head muscles to coevolve with each
other in small selected steps, thereby maintaining viable inter-
e will discuss the means by which animals have generated
developmental and physiological variation since Cam-
mediate beaks along the paths to the nutcracker and forceps
forms. Repeated selections would be needed to coordinate the
numerous, small, independent beak and head changes, all re-
quiring genetic change. Is this an accurate appraisal of the paths
of change? Or might the finch’s own means of beak development
coordinate many changes, allowing larger viable variations and
a simpler, more rapid beak evolution? Insight into the mode of
generation of variation could answer such questions about the
size, abundance, and directedness of phenotypic variations.
Research of the modern era has revealed that heritable
phenotypic variation requires genetic change, that is, DNA
sequence change. Changes occur throughout the genome, al-
though perhaps not at uniform frequency, and include changes
of single bases or short sequences or even long segments of DNA
(3). Some genetic changes are lethal, some are neutral, and fewer
are viable and selectable. Furthermore, the understanding of
variation has advanced with the knowledge that DNA sequences
encode RNA and protein, because the latter two would bear the
marks of DNA sequence change and, in principle, alter the
phenotype. Also, discoveries of gene regulation have opened
the possibility of important evolutionary changes in nontran-
scribed DNA sequences, as well. Still, there are no ‘‘laws of
variation’’ regarding its generation, only a black box of chaotic
accidents entered by genetic variation and occasionally exited by
selectable phenotypic variation.
the development and physiology of animals, namely, about the
generation of their phenotype from their genotype, the kind of
change from genetic change. From these advances, can some-
thing now be said about the nature of phenotypic variation and
its dependence on genetic change? What is really modified in
descent with modification? Have all components of a new trait
been modified a little, or a few elements a lot while others not
at all? Are many genetic changes needed for a modification of
Are there cryptic sources of variation? These questions require
concrete answers that can come only from in-depth studies of the
phenotype, that is, the animal’s development and physiology.
We propose that the phenotype of the organism plays a large
role in (i) providing functional components for phenotypic
variation and (ii) facilitating the generation of phenotypic vari-
ation from genetic change. We outline a set of concepts from
others and ourselves, organized in a theory of facilitated varia-
tion, to connect genetic and phenotypic variation (see ref. 4 for
a longer presentation). Like other theories (5–7), it identifies
regulatory changes as ones particularly important for animal
evolution, but unlike others it also emphasizes the targets of
This paper results from the Arthur M. Sackler Colloquium of the National Academy of
2006, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and
Engineering in Irvine, CA. The complete program is available on the NAS web site at
and wrote the paper.
The authors declare no conflict of interest.
†To whom correspondence should be addressed. E-mail: email@example.com.
© 2007 by The National Academy of Sciences of the USA
May 15, 2007 ?
vol. 104 ?
suppl. 1 www.pnas.org?cgi?doi?10.1073?pnas.0701035104
18. Ferrara N, Gerber HP, Lecouter J (2003) Nat Med 9:669–675.
19. Schmalhausen II (1986) Factors in Evolution: The Theory of Stabilizing Selection
ed Dobzhansky T (Univ of Chicago Press, Chicago).
20. Waddington CH (1953) Evolution (Lawrence, Kans) 7:118–126.
21. Gibson G, Dworkin I (2004) Nat Rev Genet 5:681–691.
22. Halligrimsson B, Hall B, eds (2005) Variation: A Central Concept in Biology
(Elsevier Academic, Burlington, MA).
23. Baldwin JM (1896) Am Nat 30:441–451.
24. Baldwin JM (1902) Development and Evolution (Macmillan, New York).
25. Sharloo W (1991) Annu Rev Ecol Systems 22:65–93.
26. Rutherford SI, Lindquist S (1998) Nature 396:336–342.
27. Wright S (1931) Genetics 16:97–159.
28. Carroll SB (2005) Endless Forms Most Beautiful (Norton, New York).
29. Schlosser G, Wagner G, eds (2004) Modularity in Development and Evolution
(Harvard Univ Press, Cambridge, MA).
30. Kieny M, Manger A, Sengel P (1972) Dev Biol 28:142–161.
31. Lovegrove B, Simoes S, Rivas ML, Sotillos S, Johnson K, Knust E, Jacinto A,
Hombria JC (2006) Curr Biol 16:2206–2216.
32. Csete M, Doyle J (2002) Trends Biotechnol 22:446–450.
33. Abbott AL, Alvarez-Saavedra E, Miska EA, Lau NC, Bartel DP, Horvitz HR,
Ambros V (2005) Dev Cell 9:403–414.
35. Sucena E, Delon I, Jones I, Payre F, Stern DL (2003) Nature 424:935–938.
36. Crickmore MA, Mann RS (2006) Science 313:63–68.
37. Abzhanov A, Protas M, Grant BR, Grant PR, Tabin CJ (2004) Science
38. Abzhanov A, Kuo WP, Hartmann C, Grant BR, Grant PR, Tabin CJ (2006)
39. Albertson RC, Kocher TD (2006) Heredity 97:211–221.
Gerhart and KirschnerPNAS ?
May 15, 2007 ?
vol. 104 ?
suppl. 1 ?