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The pleiotropic structure of the genotype–phenotype map: the evolvability of complex organisms

Key Points

  • Pleiotropy refers to the phenomenon of one gene or one mutation affecting multiple phenotypic traits. It has widespread implications in genetics, disease, development, ageing and evolution.

  • Although the definition of pleiotropy is straightforward, its measurement is not. This is due to many complicating factors, including the way in which traits are defined, interdependence among traits, the traits chosen for examination and the power of detecting an effect.

  • Despite the aforementioned difficulties, pleiotropy has been measured recently by mapping the QTLs underlying certain groups of traits and by phenotyping gene knockout or knockdown mutants of model organisms.

  • Contrary to the idea of universal pleiotropy, empirical data consistently suggest that the median degree of pleiotropy for QTLs or genes is only a few per cent of the total number of traits scored.

  • The pleiotropic structure of the genotype–phenotype map is strongly modular, meaning that sets of traits are co-controlled by sets of genes in a highly nonrandom manner.

  • In contrast to current theoretical models of pleiotropy, empirical data show that the average phenotypic effect of a mutation on a trait increases with the number of traits that are affected by the mutation.

  • Consideration of the empirical patterns of pleiotropy resolves the 'cost of complexity' conundrum, which asserts that complex organisms are less adaptable than simple ones as a result of the constraints that are imposed by pleiotropy.

  • The idea of the cost of complexity may be better phrased as the 'cost of pleiotropy', because the degree of pleiotropy per mutation is substantially lower than the number of traits (that is, complexity) in an organism.

  • Pleiotropy may be conferred by multiple molecular functions of a gene (type I pleiotropy) or multiple morphological and physiological consequences of a single molecular function (type II pleiotropy). Empirical data support the idea that pleiotropy is largely of type II.

  • The predominance of type II pleiotropy suggests that developing drugs that target only one particular phenotypic effect of a pleiotropic gene may be difficult.


It was first noticed 100 years ago that mutations tend to affect more than one phenotypic characteristic, a phenomenon that was called 'pleiotropy'. Because pleiotropy was found so frequently, the notion arose that pleiotropy is 'universal'. However, quantitative estimates of pleiotropy have not been available until recently. These estimates show that pleiotropy is highly restricted and are more in line with the notion of variational modularity than with universal pleiotropy. This finding has major implications for the evolvability of complex organisms and the mapping of disease-causing mutations.

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Figure 1: Possible causes of co-inheritance of phenotypic traits.
Figure 2: The degree of pleiotropy depends on the definition of phenotypic traits.
Figure 3: Distribution of the degree of pleiotropy.


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Research in the Wagner laboratory is supported by the John Templeton Foundation (grant number 12793). Pleiotropy research in the Zhang laboratory has been supported by the US National Institutes of Health.

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Genetic load

The difference between the mean fitness of the population and the fitness of the fittest genotype in the population. The more deleterious the mutations in a population, the lower the mean fitness and the higher the genetic load.

Effective population size

(Ne). A measure of the strength of random genetic drift in a population. The lower the effective population size, the stronger the genetic drift. Ne is influenced by the census population size, the breeding system, the fitness differences among individuals, the sex ratio and other factors.


A characteristic parameter of a matrix. In the case of co-variance matrices, the eigenvalues are equal to the amount of variance that is associated with the principal components of the co-variance matrix.

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Wagner, G., Zhang, J. The pleiotropic structure of the genotype–phenotype map: the evolvability of complex organisms. Nat Rev Genet 12, 204–213 (2011).

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