Systems mapping has potential to overcome inherent problems of genetic mapping: Comment on “Mapping complex traits as a dynamic system” by L. Sun and R. Wu

Abstract

The development of a zygote into an adult organism has puzzled scientists for a long time. The degree to which developmental processes are subject to genetic control – i.e., the degree to which adult traits are heritable – has been estimated by quantitative geneticists since the early 20th century [9]. Only in the second half of the 20th century, after the discovery of the structure of the DNA, the molecular mechanisms of inheritance have begun to be understood. The development of effective techniques for screening DNA polymorphisms allowed for statistical studies of the association of quantitative traits with genetic markers [8]. Since then, a suite of quantitative methods has been established for investigating statistical genotype–phenotype associations, which have been applied extensively in medical contexts as well [2,3,10]. Simultaneously, and largely independently from these developments, mathematical approaches have been devised to model the interaction of molecular components, such as enzyme kinetics, within and across cells. The field of systems biology attempts to model the mechanistic relationships between a multitude of molecular components in the developing and adult organism [7,14]. The relatively new concept of systems mapping [4,5,15], excellently reviewed by Sun and Wu [13], builds a bride between these two – hitherto largely unconnected – traditions in the biosciences and offers potential for the merging of different lines of empirical and theoretical evidence. At the core of systems mapping is a set of ordinary differential equations (ODEs) that describe the dynamics of a biological system. Sun and Wu present multiple examples of such systems, including growth rates in plants, pharmacodynamic reactions, and phenotype landscapes. The individual parameters of the ODEs are then used as variables for the genetic mapping. One inherent and often neglected ambiguity of classic genetic mappings is their dependence on the scale of the variables. For instance, the effect of an allele on a given quantitative trait might comprise both additive and non-additive (dominance) components. But under certain non-linear transformations of the phenotypic variable (such as raising it to some power or applying a log transform), the effect might change to a purely additive one, without a dominance