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Emerging concepts in developmental biology, such as facilitated variation and dynamical patterning modules, address a major shortcoming of the Modern Synthesis in Biology: how genotypic variation is transduced into functional yet diverse phenotypic variation. Still, we lack a theory to explain how variation at the cellular and tissue level is coordinated into variation at the whole-organism level, especially as priority of cellular and tissue functions change over an individual’s lifetime and are influenced by environmental variation. Here, we propose that interactions among a limited subset of physiological factors that we call, integrators, regulate most phenotypic variation at the organismal level. Integrators are unique among physiological factors in that they have the propensity to coordinate the expression of conserved gene modules of most types of tissues because they participate as nodes in a hierarchical network. In other words, integrator networks impose physiological epistasis, meaning that whole-organism phenotypic responses will be influenced by previous experiences, current environmental conditions, and fitness priorities as encoded by individual integrators. Below, we provide examples of how integrator networks are responsible for both profound and irreversible phenotypic changes (i.e., metamorphosis, sexual differentiation) as well as subtler, transient (e.g., pelage color, seasonal fluctuations in lymphoid and reproductive tissues) variation. The goal of this article is not to describe completely how integrator networks function, but to stimulate discussion about the role of physiology in linking genetic to phenotypic variation. To generate useful data sets for understanding integrator networks and to inform whole-organism physiology generally, we describe several useful tools including vector-field editing, response-surface regression, and experiments of life-table responses. We then close by highlighting some implications of integrator networks for conservation and biomedicine. [ABSTRACT FROM AUTHOR]

Abstract: Aquatic nitrate contamination has escalated over the past 50 years, primarily due to intensified fertilizer application and sewage production worldwide. Nitrate''s role in the decline of amphibian populations remains unclear, although studies suggest that nitrate exposure affects larval development. We exposed Bufo terrestris tadpoles to environmentally relevant nitrate concentrations from Gosner stage 25 through forelimb emergence. Tadpoles were exposed to fluctuating (0–30mg/L NO3-N, alternated three times per week) or constant nitrate concentrations (0, 5, 15, or 30mg/L NO3-N), and effects were compared in two water types: natural spring water and reverse-osmosis filtered water, fortified with electrolytes (ROe). We measured growth and developmental rates, survival, time to metamorphosis, metamorph body size, hepatosomatic index, and whole-body thyroxine (T4) concentrations at forelimb emergence. Based on our observations, we reached three main conclusions: (1) in constant nitrate, tadpoles in ROe water grew faster, and were generally larger with higher or similar T4 at metamorphosis than tadpoles raised in spring water, irrespective of nitrate concentration, (2) in fluctuating nitrate (flux), there were no differences in time to or size at metamorphosis in either water type relative to controls; however, mean T4 concentrations in the flux treatment showed a reversed pattern in the two water types (SP>ROe) compared to the general pattern observed with constant nitrate exposure (ROe >SP), and (3) the effect of nitrate on growth and development depended on water type. In ROe water with high nitrate (ROe-30mg/L NO3-N), tadpoles metamorphosed an average of 5 days (13%) earlier than control animals, but were similar in size to controls. However, spring water tadpoles reared in high nitrate (30mg/L) delayed metamorphosis by 7 days (18%) compared to animals reared in SP-0, and 11 days (32%) compared to tadpoles raised in ROe-30. This delayed development allowed SP-30 tadpoles to reach a larger size that was more similar to metamorphs raised in ROe water. Based on information from other studies, we conclude that, in ROe water, tadpoles exhibited an expected stress response to nitrate (e.g. metamorphosed earlier as nitrate concentration increased). However, we suggest that, in spring water, tadpoles were exposed to additional stressors that decreased growth rate and thyroxine concentrations, and that this effect was modified by nitrate. [Copyright &y& Elsevier]