Masel, J. G. | bioRxiv Science

bioRxiv2019

Biomarkers for aging identified in cross-sectional studies tend to be non-causative

Biomarkers are important tools for diagnosis, prognosis, and identification of the causal factors of physiological conditions. Biomarkers are typically identified by correlating biological measurements with the status of a condition in a sample of subjects. Cross-sectional studies sample subjects at a single timepoint, while longitudinal studies follow a cohort through time. Identifying biomarkers of aging is subject to unique challenges. Individuals who age faster have intrinsically higher mortality rates and so are preferentially lost over time, in a phenomenon known as cohort selection. In this paper, we use simulations to show that cohort selection biases cross-sectional analysis away from identifying causal loci of aging, to the point where cross-sectional studies are less likely to identify loci that cause aging than if loci had been chosen at random. We go on to show this bias can be corrected by incorporating correlates of mortality identified from longitudinal studies, allowing cross sectional studies to effectively identify the causal factors of aging.

bioinformatics↗

bioRxiv2017

Evolutionary capacitance emerges spontaneously during adaptation to environmental changes

All biological populations are to a greater or lesser degree evolvable, but the forces that shape evolvability, especially the evolution of evolvability as an adaptive response to a changing environment, have been a source of controversy. One source of enhanced evolvability is the benign status of \"cryptic sequences\" typically expressed at low levels due to molecular errors, but with the potential to be expressed more fully following mutational co-option. A genome enriched for benign cryptic sequences has a more benign mutational neighborhood, via the possibility of co-option, and thus enhanced evolvability. Whether selection for evolvability itself can be the cause of a more benign mutational neighborhood remains an open question. Here, we show that environmental change can cause the evolution of increased evolvability, despite our use of a strong-selection weak mutation regime that precludes, by design, the adaptive evolution of evolvability. Instead, enhanced evolvability arises as a byproduct of environmental change via a novel mechanism that we call \"emergent evolutionary capacitance\". When the environment changes, increased molecular error rates evolve as a strategy to rapidly change phenotypes, with the side effect of purging deleterious cryptic sequences and enhancing the mutational neighborhood for future adaptation. The behavior is strikingly similar to that seen in a model system for capacitance, the yeast prion [PSI+].

evolutionary biology↗