Discerning mechanistically rewired biological pathways by cumulative interaction heterogeneity statistics.
Changes in response of a biological pathway could be a consequence of either pathway rewiring, changed input, or a combination of both. Most pathway analysis methods are not designed for mechanistic rewiring such as regulatory element variations. This limits our understanding of biological pathway evolution. Here we present a Q-method to discern whether changed pathway response is caused by mechanistic rewiring of pathways due to evolution. The main innovation is a cumulative pathway interaction heterogeneity statistic accounting for rewiring-specific effects on the rate of change of each molecular variable across conditions. The Q-method remarkably outperformed differential-correlation based approaches on data from diverse biological processes. Strikingly, it also worked well in differentiating rewired chaotic systems, whose dynamics are notoriously difficult to predict. Applying the Q-method on transcriptome data of four yeasts, we show that pathway interaction heterogeneity for known metabolic and signaling pathways is indeed a predictor of interspecies genetic rewiring due to unbalanced TATA box-containing genes among the yeasts. The demonstrated effectiveness of the Q-method paves the way to understanding network evolution at the resolution of functional biological pathways.
Department of Computer Science, New Mexico State University, NM 88003, Las Cruces, USA.
Travis B
TB
Cotton
Department of Computer Science, New Mexico State University, NM 88003, Las Cruces, USA.
Hien H
HH
Nguyen
Department of Plant and Environmental Sciences, New Mexico State University, NM 88003, Las Cruces, USA.
Joseph I
JI
Said
Department of Computer Science, New Mexico State University, NM 88003, Las Cruces, USA.
Zhengyu
Z
Ouyang
Department of Plant and Environmental Sciences, New Mexico State University, NM 88003, Las Cruces, USA.
Jinfa
J
Zhang
Department of Computer Science, New Mexico State University, NM 88003, Las Cruces, USA.
Mingzhou
M
Song
D005075:Biological Evolution; D053263:Gene Regulatory Networks / Q000235:genetics*; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D016385:TATA Box / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*; D015003:Yeasts / Q000235:genetics*