Biology subjects

Springer, M.

Publications and source records attributed to Springer, M..

5 recordsLinked to original sources

bioRxiv2017

Assigning Function To Natural Allelic Variation Via Dynamic Modeling Of Gene Network Induction

More and more natural DNA variants are being linked to physiological traits. Yet, understanding what differences they make on molecular regulations remains challenging. Important properties of gene regulatory networks can be captured by computational models. If model parameters can be personalized according to the genotype, their variation may then reveal how DNA variants operate in the network. Here, we combined experiments and computations to visualize natural alleles of the yeast GAL3 gene in a space of model parameters describing the galactose response network. Alleles altering the activation of Gal3p by galactose were discriminated from those affecting its activity (production/degradation or efficiency of the activated protein). The approach allowed us to correctly predict that a non-synonymous SNP would change the binding affinity of Gal3p with the Gal80p transcriptional repressor. Our results illustrate how personalizing gene regulatory models can be used for the mechanistic interpretation of genetic variants.

systems biology↗

bioRxiv2017

Natural Genetic Variation Can Independently Tune The Induced Fraction And Induction Level Of A Bimodal Signaling Response

Bimodal gene expression by genetically identical cells is a pervasive feature of signaling networks. In the galactose-utilization (GAL) pathway of Saccharomyces cerevisiae, induction can be unimodal or bimodal depending on natural genetic variation and pre-induction conditions. Here, we find that this variation of modality is regulated by an interplay between two features of the pathway response, the fraction of cells that are in the induced subpopulation and their expression level. Combined, the variations in these features are sufficient to explain the observed effects of natural variation and pre-induction conditions on the modality of induction in both mechanistic and phenomenological models. Both natural variation and pre-induction conditions act by modulating the expression and function of the galactose sensor GAL3. The ability to alter modality may allow organisms to adapt their level of "bet hedging" to the conditions they experience, and thus help optimize fitness in complex, fluctuating natural environments.

genetics↗

bioRxiv2017

Small effect-size mutations cumulatively affect yeast quantitative traits

SummaryQuantitative traits are influenced by pathways that have traditionally been defined through genes that have a large loss- or gain-of-function effect. However, in theory, a large number of small effect-size genes could cumulative play a substantial role in pathway function, potentially by acting as \"modifiers\" that tune the levels of large effect size pathway components. To understand the role of these small effect-size genes, we used a quantitative assay to determine the number, strength, and identity of all non-essential genes that affect two galactose-responsive (GAL) traits, in addition to re-analyzing two previously screened quantitative traits. Over a quarter of assayed genes have a detectable effect; approximately two thirds of the quantitative trait variation comes from small effect-size genes. The functions of small effect-size genes are partially overlapping between traits and are enriched in core cellular processes. This implies that genetic variation in one process has the potential to influence behavior or disease in seemingly unconnected processes.\n\nHighlightsO_LIFour yeast quantitative traits are affected by thousands of small effect-size genes.\nC_LIO_LISmall effect-size genes are enriched in core cellular processes\nC_LIO_LIThe effects of these genes are quantitative trait-specific.\nC_LI

systems biology↗

bioRxiv2017

Polymorphisms In The Yeast Galactose Sensor Underlie A Natural Continuum Of Nutrient-Decision Phenotypes

In nature, microbes often need to \"decide\" which of several available nutrients to utilize, a choice that depends on a cells inherent preference and external nutrient levels. While natural environments can have mixtures of different nutrients, phenotypic variation in microbes decisions of which nutrient to utilize is poorly studied. Here, we quantified differences in the concentration of glucose and galactose required to induce galactose-responsive (GAL) genes across 36 wild S. cerevisiae strains. Using bulk segregant analysis, we found that a locus containing the galactose sensor GAL3 was associated with differences in GAL signaling in eight different crosses. Using allele replacements, we confirmed that GAL3 is the major driver of GAL induction variation, and that GAL3 allelic variation alone can explain as much as 90% of the variation in GAL induction in a cross. The GAL3 variants we found modulate the diauxic lag, a selectable trait. These results suggest that ecological constraints on the galactose pathway may have led to variation in a single protein, allowing cells to quantitatively tune their response to nutrient changes in the environment.\n\nAuthor summaryIn nature, microbes often need to decide which of many potential nutrients to consume. This decision making process is complex, involving both intracellular constraints and the organisms perception of the environment. To begin to mimic the complexity of natural environments, we grew cells in mixtures of two sugars, glucose and galactose. We find that in mixed environments, the sugar concentration at which cells decides to induce galactose-utilizing (GAL) genes is highly variable in natural isolates of yeast. By analyzing crosses of phenotypically different strains, we identified a locus containing the galactose sensor, a gene that in theory could allow cells to tune their perception of the environment. We confirmed that the galactose sensor can explain upwards of 90% of the variation in the decision to induce GAL genes. Finally, we show that the variation in the galactose sensor can modulate the time required for cells to switch from utilizing glucose to galactose. Our results suggest that signaling pathways can be highly variable across strains and thereby might allow for rapid adaption in fluctuating environments.

genetics↗

bioRxiv2016

Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades

Mitochondrial uncoupling protein 1 (UCP1) is essential for non-shivering thermogenesis in brown adipose tissue and is widely accepted to have played a key thermoregulatory role in small-bodied and neonatal placental mammals that enabled the exploitation of cold environments. Here we map ucp1 sequences from 133 mammals onto a species tree constructed from a [~]51-kb sequence alignment and show that inactivating mutations have occurred in at least eight of the 18 traditional placental orders, thereby challenging the physiological importance of UCP1 across Placentalia. Selection and timetree analyses further reveal that ucp1 inactivations temporally correspond with strong secondary reductions in metabolic intensity in xenarthrans and pangolins, or in six other lineages coincided with a [~]30 million year episode of global cooling in the Paleogene that promoted sharp increases in body mass and cladogenesis evident in the fossil record. Our findings also demonstrate that members of various lineages (e.g., cetaceans, horses, woolly mammoths, Stellers sea cows) evolved extreme cold hardiness in the absence of UCP1-mediated thermogenesis. Finally, we identify ucp1 inactivation as a historical contingency that is linked to the current low species diversity of clades lacking functional UCP1, thus providing the first evidence for species selection related to the presence or absence of a single gene product.

evolutionary biology↗