Biology subjects

Palme, J.

Publications and source records attributed to Palme, J..

3 recordsLinked to original sources

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

Learning The High-Dimensional Immunogenomic Features That Predict Public And Private Antibody Repertoires

Recent studies have revealed that immune repertoires contain a substantial fraction of public clones, which are defined as antibody or T-cell receptor (TCR) clonal sequences shared across individuals. As of yet, it has remained unclear whether public clones possess predictable sequence features that separate them from private clones, which are believed to be generated largely stochastically. This knowledge gap represents a lack of insight into the shaping of immune repertoire diversity. Leveraging a machine learning approach capable of capturing the high-dimensional compositional information of each clonal sequence (defined by the complementarity determining region 3, CDR3), we detected predictive public- and private-clone-specific immunogenomic differences concentrated in the CDR3s N1-D-N2 region, which allowed the prediction of public and private status with 80% accuracy in both humans and mice. Our results unexpectedly demonstrate that not only public but also private clones possess predictable high-dimensional immunogenomic features. Our support vector machine model could be trained effectively on large published datasets (3 million clonal sequences) and was sufficiently robust for public clone prediction across studies prepared with different library preparation and high-throughput sequencing protocols. In summary, we have uncovered the existence of high-dimensional immunogenomic rules that shape immune repertoire diversity in a predictable fashion. Our approach may pave the way towards the construction of a comprehensive atlas of public clones in immune repertoires, which may have applications in rational vaccine design and immunotherapeutics.

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↗