Biology Faculty Research

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    Molecular basis of product recognition during PIP5K-mediated production of PI(4,5)P2 with positive feedback
    (Journal of Biological Chemistry, 2024-08-03) Duewell, Benjamin R.; Faris, Katherine A.; Hansen, Scott D.
    The ability for cells to localize and activate peripheral membrane-binding proteins is critical for signal transduction. Ubiquitously important in these signaling processes are phosphatidylinositol phosphate (PIP) lipids, which are dynamically phosphorylated by PIP lipid kinases on intracellular membranes. Functioning primarily at the plasma membrane, phosphatidylinositol-4-phosphate 5-kinases (PIP5K) catalyzes the phosphorylation of PI(4)P to generate most of the PI(4,5)P2 lipids found in eukaryotic plasma membranes. Recently, we determined that PIP5K displays a positive feedback loop based on membrane-mediated dimerization and cooperative binding to its product, PI(4,5)P2. Here, we examine how two motifs contribute to PI(4,5)P2 recognition to control membrane association and catalysis of PIP5K. Using a combination of single molecule TIRF microscopy and kinetic analysis of PI(4)P lipid phosphorylation, we map the sequence of steps that allow PIP5K to cooperatively engage PI(4,5)P2. We find that the specificity loop regulates the rate of PIP5K membrane association and helps orient the kinase to more effectively bind PI(4,5)P2 lipids. After correctly orienting on the membrane, PIP5K transitions to binding PI(4,5)P2 lipids near the active site through a motif previously referred to as the substrate or PIP-binding motif (PIPBM). The PIPBM has broad specificity for anionic lipids and serves a role in regulating membrane association in vitro and in vivo. Overall, our data supports a two-step membrane-binding model where the specificity loop and PIPBM act in concert to help PIP5K orient and productively engage anionic lipids to drive the positive feedback during PI(4,5)P2 production.
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    The influence of explicit local dynamics on range expansions driven by long-range dispersal
    (bioRxiv, 2023-02-23) Villiger, Nathan; Paulose, Jayson
    Range expansions are common in natural populations. They can take such forms as an invasive species spreading into a new habitat or a virus spreading from host to host during a pandemic. When the expanding species is capable of dispersing offspring over long distances, population growth is driven by rare but consequential long-range dispersal events that seed satellite colonies far from the densely occupied core of the population. These satellites accelerate growth by accessing unoccupied territory, and also act as reservoirs for maintaining neutral genetic variation present in the originating population, which would ordinarily be lost to drift. Prior theoretical studies of dispersal-driven expansions have shown that the sequential establishment of satellites causes initial genetic diversity to be either lost or maintained to a level determined by the breadth of the distribution of dispersal distances. If the tail of the distribution falls off faster than a critical threshold, diversity is steadily eroded over time; by contrast, broader distributions with a slower falloff allow some initial diversity to be maintained for arbitrarily long times. However, these studies used lattice-based models and assumed an instantaneous saturation of the local carrying capacity after the arrival of a founder. Real-world populations expand in continuous space with complex local dynamics, which potentially allow multiple pioneers to arrive and establish within the same local region. Here, we evaluate the impact of local dynamics on the population growth and the evolution of neutral diversity using a computational model of range expansions with long-range dispersal in continuous space, with explicit local dynamics that can be controlled by altering the mix of local and long-range dispersal events. We found that many qualitative features of population growth and neutral genetic diversity observed in lattice-based models are preserved under more complex local dynamics, but quantitative aspects such as the rate of population growth, the level of maintained diversity, and the rate of decay of diversity all depend strongly on the local dynamics. Besides identifying situations in which modeling the explicit local population dynamics becomes necessary to understand the population structure of jump-driven range expansions, our results show that local dynamics affects different features of the population in distinct ways, and can be more or less consequential depending on the degree and form of long-range dispersal as well as the scale at which the population structure is measured.
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    Trait biases in microbial reference genomes
    (Nature Communications, 2023) Albright, Sage; Louca, Stilianos
    Common culturing techniques and priorities bias our discovery towards specific traits that may not be representative of microbial diversity in nature. So far, these biases have not been systematically examined. To address this gap, here we use 116,884 publicly available metagenome-assembled genomes (MAGs, completeness ≥80%) from 203 surveys worldwide as a culture-independent sample of bacterial and archaeal diversity, and compare these MAGs to the popular RefSeq genome database, which heavily relies on cultures. We compare the distribution of 12,454 KEGG gene orthologs (used as trait proxies) in the MAGs and RefSeq genomes, while controlling for environment type (ocean, soil, lake, bioreactor, human, and other animals). Using statistical modeling, we then determine the conditional probabilities that a species is represented in RefSeq depending on its genetic repertoire. We find that the majority of examined genes are significantly biased for or against in RefSeq. Our systematic estimates of gene prevalences across bacteria and archaea in nature and gene-specific biases in reference genomes constitutes a resource for addressing these issues in the future.
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    A generic hierarchical model of organic matter degradation and preservation in aquatic systems
    (Nature Communications, 2023-01) Shang, Haitao
    Organic matter degradation and preservation are crucial components of Earth’s carbon cycle. Empirical and phenomenological models usually contain parameters determined by site-specific data and focus on different aspects of the decay and accretion characteristics. To investigate more fundamental mechanisms, this study suggests a hierarchical model that links microscopic physical quantities to macroscopic degradation and preservation patterns. This mechanistic model predicts several commonly observed phenomena, including the lognormal distribution of degradation rate constants, the recalcitrance-dependent sensitivity to temperature, the dependence of a heterogeneous organic-matter system’s persistence on its complexity, logarithmic-time decay, and power-law degradation behavior. The theoretical predictions of this model are consistent with the observational data from marine and lake environments. This hierarchical model may provide a step towards a fundamental theory of organic matter degradation and preservation in aquatic and other ecosystems.
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    Epitope tag-specific differences in the detection of COSA-1 marked crossover sites in C. elegans spermatocytes
    (Caltech Library, 2023-01-06) Cahoon, Cori K.; Uebel, Celja J.; Villeneuve, Anne M.; Libuda, Diana E.
    Nascent crossover sites in C. elegans meiocytes can be cytologically detected using epitope-tagged versions of the pro-crossover protein COSA-1. In spermatocytes, differences exist between cytologically-detected and genetically-detected double crossover rates. Here, we examine nascent crossovers using both GFP- and OLLAS-tagged COSA-1. Similar to previous work, we find that most late pachytene spermatocytes display 5 COSA-1 foci, indicating one crossover per autosome bivalent. However, we detected more nuclei with >5 COSA-1 foci using OLLAS::COSA-1, reflecting some bivalents having 2 COSA-1 foci. These results demonstrate tag-specific differences in the detection of COSA-1 marked nascent crossovers in spermatocytes.
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    Observational Evidence and Open Questions on the Role of Internal Tidal Waves on the Concentration and Transport of Floating Plastic Debris
    (Frontiers Media, 2021-06-01) Shanks, Alan
    Tidal currents flowing over benthic relief (e.g., banks, shelf break) can produce large internal waves. These waves propagate away from their origin and are capable of crossing the continental shelf and seas. Studies of shoreward transport of larval invertebrates and fish by these internal waves unintentionally tested whether they can capture, concentrate and transport floating plastic. Plastic surface drifters deployed in front of sets of internal wave convergences were often captured (>90% captured) and transported kilometers by the waves. There are, however, few investigations into how internal tidal waves may affect the fate and distribution of floating plastic waste. A number of areas of future research are suggested: (1) How much floating plastic is found in internal wave convergences? (2) How buoyant must floating plastic be to be captured by internal waves? (3) Why did only some sets of internal waves cause concentration and transport of surface material? (4) Do concentration and transport of floating plastic vary over the spring/neap tidal cycle? (5) Do seasonal changes in the depth of the pycnocline alter the transport of floating plastic by internal waves? (6) Plastic debris deposited on shore may not be evenly distributed, but may be more abundant landward of sites on the shelf break that more readily generate large internal waves. (7) Internal waves that travel long distances (10–100 s of km) have the potential to accumulate large amounts of plastic debris. (8) At locations where internal waves cross the continental shelf, how far offshore does transport commence?
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    Excess crossovers impede faithful meiotic chromosome segregation in C. elegans
    (Public Library of Science, 2020-09-04) Hollis, Jeremy A.; Glover, Marissa L.; Schlientz, Aleesa J.; Cahoon, Cori K.; Bowerman, Bruce; Wignall, Sarah M.; Libuda, Diana E.
    During meiosis, diploid organisms reduce their chromosome number by half to generate haploid gametes. This process depends on the repair of double strand DNA breaks as crossover recombination events between homologous chromosomes, which hold homologs together to ensure their proper segregation to opposite spindle poles during the first meiotic division. Although most organisms are limited in the number of crossovers between homologs by a phenomenon called crossover interference, the consequences of excess interfering crossovers on meiotic chromosome segregation are not well known. Here we show that extra interfering crossovers lead to a range of meiotic defects and we uncover mechanisms that counteract these errors. Using chromosomes that exhibit a high frequency of supernumerary crossovers in Caenorhabditis elegans, we find that essential chromosomal structures are mispatterned in the presence of multiple crossovers, subjecting chromosomes to improper spindle forces and leading to defects in metaphase alignment. Additionally, the chromosomes with extra interfering crossovers often exhibited segregation defects in anaphase I, with a high incidence of chromatin bridges that sometimes created a tether between the chromosome and the first polar body. However, these anaphase I bridges were often able to resolve in a LEM-3 nuclease dependent manner, and chromosome tethers that persisted were frequently resolved during Meiosis II by a second mechanism that preferentially segregates the tethered sister chromatid into the polar body. Altogether these findings demonstrate that excess interfering crossovers can severely impact chromosome patterning and segregation, highlighting the importance of limiting the number of recombination events between homologous chromosomes for the proper execution of meiosis.
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    Remembrance of things practiced with fast and slow learning in cortical and subcortical pathways
    (Nature Research, 2020-12-23) Murray, James M.; Escola, G. Sean
    The learning of motor skills unfolds over multiple timescales, with rapid initial gains in performance followed by a longer period in which the behavior becomes more refined, habitual, and automatized. While recent lesion and inactivation experiments have provided hints about how various brain areas might contribute to such learning, their precise roles and the neural mechanisms underlying them are not well understood. In this work, we propose neural- and circuit-level mechanisms by which motor cortex, thalamus, and striatum support motor learning. In this model, the combination of fast cortical learning and slow subcortical learning gives rise to a covert learning process through which control of behavior is gradually transferred from cortical to subcortical circuits, while protecting learned behaviors that are practiced repeatedly against overwriting by future learning. Together, these results point to a new computational role for thalamus in motor learning and, more broadly, provide a framework for understanding the neural basis of habit formation and the automatization of behavior through practice.