Biology subjects

Thomson, M.

Publications and source records attributed to Thomson, M..

7 recordsLinked to original sources

bioRxiv2018

Mapping the complex paracrine response to hormones in the human breast at single-cell resolution

The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks.

systems biology↗

bioRxiv2018

Dissecting heterogeneous cell-populations across signaling and diseaseconditions with PopAlign

Single-cell measurement techniques can now probe gene expression in heterogeneous cell populations from the human body across a range of environmental and physiological conditions. However, new mathematical and computational methods are required to represent and analyze gene expression changes that occur in complex mixtures of single cells as they respond to signals, drugs, or disease states. Here, we introduce a mathematical modeling platform, PopAlign, that automatically identifies subpopulations of cells within a heterogeneous mixture, and tracks gene expression and cell abundance changes across subpopulations by constructing and comparing probabilistic models. Probabilistic models provide a low-error, compressed representation of single cell data that enables efficient large-scale computations. We apply PopAlign to analyze the impact of 40 different immunomodulatory compounds on a heterogeneous population of donor-derived human immune cells as well as patient-specific disease signatures in multiple myeloma. PopAlign scales to comparisons involving tens to hundreds of samples, enabling large-scale studies of natural and engineered cell populations as they respond to drugs, signals or physiological change.

bioinformatics↗

bioRxiv2018

Rice Galaxy: an open resource for plant science

Background\n\nRice molecular genetics, breeding, genetic diversity, and allied research (such as rice-pathogen interaction) have adopted sequencing technologies and high density genotyping platforms for genome variation analysis and gene discovery. Germplasm collections representing rice diversity, improved varieties and elite breeding materials are accessible through rice gene banks for use in research and breeding, with many having genome sequences and high density genotype data available. Combining phenotypic and genotypic information on these accessions enables genome-wide association analysis, which is driving quantitative trait loci (QTL) discovery and molecular marker development. Comparative sequence analyses across QTL regions facilitate the discovery of novel alleles. Analyses involving DNA sequences and large genotyping matrices for thousands of samples, however, pose a challenge to non-computer savvy rice researchers.\n\nFindings\n\nWe adopted the Galaxy framework to build the federated Rice Galaxy resource, with shared datasets, tools, and analysis workflows relevant to rice research. The shared datasets include high density genotypes from the 3,000 Rice Genomes project and sequences with corresponding annotations from nine published rice genomes. Rice Galaxy includes tools for designing single nucleotide polymorphism (SNP) assays, analyzing genome-wide association studies, population diversity, rice-bacterial pathogen diagnostics, and a suite of published genomic prediction methods. A prototype Rice Galaxy compliant to Open Access, Open Data, and Findable, Accessible, Interoperable, and Reproducible principles is also presented.\n\nConclusions\n\nRice Galaxy is a freely available resource that empowers the plant research community to perform state-of-the-art analyses and utilize publicly available big datasets for both fundamental and applied science.

bioinformatics↗

bioRxiv2018

Highly Multiplexed Single-Cell RNA-seq for Defining Cell Population and Transcriptional Spaces

We describe a universal sample multiplexing method for single-cell RNA-seq in which cells are chemically labeled with identifying DNA oligonucleotides. Analysis of a 96-plex perturbation experiment revealed changes in cell population structure and transcriptional states that cannot be discerned from bulk measurements, establishing a cost effective means to survey cell populations from large experiments and clinical samples with the depth and resolution of single-cell RNA-seq.

genomics↗

bioRxiv2017

Diffusion as a ruler: modeling kinesin diffusion as a length sensor for intraflagellar transport

An important question in cell biology is whether cells are able to measure size, either whole cell size or organelle size. Perhaps cells have an internal chemical representation of size that can be used to precisely regulate growth, or perhaps size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying size sensing and control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling. The assembly of flagella is regulated by intraflagellar transport (IFT), in which kinesin motors carry cargo adaptors for flagellar proteins along the flagellum and then deposit them at the tip, lengthening the flagellum. The rate at which IFT motors are recruited to begin transport into the flagellum is anticorrelated with the flagellar length, implying some kind of communication between the base and the tip and possibly indicating that cells contain some mechanism for measuring flagellar length. Although it is possible to imagine many complex scenarios in which additional signaling molecules sense length and carry feedback signals to the cell body to control IFT, might the already-known components of the IFT system be sufficient to allow length dependence of IFT? Here, we investigate a model in which the anterograde kinesin motors unbind after cargo delivery, diffuse back to the base, and are subsequently reused to power entry of new IFT trains into the flagellum. By modeling such a system at three different levels of abstraction we are able to show that the diffusion time of the motors can in principle be sufficient to serve as a proxy for length measurement. In all three implementations, we found that the diffusion model can not only achieve a stable steady-state length without the addition of any other signaling molecules or pathways, but also is able to produce the anticorrelation between length and IFT recruitment rate that has been observed in quantitative imaging studies.

biophysics↗

bioRxiv2017

Transient Thresholding: A Mechanism Enabling Non-Cooperative Transcriptional Circuitry To Form A Switch

Threshold generation in fate-selection circuits is often achieved through deterministic bistability, which requires cooperativity (i.e., nonlinear activation) and associated hysteresis. However, the Tat positive-feedback loop that controls HIVs fate decision between replication and proviral latency lacks self-cooperativity and deterministic bistability. Absent cooperativity, it is unclear how HIV can temporarily remain in an off state long enough for the kinetically slower epigenetic silencing mechanisms to act-- expression fluctuations should rapidly trigger active positive feedback and replication, precluding establishment of latency. Here, using flow cytometry and single-cell imaging, we find that the Tat circuit exhibits a transient activation threshold. This threshold largely disappears after [~]40 hours--accounting for the lack of deterministic bistability--and promoter activation shortens the lifetime of this transient threshold. Continuous differential equation models do not recapitulate this phenomenon. However, chemical reaction (master equation) models where the transcriptional transactivator and promoter toggle between inactive and active states can recapitulate the phenomenon since they intrinsically create a single-molecule threshold transiently requiring excess molecules in the inactive state to achieve at least one molecule (rather than a continuous fractional value) in the active state. Given the widespread nature of promoter toggling and transcription factor modifications, transient thresholds may be a general feature of inducible promoters.

biophysics↗

bioRxiv2017

Maintaining their genetic distance; limited gene flow between widely hybridising species of Geum with contrasting mating systems

Mating system transition from outcrossing to selfing frequently gives rise to sister lineages with contrasting outcrossing rates. The evolutionary fate of such lineages depends on the extent to which they exchange genes. We measured gene flow between outcrossing Geum rivale and selfing G. urbanum, two sister species derived by mating system transition, which frequently hybridise. A draft genome was generated for G. urbanum and used to develop dd-RAD data scorable in both species. Coalescent analysis of RAD data from allopatric populations indicated that the two species diverged 2-3 Mya, and that long term gene flow between them has been very low (M=0.04). G. rivale showed greater genetic diversity in sympatry than allopatry, but genetic divergence between species was no lower in sympatry than allopatry, providing little evidence for recent introgression. Clustering of genotypes revealed that, apart from four early generation hybrids, individuals in sympatric populations fell into two genetically distinct groups with <1% admixture that corresponded exactly to their morphological species classification. Although our data suggest limited gene flow, we observed joint segregation of two putatively introgressed SNPs in G. urbanum populations that was associated with significant morphological variation; this provides tentative evidence for rare introduction of novel genetic diversity by interspecific gene flow. Our results indicate that despite frequent hybridisation, genetic exchange between G. rivale and G. urbanum has been very limited throughout their evolutionary history.

evolutionary biology↗