Connect-seq to superimpose molecular on anatomical neural circuit maps, bioRxiv, 2018-10-27
AbstractThe mouse brain contains ~100 million neurons interconnected in a vast array of neural circuits. The identities and functions of individual neuronal components of most circuits are undefined. Here we describe a method, termed ‘Connect-seq’, which combines retrograde viral tracing and single cell transcriptomics to uncover the molecular identities of upstream neurons in a specific circuit and the signaling molecules they use to communicate. Connect-seq can generate a molecular map that can be superimposed on a neuroanatomical map to permit molecular and genetic interrogation of how the neuronal components of a circuit control its function. Application of this method to hypothalamic neurons controlling physiological responses to fear and stress reveal subsets of upstream neurons that express diverse constellations of signaling molecules and can be distinguished by their anatomical locations.
biorxiv neuroscience 0-100-users 2018ETDB-Caltech a blockchain-based distributed public database for electron tomography, bioRxiv, 2018-10-26
AbstractThree-dimensional electron microscopy techniques like electron tomography provide valuable insights into cellular structures, and present significant challenges for data storage and dissemination. Here we explored a novel method to publicly release more than 11,000 such datasets, more than 30 TB in total, collected by our group. Our method, based on a peer-to-peer file sharing network built around a blockchain ledger, offers a distributed solution to data storage. In addition, we offer a user-friendly browser-based interface, <jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httpsetdb.caltech.edu>httpsetdb.caltech.edu<jatsext-link>, for anyone interested to explore and download our data. We discuss the relative advantages and disadvantages of this system and provide tools for other groups to mine our data andor use the same approach to share their own imaging datasets.
biorxiv cell-biology 0-100-users 2018Inference of recombination maps from a single pair of genomes and its application to archaic samples, bioRxiv, 2018-10-25
ABSTRACTUnderstanding the causes and consequences of recombination rate evolution is a fundamental goal in genetics that requires recombination maps from across the tree of life. Since statistical inference of recombination maps typically depends on large samples, reaching out studies to non-model organisms requires alternative tools. Here we extend the sequentially Markovian coalescent model to jointly infer demography and the variation in recombination along a pair of genomes. Using extensive simulations and sequence data from humans, fruit-flies and a fungal pathogen, we demonstrate that iSMC accurately infers recombination maps under a wide range of scenarios – remarkably, even from a single pair of unphased genomes. We exploit this possibility and reconstruct the recombination maps of archaic hominids. We report that the evolution of the recombination landscape follows the established phylogeny of Neandertals, Denisovans and modern human populations, as expected if the genomic distribution of crossovers in hominids is largely neutral.
biorxiv evolutionary-biology 0-100-users 2018Independent domestication events in the blue-cheese fungus Penicillium roqueforti, bioRxiv, 2018-10-24
AbstractDomestication provides an excellent framework for studying adaptive divergence. Using population genomics and phenotypic assays, we reconstructed the domestication history of the blue cheese mold Penicillium roqueforti. We showed that this fungus was domesticated twice independently. The population used in Roquefort originated from an old domestication event associated with weak bottlenecks and exhibited traits beneficial for pre-industrial cheese production (slower growth in cheese and greater spore production on bread, the traditional multiplication medium). The other cheese population originated more recently from the selection of a single clonal lineage, was associated to all types of blue cheese worldwide but Roquefort, and displayed phenotypes more suited for industrial cheese production (high lipolytic activity, efficient cheese cavity colonization ability and salt tolerance). We detected genomic regions affected by recent positive selection and putative horizontal gene transfers. This study sheds light on the processes of rapid adaptation and raises questions about genetic resource conservation.
biorxiv evolutionary-biology 0-100-users 2018Latent developmental potential to form limb-like skeletal structures in zebrafish, bioRxiv, 2018-10-23
AbstractThe evolution of fins into limbs was a key transition in vertebrate history. A hallmark of this transition is the addition of multiple long bones to the proximal-distal axis of paired appendages. Whereas limb skeletons are often elaborate and diverse, teleost pectoral fins retain a simple endoskeleton. Fins and limbs share many core developmental processes, but how these programs were reshaped to produce limbs from fins during evolution remains enigmatic. Here we identify zebrafish mutants that form supernumerary long bones along the proximal-distal axis of pectoral fins with limb-like patterning. These new skeletal elements are integrated into the fin, as they are connected to the musculature, form joints, and articulate with neighboring bones. This phenotype is caused by activating mutations in previously unrecognized regulators of appendage development, vav2 and waslb, which we show function in a common pathway. We find that this pathway functions in appendage development across vertebrates, and loss of Wasl in developing limbs results in patterning defects identical to those seen in Hoxall knockout mice. Concordantly, formation of supernumerary fin long bones requires the function of hoxall paralogs, indicating developmental homology with the forearm and the existence of a latent functional Hox code patterning the fin endoskeleton. Our findings reveal an inherent limb-like patterning ability in fins that can be activated by simple genetic perturbation, resulting in the elaboration of the endoskeleton.
biorxiv evolutionary-biology 0-100-users 2018Polygenic Adaptation From sweeps to subtle frequency shifts, bioRxiv, 2018-10-23
Evolutionary theory has produced two conflicting paradigms for the adaptation of a polygenic trait. While population genetics views adaptation as a sequence of selective sweeps at single loci underlying the trait, quantitative genetics posits a collective response, where phenotypic adaptation results from subtle allele frequency shifts at many loci. Yet, a synthesis of these views is largely missing and the population genetic factors that favor each scenario are not well understood. Here, we study the architecture of adaptation of a binary polygenic trait (such as resistance) with negative epistasis among the loci of its basis. The genetic structure of this trait allows for a full range of potential architectures of adaptation, ranging from sweeps to small frequency shifts. By combining computer simulations and a newly devised analytical framework based on Yule branching processes, we gain a detailed understanding of the adaptation dynamics for this trait. Our key analytical result is an expression for the joint distribution of mutant alleles at the end of the adaptive phase. This distribution characterizes the polygenic pattern of adaptation at the underlying genotype when phenotypic adaptation has been accomplished. We find that a single compound parameter, the population-scaled background mutation rate Θbg, explains the main differences among these patterns. For a focal locus, Θbg measures the mutation rate at all redundant loci in its genetic background that offer alternative ways for adaptation. For adaptation starting from mutation-selection-drift balance, we observe different patterns in three parameter regions. Adaptation proceeds by sweeps for small Θbg ≲0.1, while small polygenic allele frequency shifts require large Θbg ≳100. In the large intermediate regime, we observe a heterogeneous pattern of partial sweeps at several interacting loci.
biorxiv evolutionary-biology 0-100-users 2018