Daniel S. Rokhsar - US grants

This grant will support research in theoretical condensed matter physics to develop models and do calculations in order to describe the behavior of high temperature superconducting materials. This grant was selected from more than 260 proposals submitted in response to a solicitation for proposals in High Temperature Superconductivity in April, 1989. This research may provide valuable insight into the physical mechanisms responsible for this unusual behavior. The research is supported through the Condensed Matter Thoery program with a significant contribution from the university.

Research plans are 1. to continue theoretical investigations of the mechanisms of high temperature superconductivity, with special emphasis on magnetic mechanisms and novel approaches to the physics of strong coupling superconductors, and 2. to study the statistical mechanics of phase transitions in quantum and driven non- equilibrium classical systems.

? DESCRIPTION (provided by applicant): The Berkeley Training Program in Genomics and Computational Biology provides graduate and postgraduate training and research opportunities at the University of California, Berkeley and the nearby Lawrence Berkeley National Laboratory, emphasizing the cross-disciplinary nature of this rapidly advancing field. Accordingly, the 31 training faculty and proposed trainees are drawn from diverse departments and graduate groups, and is associated with a campus-wide Designated Emphasis that formalizes the requirements for a broad education in computational biology and genomics. The program has three principal thrusts: the comparative and evolutionary analysis of genomes; the study of population level genetic variation; and the dissection of epigenetic and gene-regulatory networks. Trainees will take advantage of a rich training environment of seminars, retreats, and group meetings as well as a diverse set of formal course offerings that range from introductory to advanced methods in genomic biology. Research training will typically begin by the end of the second year, following an introductory period of laboratory rotations, coursework, and preliminary examinations. Progress of the trainees is evaluated by annual thesis reviews and regular meetings with mentors. The Program will train an average of 14 predoctoral students per year in genomics and computational biology.

9987623
Daniel Rokhsar - University of California at Berkeley
IGERT: Physical Biosciences: From Molecular Machines to Neural Imaging

This Integrative Graduate Education and Research Training (IGERT) award supports the establishment of a multidisciplinary graduate training program of education and research on the development and application of physical and computational methods for the study of biological problems at the molecular, cellular, and systems levels. The program is a joint effort of 31 faculty and research scientists drawn from seven Departments at the University of California at Berkeley and three Divisions at the neighboring Lawrence Berkeley National Laboratory. It will transcend traditional academic boundaries to produce the next generation of physical bioscientists, equally conversant with physical and biological methods and problems. Research thrust areas include biomolecular structure, dynamics, and design, and cellular signaling networks and systems neuroscience, with an emphasis on the development and application of novel molecular microscopy and detection devices and theoretical and computational modeling approaches. Students enrolled in any of nine existing Ph.D. programs will participate in personalized training, including new courses on single-molecule methods, bioinformatics, molecular biophysics, and hand-on laboratory courses in physical bioscience. Research and career placement seminars, retreats, summer internships and intensive courses, and a dual mentoring program will provide a rich environment for multidisciplinary training.

IGERT is an NSF-wide program intended to meet the challenges of educating Ph.D. scientists and engineers with the multidisciplinary backgrounds and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing new, innovative models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries. In the third year of the program, awards are being made to nineteen institutions for programs that collectively span all areas of science and engineering supported by NSF. The intellectual foci of this specific award reside in the Directorates for Biological Sciences, Mathematical and Physical Sciences, Engineering, and Education and Human Resources.

DESCRIPTION (provided by applicant): Research on Xenopus has provided numerous new insights into cell and developmental biology. The eggs are readily manipulated by microsurgery and microinjection, and with their large size and abundance, either normal or manipulated eggs provide excellent material for biochemical and cell biological analysis. In order to make Xenopus useful for the modern age of systems biology where proteomic and genomic analyses promise a comprehensive understanding of life's processes, a high quality assembly of the Xenopus genome is needed. A high quality genome structure will provide a comprehensive catalog of gene content and proteome, authoritative data on conservation of chromosome structure with other vertebrates, and will improve regions of mis-assembly, bringing short scaffold regions into a chromosome-scale assembly. This proposal builds on the previous high quality draft genome assembly produced at the Department of Energy's Joint Genome Institute. While the quality is good in gene-rich regions, the long-range assembly of the genome is not as good as that for other tetrapods. This proposal will bypass the previous difficulties in assembling over the long range, by avoiding cloning-based methods of sequence mapping and long-range assembly. Instead we will use high throughput DNA sequencing and statistically based map assembly to generate a physical and genetic map, incorporating newly identified Single Nucleotide Polymorphisms (SNPs) and previously identified Simple sequence length polymorphisms (SSLPs). We will provide support for genome annotation by Metazome and Xenbase and ensure that the resources are made widely available. PUBLIC HEALTH RELEVANCE: Work on model organisms has allowed the discovery of many fundamental properties of animals, and thereby allowed new insights into how human embryos develop and function. Xenopus offers large embryos that develop outside the mother, which has enabled discoveries on cell proliferation and many developmental events. The genome structure and full gene set will permit new genes and functions to be identified, functions that are highly relevant to human development and disease.

DESCRIPTION (provided by applicant): Research on the amphibian Xenopus has provided numerous new insights into cell and developmental biology. With their large size and abundance, they provide unparalleled material for biochemical and cell biological analysis of complex processes such as the cell cycle and chromosome mechanics. For embryological experiments, the embryos are readily manipulated by microsurgery and by microinjection can be subjected to gain or loss of gene function. In order to make Xenopus more useful for the modern age of systems biology where proteomic and genomic analyses promise a comprehensive understanding of life's processes, we propose here to complement the genome assembly of Xenopus tropicalis with a gene and protein level genome assembly for Xenopus laevis. The allotetraploid Xenopus laevis is in wider use than the smaller, diploid Xenopus tropicalis, because of its history, robustness, and the size and quantity of eggs that can be obtained for embryological and cell biological experiments. We propose to carry out high throughput sequencing of X. laevis, and generate a gene-scale assembly. By selecting regions complementary to the X. tropicalis sequence we will be able to assemble X. laevis genes from relatively inexpensive, short read data. The project provides some computational challenges that will need to be overcome and the approaches developed will be of wide utility in characterizing genomes of other organisms. We will provide support for genome annotation by Xenbase and deposit gene and protein collections in public databases to ensure that the resources are widely available.

DESCRIPTION (provided by applicant): Research on the amphibian Xenopus has provided numerous new insights into cell and developmental biology. With their large size and abundance, they provide unparalleled material for biochemical and cell biological analysis of complex processes such as the cell cycle and chromosome mechanics. For embryological experiments, the embryos are readily manipulated by microsurgery or microinjection, and can be subjected to both gain or loss of gene function. In order to make Xenopus more useful for the modern age of systems biology where proteomic and genomic analyses promise a comprehensive understanding of life's processes, we propose here to continue improvement of both the short range, and long range (chromosome level) assemblies of Xenopus tropicalis and Xenopus laevis. To achieve new insights into the function of both coding and non-coding DNA in the Xenopus clade, and add new information from outgroups, we will assemble the pseudotetraploid genomes of X. mulleri, X. epitropicalis, and X. borealis. These allotetraploid Xenopus species will provide new insights into the evolution of tetraploid genomes and aid in annotating non-coding sequences of Xenopus. In addition, we will assemble genomes for other outgroups, including the direct developing frog Eleutherodactylus coqui, the Tungara frog Engystomops, and the spadefoot toad, Spea, all of which are models for developmental, neurobiological or behavioral studies. These will also provide outgroup sequences for comparison and annotation, as well as enabling molecular approaches for the communities who study these frogs for their developmental or neurobiological advantages. We will provide genome assemblies and automated annotation of the comparative information to Xenbase and deposit gene and protein collections in public databases to ensure that the resources are widely available.

DESCRIPTION (provided by applicant): The Pacific Biosciences PacBio RS sequencing system will be used for high-throughput DNA sequencing in applications demanding long-range sequence information at the scale of tens of kilobases. The technology and characteristics of this sequencing technology are notably different than for other sequencing methodologies. In particular, the ability to obtain long sequence reads affords several critical advantages for a number of applications, including (1) the sequencing of novel genomes, (2) EST and transcriptome characterization in organisms lacking a sequenced or well-mapped genome, (3) the analysis of alternative pre-mRNA splicing, (4) amplicon sequencing. In addition to longer read lengths, the PacBio sequencing technology also provides rapid turnaround time. The PacBio RS will be applied to a diverse array of NIH-funded projects as well as other projects of high relevance to biomedical science, including the characterization of multigene families involved in sensory perception; the elucidation of the patterns and mechanisms of alternative pre-mRNA splicing; the characterization of genomes of genetic and evolutionary models of human development and disease; an analysis of the genetic loci associated with cancer; and an investigation of the susceptibility of mammalian cells to nutritional ions and environmental toxins. There are currently no PacBio sequencers on the UC Berkeley campus. The proposed instrument would be located close to its users as part of the Coates Genome Sequencing Center, and managed as part of the unified campus-wide sequencing core facility and associated Computational Genomics Resource Laboratory. Acquisition of this instrument will support researchers pursuing these projects, which promise to illuminate the fundamental mechanisms underlying human biology and disease.

DESCRIPTION (provided by applicant): Xenopus is an extraordinary model for biomedical research that offers many experimental advantages that facilitate both basic and applied research. In recent years, genome sequencing has transformed the frog into a powerful genomic and proteomic tool for understanding the regulatory function of genes, chromatin, and multiple cellular processes, further advancing Xenopus as a tool for systems biology. The overarching goal of this grant is to integrate and analyze this data to improve the gene annotations and reference genomes for Xenopus tropicalis and X. laevis so that the greater community of developmental biologists, stem cell and regeneration biologists, and cell biologists can access and capitalize on this data. A challenge is to carry out this integration, and the generation of a high quality gene annotation, in a systematic but cost-effective manner. New methods are needed to efficiently integrate this data. We have three aims: (1) Integrate RNA-seq, epigenetic maps, and transcriptional start site sequencing into prediction of Xenopus gene structures. (2) Efficiently combine manual curation and bulk analysis to systematically improve gene structure annotation through a tight and rapid feedback loop between an expert curator and computational biologists, producing quantitative metrics for progress. (3) Systematically improve draft genomes to include complete genes by using existing and newly generated data to (a) close or partially fill gaps in genes, (b) fix local errors in sequence (e.g., deletions in assembly), and (c) improve global organization of genome. Throughout the project, priority will be placed on genic regions of interest to the broader Xenopus community.

Yams (genus Dioscorea) are an important source of food and income for millions of smallholder farmers in the tropical and sub-tropical regions of Africa, Asia, the Pacific, and Latin America. Rich in carbohydrates, and containing protein and vitamin C, the year-round availability of yams makes them preferable to seasonal crops. The importance of yams in West Africa is exemplified by their vital role in traditional culture, rituals and religion; yam production is declining, however, due to threats from pests and diseases. Thus, in the context of surging global population growth, improved yam breeding techniques are urgently needed. Water yam, also called greater yam (Dioscorea alata) is the most widely distributed cultivated yam species in the world, and its advantages include high nutritional content, long storability of tubers, and ability to yield in poor quality soil. This project will leverage cutting-edge DNA sequencing and computational analysis to provide a high quality water yam genome assembly and genetic map to the yam community, which will allow breeders to use modern genetic methods to breed the crop more efficiently. The project will also characterize the natural genetic variability present in global collections, yielding insight into how they may be used to improve the crop, and contributing to an understanding of the relationship between water yam DNA sequence and traits important to smallholder farmers. Bringing water yam into the modern genomics era will facilitate the accelerated release of improved varieties to the farmers that need them.

The water yam Dioscorea alata is superior to most cultivated yam species due to its potential to yield under low to average soil fertility, ease of propagation, early vigor for weed suppression, and low post-harvest losses. Threats, however, include anthracnose disease, which can cause losses of up to 90% of production, and breeding for desired traits in water yam is arduous due to its autopolyploid and heterozygous nature, long growth cycle, and erratic flowering. This project will accelerate the improvement of water yam by (1) constructing a high quality chromosome-scale genome assembly for D. alata, interpreted through annotation and comparative analysis, (2) producing a framework genetic map for D. alata via analysis of mapcrosses segregating for traits important for farmers, and (3) characterizing the global collection of D. alata cultivars. Advanced technologies such as PacBio de novo sequencing, whole-genome resequencing, genotyping-by-sequencing, flow cytometry for ploidy analysis, and publicly available and custom bioinformatics tools, will be leveraged. The chromosome-scale genome assembly and genetic map will lay the groundwork for more efficient breeding approaches such as genomic selection in water yam. Quantitative trait locus analysis of mapping populations segregating for anthracnose resistance and tuber quality is expected to yield specific sequence variants linked to, and thus mechanistic insight into, those traits. Study of water yam diversity across global collections will elucidate its breeding history, reveal bottlenecks, and suggest strategies for broadening the gene pool. All sequencing resources will be publicly available through the NCBI and the phytozome plant genomics resource.