Joanne A. Fox

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice

Tumors derived from individuals with hereditary non-polyposis colorectal cancer syndrome frequently demonstrate mutations in both alleles of hMSH2, a key gene in DNA mismatch repair (MMR). Sporadic tumors also frequently exhibit MMR deficiency. In keeping with the role of MMR in the maintenance of genome integrity, mice deficient in MSH2 via gene targeting demonstrate a high incidence of thymic lymphomas and small intestinal adenocarcinomas. To investigate the effects of MSH2 deficiency in normal tissues, mice containing a retrievable transgenic lacI reporter gene for mutation detection were crossed with MSH2−/− mice. Mice homozygous for MSH2 deficiency revealed 4.8, 11.0 and 15.2-fold elevations in spontaneous mutation frequency in DNA obtained from brain, small intestine, and thymus, respectively, as compared to heterozygous or wild-type mice. Mutations most frequently recovered from MSH2−/− mice were single base substitutions (77%), particularly base transitions (64%). Frameshifts occurred less frequently (19%) and fell within very short (3 – 5 bp) mononucleotide runs. Thus the number of key growth control genes potentially impacted by MMR deficiency extends beyond those containing repetitive sequences. These results highlight the capacity for MSH2 deficiency to serve as a potent driving force during the multi-step evolution of tumors.

Disruption of a single Pten allele augments the chemotactic response of B lymphocytes to stromal cell-derived factor-1.

The tumor suppressor, Pten, has emerged as a critical negative regulator of phosphatidylinositol-3-kinase-dependent intracellular signaling pathways responsible for phenomena such as cellular adhesion, proliferation, and apoptosis. Herein, we present evidence that Pten regulates chemokine-dependent events in B lymphocytes. Primary B cells isolated from Pten+/− mice demonstrated increased responsiveness to stromal cell-derived factor-1-induced chemotaxis. This was accompanied by an elevated level of protein kinase B phosphorylation on Ser473. Our results suggest not only that Pten may be an important regulator of stromal cell-derived factor-1-directed chemotaxis, but also that Pten heterozygosity is associated with increased cellular sensitivity to this chemokine, likely via dysregulation of events lying downstream of phosphatidylinositol-3-kinase. These observations suggest a mechanism by which loss of a single Pten allele may confer a selective advantage on cells during multistep tumor progression.

The Bioinformatics Links Directory: a Compilation of Molecular Biology Web Servers

The Bioinformatics Links Directory is an online community resource that contains a directory of freely available tools, databases, and resources for bioinformatics and molecular biology research. The listing of the servers published in this and previous issues of Nucleic Acids Research together with other useful tools and websites represents a rich repository of resources that are openly provided to the research community using internet technologies. The 166 servers highlighted in the 2005 Web Server Issue are included in the more than 700 links to useful online resources that are currently contained within the descriptive biological categories of the Bioinformatics Links Directory. This curated listing of bioinformatics resources is available online at the Bioinformatics Links Directory web site, . A complete listing of the 2005 Nucleic Acids Research Web Server Issue servers is available online at the Nucleic Acids web site, , and on the Bioinformatics Links Directory web site, .

A compilation of molecular biology web servers: 2006 update on the Bioinformatics Links Directory

The Bioinformatics Links Directory is a public online resource that lists the servers published in this and all previously published Nucleic Acids Research Web Server issues together with other useful tools, databases and resources for bioinformatics and molecular biology research. This rich directory of tools and websites can be browsed and searched with all listed links freely accessible to the public. The 2006 update includes the 149 websites highlighted in the July 2006 issue of Nucleic Acids Research and brings the total number of servers listed in the Bioinformatics Links Directory to over 1000 links. To aid navigation through this growing resource, all link entries contain a brief synopsis, a citation list and are classified by function in descriptive biological categories. The most up-to-date version of this actively maintained listing of bioinformatics resources is available at the Bioinformatics Links Directory website, . A complete list of all links listed in this Nucleic Acids Research 2006 Web Server issue can be accessed online at . The 2006 update of the Bioinformatics Links Directory, which includes the Web Server list and summaries, is also available online at the Nucleic Acids Research website, .

Keeping pace with the data: 2008 update on the Bioinformatics Links Directory

The Bioinformatics Links Directory, http://bioinformatics.ca/links_directory/, is an online resource for public access to all of the life science research web servers published in this and previous issues of Nucleic Acids Research, together with other useful tools, databases and resources for bioinformatics and molecular biology research. Dependent on community input and development, the Bioinformatics Links Directory exemplifies an open access research tool and resource. The 2008 update includes the 94 web servers featured in the July 2008 Web Server issue of Nucleic Acids Research, bringing the total number of servers listed in the Bioinformatics Links Directory to over 1200 links. A complete list of all links listed in this Nucleic Acids Research 2008 Web Server issue can be accessed online at http://bioinfomatics.ca/links_directory/narweb2008/. The 2008 update of the Bioinformatics Links Directory, which includes the Web Server list and summaries, is also available online at the Nucleic Acids Research website, http://nar.oxfordjournals.org/.

Conducting Research on the Web: 2007 Update for the Bioinformatics Links Directory

The Bioinformatics Links Directory, http://bioinformatics.ca/links_directory, is an actively maintained compilation of servers published in this and previous issues of Nucleic Acids Research issues together with many other useful tools, databases and resources for life sciences research. The 2007 update includes the 130 websites highlighted in the July 2007 Web Server issue of Nucleic Acids Research and brings the total number of servers listed in the Bioinformatics Links Directory to just under 1200 links. In addition to the updated content, the 2007 update of the Bioinformatics Links Directory includes new features for improved navigation, accessibility and open data exchange. A complete listing of all links listed in this Nucleic Acids Research 2007 Web Server issue can be accessed online at, http://bioinformatics.ca/links_directory/narweb2007. The 2007 update of the Bioinformatics Links Directory, which includes the Web Server list and summaries is also available online, at the Nucleic Acids Research web site, http://nar.oupjournals.org.

A novel lacI transgenic mutation-detection system and its application to establish baseline mutation frequencies in the scid mouse

To assess DNA mutations in vivo, we have established a new transgenic mouse line, BC-1, carrying a lacI target gene for mutation detection within a bacteriophage shuttle-vector. The lacI gene was positioned within sequences derived from a rearranged murine immunoglobulin gene locus, a feature that distinguishes the BC-1 transgene from other shuttle vector systems. As mutations in lacI transgenes likely reflect mutations occurring throughout the genome, these systems have been successfully used to investigate spontaneous and induced mutations in a variety of tissues. An important additional application of the transgenic systems is the characterization of lacI mutations occurring in murine strains having specific DNA repair defects. For this study, scid (severe combined immunodeficiency) mice were selected as animals with this mutation have a defect in double-strand DNA break repair. To determine what impact the scid mutation might have on spontaneous mutation frequencies within DNA recovered from various tissues, these mice were crossed with the BC-1 line. Interestingly, mutation frequencies within BC-1/scid mouse DNA were not significantly different from those of BC-1 control mice. Furthermore, spontaneous lacI mutations obtained from BC-1 and from BC-1/scid liver DNA were similar in spectrum. As spontaneous BC-1 liver mutations were similar to those reported previously for other lacI systems, such as the Big Blue transgenic line, this suggested that the nature of the DNA sequences flanking the reporter gene did not modify lacI mutation rate or character.

Design and Implementation of a Genomics Field Trip Program Aimed at Secondary School Students

With the rapid pace of advancements in biological research brought about by the application of computer science and information technology, we believe the time is right for introducing genomics and bioinformatics tools and concepts to secondary school students. Our approach has been to offer a full-day field trip in our research facility where secondary school students carry out experiments at the laboratory bench and on a laptop computer. This experience offers benefits for students, teachers, and field trip instructors. In delivering a wide variety of science outreach and education programs, we have learned that a number of factors contribute to designing a successful experience for secondary school students. First, it is important to engage students with authentic and fun activities that are linked to real-world applications and/or research questions. Second, connecting with a local high school teacher to pilot programs and linking to curricula taught in secondary schools will enrich the field trip experience. Whether or not programs are linked directly to local teachers, it is important to be flexible and build in mechanisms for collecting feedback in field trip programs. Finally, graduate students can be very powerful mentors for students and should be encouraged to share their enthusiasm for science and to talk about career paths. Our experiences suggest a real need for effective science outreach programs at the secondary school level and that genomics and bioinformatics are ideal areas to explore.

Education in Computational Biology Today and Tomorrow

The etymology of the word “education” in Wikipedia is enlightening: “a rearing” and “I lead forth” (http://en.wikipedia.org/wiki/Education#Etymology). Computational biology educators are leading and raising the next generation of scientists and, in doing so, are in need of new tools, methods, and approaches. The need for education in science, and in computational biology in particular, is greater than ever. Large datasets, -omics technologies, and overlapping domains permeate many of the big research questions of our day. PLOS Computational Biology originally created the Education section to highlight the importance of education in the field [1]. Thus, it was a great honor when Fran Lewitter, Education Editor for the past eight years, along with Philip E. Bourne and Ruth Nussinov, contacted us to work as editors of the PLOS Computational Biology Education section. In our minds, educational initiatives in computational biology and bioinformatics serve two important goals: to communicate digital biology with each other, and to educate others on how best to do this. These are themes we practice as educators in our university teaching, in our involvement with the bioinfomatics.ca workshops series, and in our outreach efforts. We are very excited to continue Frans great vision as we continue her work with the PLOS Computational Biology staff. Examples of tutorials, specialized workshops, and outreach programs that bridge the knowledge gap created by this fast pace of research have been previously highlighted in this collection. There have been several types of articles, but two stand out. Firstly, there are tutorials about a specific biological problem requiring a specific approach, tools, and databases. For example, ”Practical Strategies for Discovering Regulatory DNA Sequence Motifs„ by MacIsaak and Fraenkel [2]. Tutorial articles provide theoretical context, as well as the type of questions and how to answer them. The other type of article we frequently find in the Education collection are “primers” or “quick guides.” For example, Eglens “A Quick Guide to Teaching R Programming to Computational Biology Students” [3] or Bassis “A Primer on Python for Life Science Researchers” [4]. Both of these examples from the Education collection address an important niche within the community. The “Quick Guide” series provides a more generic introduction to an approach in computational biology that can be applied across multiple domains. All of these types of articles will continue to be well-supported and encouraged in the Education collection. Many other articles have also been well-received, and seem to address gaps in the education material. We want to revisit older collection papers and identify where methods and technologies have evolved to a point where new methods are now in use, and invite previous or new authors to contribute. These initiatives help to extend computational biology beyond the domain of specialized laboratories. Researchers, at all levels, need to keep themselves up-to-date with the quickly changing world of computational biology, and trainees need programs where bioinformatics skills are embedded so they can have comprehensive training. New bioinformatics workflows can be adopted more widely if education efforts keep pace. As previously pointed out [5], starting early is also very important. There is still room for programs that capture the excitement and enthusiasm of secondary school students and convey the potential of computational biology to the public. We welcome additions to the PLOS Computational Biology “Bioinformatics: Starting Early” collection (www.ploscollections.org/cbstartingearly). We would like to involve the community in this endeavor. With this editorial, we are calling out to educators and researchers who have experience in teaching, specifically, those keen to raise the expectations and the inquisitiveness of the next generation of biologists. The Education collection will continue to publish leading edge education materials in the form of tutorials that can be used in a “classroom” setting (whatever that may mean nowadays: stated more generically, “the places where people learn”). We will continue to encourage articles set in the context of addressing a particular biological question and, as mentioned above, we welcome new “primers” and “quick guides.” We will also be inviting tutorials from the various computational meetings. A new category of papers that is in the pipeline for the Education collection is the “Quick Tips” format, the first of which was just published [6]. The “Quick Tips” articles address specific tools or databases that are in wide use in the community. We also hope, and plan, to incorporate new thinking and perspectives in the greater field of education of computational biology and bioinformatics. For example, articles that highlight the use of new tools such as those used in cloud computing or methods for using third and fourth generation sequencing technologies are encouraged. We would also like to see articles that incorporate best practices in teaching, including the use of new media, flexible online teaching tools, and the use and re-use of large well-defined data sets that are computed on in classes, courses, and programs. We encourage articles that highlight new types of training initiatives, the use of workflows to help students in the path to reproducibility in science, and open course materials (open lecture notes and open course notes and datasets for exercises) that reach more learners. In the end, the Education section belongs to the community and thus comes with responsibilities. We need to identify the gaps and the material with which we want to educate ourselves; we need to recognize and encourage great teachers and writers to communicate openly about what works best with the specific methods. We invite you to contact us via gro.solp@loibpmocsolp with your ideas for the kind of articles you would like to see in the PLOS Computational Biology Education section. We hope to see you in the classroom soon, where we learn together. About The Authors Joanne A. Fox (xofnosilaennaoj@ on Twitter) has a PhD in Genetics from the University of British Columbia (UBC). As a faculty member at the Michael Smith Laboratories and in the Department of Microbiology and Immunology at UBC, she is involved in a range of education and outreach initiatives at the undergraduate and secondary school levels, and teaches a variety of courses. She is a former instructor and current review committee member of the Canadian Bioinformatics.ca Workshops. B.F. Francis Ouellette (offb@ on Twitter) did his graduate studies in Developmental Biology and is now an Associate Professor in Cell and Systems Biology at the University of Toronto, as well as a senior scientist and Associate Director of Informatics and Biocomputing at the Ontario Institute for Cancer Research. He was one of the founders and is still the scientific director and an instructor for the Canadian Bioinformatics.ca Workshops. The authors have worked together in the past, and have known each other for more than 15 years.