Biomedical Computation at Stanford (BCATS)

Keynote Addresses

	Lin Chao Evolution of Bacterial Aging
	Michael Eisen Activation of the Drosophila genome in early development
	Armin Spura From raw signal to annotations: An overview of Ion Torrent’s sequencing software pipeline

BCATS Symposium

Topics

Lin Chao

Professor

Section of Ecology, Behavior and Evolution, UCSD; Scripps Institution of Oceanography (MBRD)

Evolution of Bacterial Aging

Professor Lin Chao is an American evolutionary biologist and geneticist. Professor Chao gained his PhD in 1977 from the University of Massachusetts Amherst, as a student of Bruce R. Levin (now at Emory University), and was a NIH postdoctoral fellow at Princeton University in the laboratory of Edward C. Cox. He spent most of his career in the Department of Biology of the University of Maryland, College Park and is currently at the Ecology, Behavior and Evolution Section of the University of California, San Diego. Professor Chao is best known for his early work on the evolution of bacteriocins, his demonstration of Muller’s ratchet in the RNA Virus Phi-6 and his work on sex in viruses. More recently, he was instrumental in the demonstration of the evolution of parasitic genetic elements in co-infecting bacteriophages and experimental tests of Fisher’s geometric model. He argued that "life is evolution by natural selection". The approach generally used in his laboratory is called microbial experimental evolution.

Deleterious mutations appearing in a population increase in frequency until stopped by natural selection. The ensuing equilibrium creates a stable frequency of deleterious mutations or the mutational load. Here I develop the comparable concept of a damage load, which is caused by harmful non-heritable changes to the phenotype. A damage load also ensues when the increase of damage is opposed by selection. The presence of a damage load favors the evolution of asymmetrical transmission of damage by a mother to her daughters. The asymmetry is beneficial because it increases fitness variance, but it also leads to aging or senescence. A mathematical model based on microbes reveals that a cell lineage dividing symmetrically is immortal if lifetime damage rates do not exceed a threshold. The evolution of asymmetry allows the lineage to persist above the threshold, but the lineage becomes mortal. In microbes with low genomic mutation rates, it is likely that the damage load is much greater than the mutational load. In metazoans with higher genomic mutation rates, the damage and the mutational load could be of the same magnitude. A fit of the model to experimental data shows that Escherichia coli cells experience a damage rate that is below the threshold and are immortal under the conditions examined. The model estimates the asymmetry level of E. coli to be low but sufficient for persisting at higher damage rates. The model also predicts that increasing asymmetry results in diminishing fitness returns, which may explain why the bacterium has not evolved higher asymmetry.

Michael Eisen

Associate Professor

Department of Molecular and Cellular Biology, University of California at Berkeley; Life Sciences Division, Lawrence Berkeley National Lab

Activation of the Drosophila genome in early development

Michael Eisen's lab uses a combination of experimental, computational and evolutionary genomic techniques to study how genomes encode the complex spatial and temporal patterns of gene expression that drive animal development, using flies in the genus Drosophila as a model system. He was named a Pew Scholar in the Biomedical Sciences in 2001 (and now serves on their board), received a Presidential Early Career Award for Science and Engineering in 2004 and was named an Investigator of the Howard Hughes Medical Institute in 2008. He is currently an Associate Professor of Genetics, Genomics and Development in the Department of Molecular and Cell Biology, and holds appointments in the Department of Integrative Biology and Museum of Comparative Zoology.

The earliest stages of development in most metazoans are driven by maternally deposited proteins and mRNAs, with widespread transcriptional activation of the zygotic genome occurring hours after fertilization, at a period known as the maternal-to-zygotic transition (MZT). In Drosophila, the MZT is preceded by the transcription of a small number of genes that initiate sex determination, patterning, and other early developmental processes; and the zinc-finger protein Zelda (ZLD) plays a key role in their transcriptional activation. To better understand the mechanisms of ZLD activation and the range of its targets, we used chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) to map regions bound by ZLD before (mitotic cycle 8), during (mitotic cycle 13), and after (late mitotic cycle 14) the MZT. Although only a handful of genes are transcribed prior to mitotic cycle 10, we identified thousands of regions bound by ZLD in cycle 8 embryos, most of which remain bound through mitotic cycle 14. As expected, early ZLD-bound regions include the promoters and enhancers of genes transcribed at this early stage. However, we also observed ZLD bound at cycle 8 to the promoters of roughly a thousand genes whose first transcription does not occur until the MZT and to virtually all of the thousands of known and presumed enhancers bound at cycle 14 by transcription factors that regulate patterned gene activation during the MZT. The association between early ZLD binding and MZT activity is so strong that ZLD binding alone can be used to identify active promoters and regulatory sequences with high specificity and selectivity. This strong early association of ZLD with regions not active until the MZT suggests that ZLD is not only required for the earliest wave of transcription but also plays a major role in activating the genome at the MZT.

Armin Spura

Bioinformatician

Ion Torrent

From raw signal to annotations: An overview of Ion Torrent’s sequencing software pipeline

Armin currently leads the global Bioinformatics support team, covering Ion Torrent as well as the SOLiD/5500 platform. Prior to joining Life Technologies Armin held various managerial roles with ForteBio and Ingenuity Systems, spanning field support, product management, and R&D. He holds a PhD from Brown University in Molecular Biology and received his undergraduate degree in Biochemistry from the University of Tübingen in Germany.

The advent of next-generation DNA sequencing technology has enabled quick and low-cost variant analysis of NGS data. For our Proton instrument, we have built a data analysis suite that can progress from sequencing to alignment for a whole exome in 8hrs. This talk will focus on the individual elements of our analysis pipeline, from base calling via variant calling to providing functional annotations. The emphasis will be on Ion Reporter(TM) , a cloud-hosted informatics platform for analysis, annotation, and archiving of Ion Torrent sequencing data, as well as on recent accuracy improvements to the platform.

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