Mark Welch, D. Lab
David Mark Welch
Director of the Josephine Bay Paul Center
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Dr. David Mark Welch is an evolutionary biologist with a background in biochemistry and molecular biology. His research spans processes of metazoan genome evolution to how rare and unknown microbes shape ecosystems, and is united by an overarching interest is the molecular mechanisms by which natural selection and evolutionary history create biological diversity. As a graduate student with Matthew Meselson, Mark Welch found the first molecular evidence for the long-term absence of meiosis in an animal, which ushered in a new interest in using molecular genetic tools to study asexual evolution. His continued research in this area led to a mature theory uniting unique aspects of the ecology, genome evolution, and DNA repair processes of these animals, bdelloid rotifers, to explain their unexpected evolutionary success. Elements of this synthesis have been confirmed and expanded with the recent sequencing of a complete bdelloid genome, an effort of Mark Welch, JBPC scientist Irina Arkhipova, and an international team of collaborators. The focus of his lab’s current research in this area is the novel antioxidant and DNA repair pathways of bdelloids. The Mark Welch lab is also leveraging previous work exploring the ecological and evolutionary dynamics of sex and speciation in rotifers to investigate cellular, molecular, and genetic processes of aging from the perspective of evolutionary ecology and comparative genomics. Through collaborations with other scientists at the JBPC, Mark Welch extends his exploration of biological diversity to the realm of microbes. He led the development of the bioinformatics tools necessary to analyze the first massively-parallel tag sequence datasets that demonstrated the existence of a “rare biosphere” of microbial taxa and currently leads the teams developing the Visualization and Analysis of Microbial Population Structures project and the Global Names Discovery, Indexing, and Reconciliation Service. As Director of the Bay Paul Center he also oversees development of bioinformatic resources for the Encyclopedia of Life.
DNA Damage Prevention and Repair in an Anciently Asexual Animal
Why the process of meiosis and syngamy (sexual reproduction) is nearly universal among animals and why the vast majority of species that abandon it suffer rapid extinction is one of the central mysteries of biology, with broad implications in genetics, genomics, and evolution. Bdelloid rotifers—common aquatic microscopic animals similar in complexity to nematodes—are perhaps the most successful and diverse metazoans to have abandoned sexual reproduction.
We are part of the international consortium that recently reported on the first sequencing, assembly, and analysis of a bdelloid genome. Whole genome analysis revealed features supporting our earlier conclusion that bdelloid rotifers are long-term asexuals: there are many large-scale genome rearrangements inconsistent with pairing of homologous chromosomes in meiosis, and an absence of genes involved in forming the synaptonemal complex. Other unusual features included extensive gene conversion between former haplotypes, and a non-metazoan origin of ~8% of coding sequences through horizontal gene transfer. These results support our hypothesis that the genome structure of bdelloids is shaped not only by long term evolution without meiosis but also by the desiccation-prone niche to which bdelloids have adapted, which selects for enhanced mechanisms to ensure genome integrity.
Our ongoing research is focused on these mechanisms, specifically genes we have identified in bdelloid genomes involved in DNA damage prevention and repair (DDPR). We find these genes in multiple divergent copies in every bdelloid species we have examined, and our bioinformatic analyses suggest many have evolved specialized or novel functions. Some, including those encoding X family polymerases, DNA-PKcs, and Artemis, are absent from the standard invertebrate models Drosophila and C. elegans and are therefore generally—but incorrectly—considered “vertebrate-specific.” Bdelloids thus present a new opportunity to better understand the evolution of these genes and to gain new insight into the full potential activity of their proteins. We have also identified genes acquired by bdelloids through horizontal gene transfer that encode proteins involved in the production antioxidants and the repair of glycosylated, alkylated, or dimerized nucleotides.
Evolutionary Ecology and Comparative Genomics of Aging.
In collaboration with Terry Snell at Georgia Tech we previously examined the ecological and evolutionary dynamics of sex and speciation in the Brachionus plicatilis group of facultatively sexual monogonont rotifers. We have made use of this knowledge, as well as genomic resources we developed during the project and the intrinsic advantages of Brachionus as a model system, to study the biology of aging from the perspective of evolutionary ecology and comparative genomics. We recently collected whole transcriptome expression data from five life history stages of Brachionus and found significant differences in the expression of sirtuins and oxidative damage response genes known to mediate aging in humans, and a surprising upregulation during senescence of genes involved in multiple DNA damage response pathways. These results, combined with our genomic and biochemical investigation of DNA damage prevention and repair genes in bdelloids, suggest that rotifers may be particularly efficacious models for studying the relationship between DNA damage and aging.
Aging research in my lab now centers on investigating the gene networks involved in aging, and understanding how and why ecological differences select for different responses to aging stimuli. Caloric restriction (CR) by either reduced daily feeding or alternate day feeding and fasting (intermittent feeding) is one of the most reliable means of extending lifespan in diverse organisms, but the complex genetic mechanisms are poorly understood. Competing theories predict different molecular pathways invoked in response to CR, and forecast different lifespan outcomes. We have conducted life history experiments with more than a dozen Brachionus species and find that closely related species display different phenotypes in response to caloric restriction. These include: extended lifespan in response to either daily CR or intermittent feeding; extended lifespan in response to daily CR but decreased lifespan with intermittent feeding; no significant change in lifespan with either treatment, and decreased lifespan with either treatment. We are currently examining whole transcriptome expression data from species with these different responses. Our goal is to identify subtle differences in the gene networks responsible for these phenotypes and to link these with ecological differences between species and their adaptation to different environments. Preliminary analyses confirm the suggestion from life history assays that daily CR and intermittent feeding invoke different molecular mechanisms: intermittent fasting appears to be part of a generalized stress response while daily CR has effects on a variety of metabolic processes. In more detailed studies of a single species, we have found that both forms of CR have a maternal component, in that mothers on a CR diet have offspring with greater lifespan and fecundity even when the offspring are raised under ad libitum conditions. Strikingly, we also found that maternal CR can rescue the detrimental effect of maternal age on offspring lifespan and fecundity.
Analyzing the Diversity of Microbial Communities.
In collaboration with other scientists in the Josephine Bay Paul Center I investigate patterns of microbial diversity in marine ecosystems and the human body, with the goal of developing methods to monitor changes that reveal ecosystem health and the limits of environmental resiliency. Monitoring microbiomes associated with animals and plants can reveal disruptions in established diversity patterns and serve as an early indicator of the adverse health effects of environmental stressors. Monitoring the microbiome of keystone and foundational species can play an important predictive role in overall environmental maintenance as well as in specific instances of conservation biology where the health of the animal is otherwise difficult to measure.
Large-scale surveys of microbial diversity are now economically feasible, but present a considerable challenge in data analysis. I lead development of the VAMPS project (Visualization and Analysis of Microbial Population Structures) to address this challenge. VAMPS is a free, open-source database-driven website that allows researchers to analyze microbial community diversity and the relationships between communities, to explore these analyses in an intuitive visual context, and to download analyses and images for publication. A major strength of VAMPS is that researchers can not only examine datasets within their own projects but can compare these with datasets from NSF Long Term Ecological Research sites, the International Census of Marine Microbes, the Human Microbiome Project, and hundreds of other individual projects. VAMPS currently hosts more than 900 projects encompassing more than 25,000 datasets and over 400 million sequence tags, and is used by nearly 1500 investigators from around the world.