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Call For Papers: 2nd International Symposium on Animal Functional Genomics
1 Immunogenetics Laboratory and Center for Animal Functional Genomics, Department of Animal Science, Michigan State University, East Lansing, Michigan
2 Department of Dairy Science, University of Wisconsin-Madison, Madison, Wisconsin
THIS SPECIAL ISSUE of Physiological Genomics highlights 12 papers that reflect presentations made by 110 international delegates of the 2nd International Symposium on Animal Functional Genomics (2nd ISAFG) held May 16th-19th, 2006, at Michigan State University (East Lansing, MI). This was the second such Symposium hosted by Michigan State University's Center for Animal Functional Genomics (http://www.cafg.msu.edu); the first Symposium was convened in May 2003. Readers of this Special Issue are encouraged to refer to the ISAFG web site (http://www.isafg.msu.edu) to view abstracts from both Symposia. Delegates of the 2nd ISAFG heard outstanding invited lectures by 11 preeminent genomics scientists including David Allison (keynote address; see this issue Ref. 4), Christina Kendziorski and Michael Newton (statistical genomics), Gustavo Stolovitzky and Eric Schadt (bioinformatics), Michael Murtaugh and David MacHugh (animal health; see this issue Refs. 1, 6), Aaron Hsueh and Richard Schultz (reproduction), and Leif Andersson and Juan Medrano (growth and metabolism). In addition to new insights gained from studies in humans and lab animals that were covered by these invited lectures, 68 oral and poster presentations made by the 2nd ISAFG delegates included agriculturally and aquaculturally important topics in species that ranged from farm animals (sheep, pigs, chickens, turkeys, and cattle) to zebra muscles and rainbow trout.
A main objective of the 2nd ISAFG was to provide a forum for the exchange of updated information about animal functional genomics research, including use of data from animal models and isolated cells and cell lines, to address issues of production animal agriculture and aquaculture. The Symposium was supported by National Research Initiative Grant 2006-35205-16706 from the US Department of Agriculture-Cooperative State Research, Education, and Extension Service and nine generous corporate partners that have been instrumental in developing functional genomics reagents and tools for the animal and veterinary sciences communities (Applied Biosystems, Beckman Coulter, Fisher Scientific, Genomic Solutions, Invitrogen, Molecular Devices, Operon, Tecan, and ArrayIt). A second objective of the Symposium was to share visions for future impacts and applications of functional genomics research on animal production systems throughout the world. An outstanding International Organizing Committee, which included Antonio Reverter (Australia), Bonnie Mallard (Canada), Christian Burvenich (Belgium), David Henderson (USA), Elizabeth Glass (Scotland, UK), Luiz Furlan (Brazil), and Peter Heegaard (Denmark), worked diligently to ensure that the 2nd ISAFG international guest speakers and delegates covered topics in animal functional genomics that have global importance and impact. The final objective of the Symposium was to provide an arena for frank discussions about how to implement new technologies, methodologies, and gene expression information to bridge gaps between discovery and application. Such gap bridging seems a daunting task in the animal and veterinary sciences both because of the lack of fully annotated gene expression databases in these species and because the issues facing agriculture and aquaculture do not conjure up the same sense of urgency (or funding) as biomedical issues do. However, farm animals and fish are used to both clothe and feed humans, and many of the issues studied in these species make them excellent models for biomedical research (please refer to the following web site for additional comments on this topic: http://www.adsbm.msu.edu). Therefore, identifying, interpreting, and elucidating the function of genes, gene variants, and protein networks that underlie gene expression and thus the health, reproduction, and growth and development of livestock, poultry, and aquacultural species are in fact important and urgent. Furthermore, domestic species are invaluable in comparative genomics research and in defining highly conserved noncoding regulatory regions of genomes. These issues were the foci of the five disciplinary sessions (Statistical Genomics, Bioinformatics, Animal Health, Animal Reproduction, and Animal Growth & Metabolism) at the 2nd ISAFG.
Three papers included in this Special Issue represent the growing impact of international animal health research presented at the 2nd ISAFG. For example, in their invited 2nd ISAFG paper, O'Gorman and colleagues (6) describe novel results from real-time quantitative RT-PCR and mapping experiments for a set of Th1-Th2 polarizing cytokine genes that they showed to be differentially expressed in peripheral blood mononuclear cells of two African cattle breeds divergent in their tolerance to the protozoan parasite, Trypanosoma congolense. The cattle breeds studied included trypanotolerant N'Dama (Bos taurus) and trypanosusceptible Boran (Bos indicus). As the authors explain, T. congolense is the cause of African Trypanosomiasis, or sleeping sickness, in susceptible cattle, a fatal wasting disease that is accompanied by severe anemia, immunosuppression, and increased risk for secondary infections. T. congolense is transmitted from animal to animal in the saliva of biting tsetse flies and is thus of particular concern for the tsetse belt of Sub-Saharan Africa, where large populations of cattle become infected and die. Through their experimental infection studies performed in Africa, these investigators have elucidated expression differences in key acquired immune response genes that may underlie genetic differences in trypanotolerance versus trypanosusceptiblity. Future identification of polymorphism in these genes or proteins that regulate their expression may render them useful in marker-assisted selection for protozoan resistance in African cattle.
Livestock around the world also are plagued by disease caused by enteric pathogens. As such, the study of mucosal immunity in these species is critical. In their invited 2nd ISAFG review paper, Dvorak and colleagues (1) summarize a cluster of their recently published studies in which combinations of differential subtraction, cDNA microarray analysis, and radiation hybrid mapping were utilized to dissect out novel Peyer's patches genes involved in mucosal immunobiology of the pig small intestine. Peyer's patches are critically important to health in all mammalian species because they play a central role in balancing the conflicting functions of absorption of nutrients and tolerance to commensal bacteria and food antigens with immune resistance to enteric pathogens. These authors report on a cluster of novel porcine genes they identified as being uniquely expressed in the Peyer's patch, supporting their notion that specialized biochemical and molecular processes unique to the small intestine of the pig are required to carry out its complex physiological activities. These genes may be good candidates for improved nutrition and manipulated mucosal immune defense in the pig (and possibly other species, including humans).
Along the same theme of host-enteric pathogen interaction, the 2nd ISAFG paper by Murphy and colleagues (5) describe what could possibly end up being a landmark study in which the transcriptomes of primary bovine monocyte-derived macrophages were analyzed by microarray analysis following in vitro infection with one of two closely related but pathologically different Mycobacterial species, Mycobacterium avium subspecies avium (MAA) or M. avium subspecies paratuberculosis (MAP). In cattle, MAA elicits a strong protective Th1-based inflammatory response by infected macrophages and does not cause disease. In contrast, MAP infection ultimately leads to an inappropriate Th2-based immune response resulting in a chronic wasting and ultimately fatal inflammatory bowel disease of cattle (and other ruminants) called Johne's disease. These authors present intriguing data that suggest that MAP infection uniquely elicits a gene expression signature in bovine macrophage cells that encompasses a major portion of the macrophage transcriptome and includes a particularly large cluster of genes encoding proteins involved in or regulated by three MAP kinase signaling pathways. The noted transcriptome changes readily explain why MAP survives and proliferates well in bovine macrophages and thus the persistence and virulence of this enteric pathogen in dairy and beef cattle populations throughout the world. Pending additional research, these genes could prove to be excellent targets for drug discovery aimed at preventing or treating Johne's disease.
Another concern for livestock health worldwide is the negative effects that environmental and physiological stressors may have on immune status. In their 2nd ISAFG paper, Weber and colleagues (12) describe a series of well-controlled experiments in which cDNA microarray analysis and cell phenotyping were used to characterize changes in the transcriptome and behaviors of bovine blood neutrophils subjected to the master stress hormone, glucocorticoid. Neutrophils are innate immune cells that respond rapidly to infectious and other noxious agents present at sites of tissue infection and inflammation. However, these first-line immune defenders also can cause significant inflammatory tissue damage if their activities are not tightly regulated. Glucocorticoids are released by the adrenal cortex during an animal's stress response, including during infection and inflammation, and are well known for their potent yet ill-defined anti-inflammatory properties. These steroids enter the cytoplasm of target cells and bind to homologous receptors, which are ligand-activated transcription factors that coordinately regulate the expression of dozens of genes simultaneously. Results of this study revealed that the transcriptome of bovine neutrophils is unexpectedly complex and plastic, responding to glucocorticoid stimulation with acute downregulation, as well as profound induction of large numbers of steroid-responsive genes. The expression changes documented in this study were associated with extended life span of the cells, depressed proinflammatory and profibrosis potential, and activated bactericidal and wound healing capacities. This work suggests that glucocorticoids, rather than being detrimental, may induce beneficial adaptive changes in neutrophils during times of stress that are geared towards tissue repair.
In addition to health, efficient reproduction is key to successful agriculture across the globe. Many beef and dairy producers have turned to embryo transfer as a means to facilitate reproductive efficiency and to expedite genetic progress for production efficiency, herd health, and meat quality. However, this is an expensive endeavor that is often met by additional economic losses due to early embryonic mortality and failed pregnancies. In their 2nd ISAFG paper, El-Sayed and colleagues (2) describe an elegant study in which they used a custom-designed cDNA microarray to examine the transcriptional profiles of blastocyst-stage bovine embryos in relation to pregnancy success following transfer of the embryos into recipient cows. They identified more than 50 genes whose expression profiles were differentially expressed in embryos that resulted in live calves born versus those that did not result in pregnancy or those that resulted in early embryonic loss. A particularly enriched cluster of genes in the successful pregnancy embryos encode proteins involved in implantation and placental development, growth factors, signal transduction, and carbohydrate metabolism. Thus, this study has revealed blastocyst-specific genes whose expression could be manipulated in the future to enhance pregnancy success following embryo transfer.
Additional 2nd ISAFG papers included in this Special Issue represent state-of-the-art thinking and approaches for the acquisition, analysis, interpretation, and application of large-scale gene expression data derived from food-producing mammals, poultry, and fish. Though these animal species are important societally and economically, elucidation of their genome sequences and development of genomics tools and annotated databases for them have lagged well behind those for human and laboratory animal species. Despite this, and with recent support from key Federal funding agencies and corporate sponsors, the animal and veterinary sciences communities have remained diligent in pushing forward the sequencing of genomes for four key agricultural animals (cattle, chickens, horses, and pigs) and have developed their own expressed sequence tag (EST) and cDNA resources for the construction of species- and tissue-specific cDNA libraries and databases. These also have been exploited for the creation of variably annotated cDNA and oligonucleotide microarrays. A wide variety of these new resources are described in this Special Issue, including in the papers by Dvorak et al. [pigs (1)], El-Sayed et al., Murphy et al., O'Gorman et al., Saama et al., and Weber et al. [cattle (2, 6, 9, 12)], Wang et al. [chickens (11)], and Salem et al. [rainbow trout (10)]. Of particular note, the paper by Wang and colleagues (11) describes a strategy for development of a full-length chicken cDNA database (available at http://bioinfo.hku.hk/chicken/), which was created by aligning existing chicken ESTs along full-length cDNAs from the human and mouse databases and establishing open reading frames for each transcript. This new database resource will be instrumental for fine mapping and annotating the sequenced chicken genome and in interpreting information from future functional genomics studies that utilize this globally important agricultural animal. Also of note, Salem and colleagues (10) describe a unique salmonid cDNA microarray resource and rainbow trout model of muscle atrophy in their 2nd ISAFG paper, which were used to study gene expression in relation to muscle degradation. The regulation of muscle mass is of obvious importance to agricultural and aquacultural success worldwide. These investigators identified more than 200 genes involved in muscle deterioration, many of which are also involved in mammalian muscle atrophy caused by such perturbations as nutritional restriction and chronic metabolic disease (e.g., diabetes), as well as many genes that have not been defined in mammal muscle studies.
In another vein of animal genomics research scholarship, some of the best and most forward-thinking statistical minds have applied their expertise in traditional animal breeding and genetics to explore powerful experimental designs and methods for the analysis of large-scale gene expression data to help animal and veterinary scientists reveal the marvels of their biological systems and explain the molecular basis for genetic variation that is often substantial in those systems. This is well documented in the 2nd ISAFG papers by Mao et al. (3), Reverter et al. (7), Rosa et al. (8), and Saama et al. (9). Briefly, Mao and colleagues (3) propose an extension of the Kempthorne genetic model for studying epistasis between two loci in the presence of Hardy-Weinberg disequilibrium, as well as linkage disequilibrium, and provide formulae for power and sample size calculations for such studies. Reverter and colleagues (7) present an application of a large-scale multivariate mixed model approach and applied it to the joint analysis of nine microarray experiments comprising 147 arrays in a model system related to the development of muscle mass and deposition of adipose tissue in beef cattle under 47 different experimental conditions. Using the information from this analysis and a subsequent correlation-based approach, these authors were able to construct a preliminary gene network that regulates meat quality in cattle. In a related line of investigation, the review paper by Rosa and colleagues (8) presents several design strategies that are intended to increase the efficiency of microarray experiments in the context of genetical genomics studies. These are extremely high-dimensional studies that combine quantitative information on phenotypic traits and gene expression with pedigree structure and genotype data resulting in the rapid elucidation of gene interactions and pathways involved in a physiological scenario of interest. This approach also enables the estimation of variance components and heritability of transcript abundances. In another such study, Saama and colleagues (9) propose a novel statistical data analysis protocol for studying the transcriptome of bovine oocytes, which also enables investigators to decipher how meiotic maturation affects the oocyte transcriptome.
The tremendous shift in statistical scholarship described above has been paralleled by the efforts of a newer breed of scholar, the bioinformatician, who patiently and eagerly facilitates connections and better understanding between biological and statistical scientists to extract the most information possible from large-scale gene expression data sets. This "conflict of disciplines" is well described in the 2nd ISAFG keynote paper by Mehta and colleagues (4), who portray with immense clarity the key challenges, opportunities, and developments in statistical data analysis and interpretation of data from genome-level and other high-dimensional biological studies. Special attention is devoted in this outstanding commentary to the development of an epistemological framework for the validation of preoffered statistical procedures and informatics algorithms, such that statisticians and bioinformaticians are able to judge their methods not only as sound in their minds but also as yielding the information that biologists consider important and well connected to the hypothesis being tested. It was clear from round table discussions at the 2nd ISAFG that all scientists look forward to a future where this level of understanding across the disciplines enables knowledge generation that is accurate and relevant.
The presentations of the 2nd ISAFG and accompanying papers in this Special Issue are outstanding examples of how research on the functional genomics of livestock, poultry, and aquacultural animals has blossomed in the past 5 years. However, these works also illuminate the increasing need for sound statistical judgment, enlightened bioinformatics, and development of well-annotated gene expression databases for the agricultural and aquacultural animal species. These promise to be key topics of presentation and discussion at the 3rd ISAFG, which is to be chaired and hosted by Elizabeth Glass and her colleagues at the Roslin Institute (UK) in May 2008.
We sincerely appreciate the outstanding contributions of the invited speakers and other delegates of the 2nd ISAFG, including the authors of papers included in this Physiological Genomics Special Issue. We extend our whole-hearted thanks to the Editorial Board of Physiological Genomics for agreeing to publish these 2nd ISAFG papers as a cluster in this Special Issue and for facilitating efficiency and rigor in the peer review process. To the readers of this Special Issue, we hope you enjoy and learn from the experiences of authors of these 2nd ISAFG papers and encourage you to join us at the 3rd ISAFG.
FOOTNOTES
Address for reprint requests and other correspondence: J. L. Burton, Immunogenetics Lab. and Center for Animal Functional Genomics, Dept. of Animal Science, Michigan State Univ., E. Lansing, MI (e-mail: burtonj{at}msu.edu).
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).
REFERENCES
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