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Exploring Horizons for Domestic Animal Genomics: Workshop Summary 2 The Value of Sequencing Domestic Animal Genomes Sequencing the genomes of domestic animals could be beneficial to animal production practices, animal health and welfare, and to our understanding of the genetic basis of diseases in both animals and humans. Beyond these more applied areas of study, sequencing genomes also presents opportunities for increasing our basic knowledge of the evolutionary pathways of these and related species. The precise benefits will vary somewhat from species to species, but in general they fall into three categories. SEQUENCING FOR AGRICULTURE The first, and most familiar category is the array of economic benefits that farmers, ranchers, and pet owners could expect from the genetic sequencing of their animals. For thousands of years, these animals have been bred for desirable traits, including disease resistance and rapid growth in farm animals, and the color of the coat or shape of the head in pets. The precision of traditional, selective breeding is low and genetic change is poorly characterized. Theoretically, with information from a sequenced genome, it will be possible to have much more precision with breeding efforts and even to genetically engineer specific traits by adding, removing, or altering individual genes. In agriculture, the traits of interest are primarily production traits, noted Steven Kappes, of the U.S. Department of Agriculture’s Agricultural Research Service (USDA-ARS). “We have quite a list of traits that we look at within farm animals,” said Kappes, director of U.S. Meat Animal Research Center in Clay Center, Nebraska. “These include growth—both prenatal and postnatal— reproduction, egg production, and carcass traits, including fat deposition within
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Exploring Horizons for Domestic Animal Genomics: Workshop Summary and between the muscles, inside organs, and layered under the skin.” Other production traits are meat tenderness and palatability, as well as milk production. Kappes pointed out that in many cases scientists already have found the general location on a chromosome for a gene that expresses a particular trait in an animal. The technical term for the general location of a gene, which affects a particular trait that is measured on a quantitative scale, is a “quantitative trait locus,” or QTL. “We have in excess of 30 QTLs in cattle for these different traits,” Kappes said, plus a similar number in pigs and a dozen or so in chickens. Once a particular animal genome is sequenced, it might be possible to determine which gene or genes affect a trait, and thus give breeders the information they need to enhance the production traits of that animal. SEQUENCING FOR ENHANCED BASIC SCIENTIFIC UNDERSTANDING Besides the agricultural benefits, genomic sequencing of domestic animals will be important in a number of areas of basic science, particularly in understanding the evolutionary relationships between species. “Nothing in biology really makes sense except in light of evolution,” commented Stephen O’Brien, chief of the Laboratory of Genomic Diversity and head of the Section of Genetics at the National Cancer Institute (NCI). The genome of each species is the end result of millions of years of mutation and natural selection. The genome of every mammal alive today, for instance, can be traced back to the genome of an ancestral mammal that lived some 200 million years ago, and the genomes of the different species provide a record of how the descendants of that proto-mammal gradually diverged into many different forms, as well as a guide to how today’s mammals are related to one another. When we explore the evolution of a living species, we assume that its presence here today is the result of that species successfully adapting and negotiating the myriad of ecologic and environmental challenges over time, O’Brien explained. “Nestled in the genomes of living species are the historic footprints of the adaptive events that led them to where they are today.” In other words, comparing the genomes of various mammals alive today might be the best option for understanding how the species evolved as they did. Several other evolutionary questions can be addressed by sequencing a variety of mammals, O’Brien said. “We don’t know which of the genes make us human, as opposed to apes or as opposed to non-ape primates, or as opposed to other orders of mammals.” Only by sequencing the genomes of other animals and comparing them gene by gene with the human genome will it be possible to answer this fundamental question. Some preliminary comparisons between humans and other mammals already have been made, said Harris Lewin of the
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Exploring Horizons for Domestic Animal Genomics: Workshop Summary University of Illinois, and they illustrate the kinds of discoveries that could be made by comparing full genomes. “When we do the comparisons, we find things in other species that are either very rapidly evolving or are completely missing from the genomes of humans. In the mouse, for example, there are 200 to 300 genes that are not present in humans or cattle.” By studying these genes, Lewin said, researchers could uncover ways in which species evolution diverged onto two or more different paths to achieve similar metabolic functions. Furthermore, O’Brien said, comparing the ways in which evolution has structured different genomes should help researchers uncover the logic of that organization. “We don’t really know,” he said, “why the genes are arranged in the way that they are—why they’re next to the ones that they are. We have some clues in certain cases where the genes are clustered, but by and large we don’t really understand whether it was a random process or whether there was an adaptive value to it.” By having a number of genomes to compare, researchers might be able to find patterns in this structure across different species of mammals and speculate as to the arrangement of genes. SEQUENCING FOR HUMAN HEALTH AND MEDICAL RESEARCH A third category of benefits to sequencing domestic animal genomes could have more immediate practical applications. When the human genome was sequenced, it was hailed as a major step toward finding new medical treatments and other means of benefiting human health, but it was only one step, and there is much that remains unknown about the human genome and how it structures human development. By sequencing the genomes of other mammals, biomedical researchers seek to answer more of the remaining questions about the human genome and its potential for improving human health. What remains unknown about the human genome? First, although the sequencing of the genome allows researchers to determine the genes that are characteristic of humans, the functions of most of those genes remains unknown. According to O’Brien, “of the 30,000-odd genes that have been identified by various algorithms,” only about 8,000 have been named and their functions identified. Furthermore, he noted, the genes make up only part of the genome, and the remainder is even more mysterious. “The genes are nested in a sea of non-coding regions, including cryptic regulatory elements, promoters, enhancers, silencers, transcription factor binding sites and all kinds of interesting features that have been discovered and are yet to be discovered.” Once a genome has been sequenced, there is still much more to do and many questions to address, noted O’Brien. “And one of the ways in which we are hoping to approach some of these questions is through applications of a comparative sense.” That is, by studying the genomes of other species,
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Exploring Horizons for Domestic Animal Genomics: Workshop Summary researchers expect to make inferences based on what is not yet understood about the human genome. To determine the function of human genes, for example, researchers can look for similar genes in other animals whose functions are known. If scientists have identified a particular gene in the mouse and know what it does, they can search the human genome for a gene with a similar sequence and surmise that the human gene probably has a function similar to the one in the mouse. This is part of annotating—or creating a set of comments, notations, and references describing the experimental and inferred information about a gene or protein. In its most elementary form, the human genome may be described as a shorthand list of three billion “letters”—A, T, C, and G—each of them representing one of four nucleic acid bases: adenine, thymine, cytosine, and guanine, respectively. Bases are small, nitrogenous molecules, which in deoxyribose nucleic acid (DNA) occur in pairs (base pairs). For example, in DNA, only adenine/thymine, and cytosine/guanine, can pair together. But this base sequence information, or code, is useful only to the extent that researchers can interpret and apply it, which is why having other genomes available to study is so valuable. Harris Lewin offered one example of how the genome of another organism can benefit the understanding of the human genome. He compared a long stretch of human DNA with the corresponding stretch of DNA in the cow, looking for similarities and differences. Because humans and cattle had a common ancestor—although it was some 60 million years ago—it is generally possible to align a stretch of DNA from one species with a stretch in the other that shares the same genes and other features, and the pattern of similarities and differences between the two stretches is very informative to the educated eye. Over those 60 million years, random mutations accumulated in both the ancestral line that led to humans and the one that led to cows, so that many of the base pairs in their DNA are no longer the same. But some pairs are much more likely to change than others. The bases that make up a gene, for instance, are relatively resistant to change because most changes in the gene (known as mutations) are detrimental to the animal—some are even fatal—and so natural selection tends to conserve the pattern of bases in a gene. By contrast, in stretches of DNA that have no apparent purpose—for instance, old genes that are no longer functional—the mutations will accumulate unabated. The result is a clear pattern of similarities and differences in the DNA of the two species. Similar patterns suggest that an important function has been conserved between the two species; different patterns suggest that function is not strongly dependent upon the particular sequence of base pairs in that segment of the DNA. When Lewin compared the two corresponding stretches of DNA—one from humans and one from cattle—he discovered something interesting. “There is a 12-kilobase region (i.e., one that is about 12,000 base pairs long) and if you
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Exploring Horizons for Domestic Animal Genomics: Workshop Summary go through and you annotate the human genome sequence, you see absolutely that there are no annotated genes in this region. So what is this region doing?” There is clearly something important about that region, something so vital to the functioning of the two species that its sequence has been mostly conserved over 60 million years, but nobody knows what it is. Indeed, Lewin said, comparisons between the mouse and the human genome have shown that “only 56 percent of the conserved sequences between the mouse and the human could be accounted for by known features of genes.” In other words, 44 percent of the DNA that has been conserved during the tens of millions of years that mice and humans have been diverging lacks the usual “landmarks” that scientists typically are able to look for. “This is an extremely important point,” Lewin said. “We have absolutely no idea what the functions of these regions really are.” “We have a lot to understand about this type of conservation,” Lewin continued. “Having the cattle sequence or the pig sequence or any other mammalian genome from an animal that’s as distant from the primates as we can get is going to help us to annotate these very interesting and compelling regions of the genome.” Beyond such comparative genomics, said Steven Kappes, scientists will need to compare what is happening at the protein level in various species, or what he termed “comparative proteomics.” “I think we’re going to find that this is going to be a lot more informative than even comparative genomics—really looking at what these genes are doing in different systems. And farm animals provide a very unique perspective to identify these genes and determine gene function.” In the case of a gene called insulin-like growth factor 1 (IGF-1), for example, researchers believed they knew the function of the protein produced from the gene. But, Kappes said, “Then we started looking at more tissues and all of a sudden it turned up in a lot more tissues than we ever expected. We began to hypothesize what it was doing in these different tissues, and pretty soon the true function of that gene and its corresponding protein became cloudier and cloudier. So utilizing different animals will allow us to get at the true function of that gene, and then allow us to break down what that gene product (or protein) is doing in that biochemical pathway, and to look across different organs and tissues at different developmental moments in the organism’s life, to really identify how it’s regulated and how it functions.” In another case, Kappes said, a researcher discovered that a reproductive hormone was playing a key role in the development of muscle in an early embryo. “What is it doing in muscle development?” This discovery illustrated how little currently is known about the functions of many genes, but with further analyses of different animals and their traits, Kappes noted, “we will have a much better chance of truly understanding what they do.”
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Exploring Horizons for Domestic Animal Genomics: Workshop Summary ADVANTAGES OF DOMESTIC ANIMALS FOR COMPARATIVE GENOMICS For researchers doing comparative genomics and comparative proteomics, domestic animals have one strong advantage over most other species: there is a long history of studying these animals. Scientists are familiar with their development, their resistance to disease, and determining how to work experimentally with them in various ways. For example, Lewin said, “Almost every human in-vitro fertilization fertility clinic employs methods that were first developed for cattle and sheep. Artificial insemination, embryo transfer, freezing semen, and sexing were all first developed for use in cattle and sheep. Furthermore, if you look at the species in which cloning has been most successful, it’s actually in the ruminants [cattle, sheep, and related animals]. So application of functional genomic technology to early mammalian development using the cow and the sheep is going to be an extremely important tool to us in our understanding the early events in nuclear reprogramming and what causes embryos to live or die past a certain point, prior to and after implantation.” As a result of all the research done on domestic animals over the past several decades, decoding the genomes of cows, pigs, and others will have tremendous value for human medicine, Kappes said. “Comparative genomics will utilize a lot of the research background that we have done for the last forty or fifty years.” One area in which the genomes of domestic animals could be particularly valuable, Lewin said, is biosecurity. “There is an awareness of the problem that we’re facing in risk to both human and animal health from zoonotic pathogens such as anthrax. Understanding the genes involved and creating a wider array of genomic tools is going to allow us to do the things that we need to do to protect not only the animals, but the human population as well.” Such measures will include, Kappes said, learning about how the organisms that cause disease interact with their hosts and how they are transferred from host to host. “This is important for food security, food safety, [defensive] biologic warfare and understanding the interactions of the microbe and the animal. It is another area that we have not tapped very well and we will see a tremendous amount of information come out of that.”
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