For several decades swine have been a valuable model for human health and disease  and cited in . As a general rule, animal models for human disease provide researchers with the knowledge of disease progression, and insights into new therapies. These potential therapies include drug discovery, validation, and toxicology but also can be extended to include gene therapy, surgical interventions and physical therapy. Rodent models, largely the mouse but more recently the rat, have been used widely to study many human health issues . Unfortunately, as in the case of cystic fibrosis, the rodent models do not always fully mimic the relevant human symptoms.
Genetic modification is often required to create, or improve the quality of, a model. Gene transfer into the genome of livestock species was first achieved in 1985 via pronuclear injection . While this was a tremendous advance, transgenesis by pronuclear injection is limited to adding a gene(s) at a random location, and has the potential to cause insertional mutations [5, 6] as well as altering the expression of adjacent host DNA sequences. There have been many attempts to overcome this problem by insertion of large DNA fragments (YAC or BACs) , and matrix attachment regions or scaffold attachment regions [8, 9]. With the advent of somatic cell nuclear transfer (SCNT) it became possible to select donor cells with the desired integration prior to creating the animal. While SCNT has been useful for transgenesis, the greater advantage is realized when targeting of a gene via homologous recombination is desired. In mice and recently rats, this is accomplished through the use of embryonic stem cells. However, there has been no verified germ-line competent embryonic stem cell in swine. Despite not having a germ-line competent ES cell line, investigators have developed induced pig pluripotent cell lines [10–12] which may prove to be useful for the production of genetically modified pigs. Utilizing SCNT seven genes and 1 transgene have been knocked out in swine: alpha 1, 3 galactosyltransferase (GGTA1;  the cystic fibrosis transmembrane conductance regulator (CFTR; [14, 15], Immunoglobulin light chain kappa (IgLK) , Immunoglobulin heavy chain (IgH) , spinal muscle neuron (SMN; ), Green Fluorescent Protein transgene (eGFP; ), SIGLEC1 (Whitworth et al. 2011 unpublished data) and peroxisome proliferator-activated receptor-gamma (PPARγ); , and there are two knock ins ). While the efficiency of cloning still remains low  a complete swine genome will enhance the identification and modification of genes that are relevant to human disease. This is especially true for genetic modification of existing genes or inserting a transgene at a given location. Prior to completion of the swine genome the first step in developing a construct was to look comparatively at the sequences of other species. The next step was to search both assembled and raw data for similar sequences. And finally the construct could be built. One of the complications that can arise is the presence or absence of multiple members of a gene family. With the latest draft of the genome completed and the limited annotation associated with it we have some assurance that there is only a single copy a given gene, or multiple family members of the gene. A great example here is SMN. In humans there are two spinal muscle neuron genes (SMN1 and SMN2). In pigs there is only a single gene for spinal muscle neuron. In humans mutations in both alleles of SMN1 result in reliance on SMN2 and the development of spinal muscle atrophy (the number one genetic cause of adolescent mortality in North America). Thus to make a model of spinal muscle atrophy one must not only knockout SMN, but also a human SMN2 must be added as a transgene . Prior knowledge of the number and location of specific sequences makes these projects move forward much more rapidly.
Completion of the swine genome will be a key informational tool for the understanding of human sequences and their potential role in the development of biomedical models. Using comparative genomics, we can begin to investigate and identify cross-species conserved putative genes and regulatory elements as well as single nucleotide polymorphism of genes specific to human diseases. As an example the completion of the human genome, researchers were able to identify the gene mutation that caused sickle cell anemia . Additionally the completion of the swine genome will be useful in the development of new techniques such as cell-based transgensis. Utilizing cell based transgenesis with site specific modification of the pig genome, one can be begin to modify gene function for the enhanced development of novel disease models in several research areas such as cardiovascular disease, xenotransplantation, and neurodegenerative diseases.
Importance of the pig as a biomedical model
Although the classical model organisms have provided important information about the basic biology of genes and proteins, these models often have limited usefulness due to their inability to sufficiently represent the human disease. In addition, there has been a dramatic decline in the productivity of new drugs  which appears to be associated with the current selection of in vivo models. The current animal models do not reflect the pathophysiology of many human diseases well enough to attain sufficient insight into the efficacy of novel drugs, drug therapy or medical devices; e.g. Cystic Fibrosis [14, 15, 23], Spinal Muscle Atrophy  and Parkinson’s Disease . While the pig may not be an obvious choice for a biomedical model, it has been a top choice as a model of human health and disease due to the similarities in anatomy, genetics and pathophysiology.
When compared to other large animal models, swine reach sexual maturity early (6–8 months), have a short gestation length (~4 months) and give birth to multiple offspring. Additionally swine are not seasonal breeders and can therefore produce offspring at any time during the year. Due to the economic and agricultural importance of swine, there is a great deal of information, and logistical support on standardized housing, feeding, and reproductive management and healthcare. Swine also provide a variety of genetic backgrounds as there are numerous breeds of both standard and miniature pigs that have been selected to thrive in a variety of environmental conditions. It may be that the different breeds of swine will represent the various ethnic groups from various regions of the world.
Animal models are essential for insight into etiology and pathogenesis of human diseases and the development of new strategies for disease prevention and treatment. With regard to human anatomy, physiology and pathophysiology, the pig is a favorable animal model . Structure and function of the swine gastrointestinal tract as well as the morphology and pharmacokinetics of the pancreas are similar to humans . However one difference between humans and pigs is the lymphatic system as the cortex and medulla of the swine lymph node is reversed compared to the human lymph node . With similarities and differences between pigs and humans we can begin to utilize genomic tools to analyze human diseases and the molecular mechanisms of these diseases in the pig. Previous genetic analysis of the pig has led to identification of a quantitative trait loci for cutaneous melanoma , as well as a novel mutation (Arg to Cys) in the LDL receptor which contributes to spontaneous hypercholesterolemia . Additionally pig models have identified markers for puerperal psychosis  and RACK1 as a marker of malignancy for human melanocytic proliferation . As sequences identified in the human are associated with specific disease conditions, an immediate search can be conducted to look for similar genetic variation in the pig. If the variation exists, then those animals can be identified and tested; or if the variation does not exist, then a new genetic modification can be contemplated that would recreate the human phenotype. With a sequenced pig genome and the development of new genetic tools such as SNP chips, investigators will continue to perform genetic analysis of pig populations for molecular mechanisms of human diseases.
The pig genome
The pig genome has been sequenced and is currently being characterized by the Swine Genome Sequencing Consortium (SGSC) using the hybrid approach combining hierarchical shotgun sequencing of BAC clones and whole genome sequencing . By using the 3x coverage of the BACS and the 3x coverage of the whole genome approach, the SGSC will be able to construct a 6x coverage of the swine genome. Currently the revised assembly (Sscrofa Build 10) has been released and is available for use by the scientific community (ftp://ftp.ncbi.nih.gov/genbank/genomes/Eukaryotes/vertebrates_mammals/Sus_scrofa/Sscrofa10.2/ or http://www.ncbi.nlm.nih.gov/genome/guide/pig/).
The swine genome is comprised of 18 autosomes and 2 sex chromosomes (X and Y chromosomes) and is estimated to be 2.7 Gb. The pig genome is ~7% smaller than the human, while the mouse and dog genomes are 14% smaller. In addition to the similarity in size of genome, there is extensive homology of the swine genome to the human. On a nucleotide level swine are 3x more similar to humans than mice are to humans . On average the synteny blocks of swine-human are farther down the phylogenetic tree than the mouse or dog . Since there are larger syntenic blocks between swine and humans, positional cloning from the pig is generally straightforward and local regulatory interactions between enhancer regions are more likely conserved.