swine have served as an important biomedical model for humans for decades ; previous authors have summarized such models in more detail 1 - 5 .
limitations on reference citations for this review has meant that only the most recent will be cited to cover the latest developments and the broadest range of current pig models .
advances using these genomic tools are described in the other reviews in this issue 6 , 7 .
generally speaking , studying animal models of human disease helps scientists understand the mechanisms involved in the disease pathogenesis and thus provides tools for development of gene therapy to cure the disease / condition in humans . to date , the humanized mouse has been widely used to advance our understanding of human hematopoiesis , innate and adaptive immunity , autoimmunity , infectious diseases , cancer biology and regenerative medicine 8 . unfortunately , the humanized mouse and many mouse disease models often do not faithfully mimic the relevant human conditions .
an example is the well developed swine atherosclerosis model which has facilitated analyses of disease progression and pathogenesis and testing of new therapeutics 9 , 10 .
this review will probe , as detailed examples , genomic studies of melanoma and of infectious disease resistance , highlighting issues to consider in designing such genomic studies .
it will end with a short discussion of the potential for genomic approaches to develop new alternatives for control of viral infectious diseases , targeting porcine reproductive and respiratory syndrome virus ( prrsv ) , and the potential for applying knowledge gained with this virus for human infectious disease studies .
as outlined in table 1 the swine has been used as a major mammalian model for human biology 11 . the similarity in size , particularly for miniature pigs , and physiology , and in organ development and disease progression
the ability to deliberately time studies , image internal vessels and organs using standard human technologies , and collect repeated peripheral samples and , at kill , detailed tissue samples , has meant that the pig is an excellent biomedical model for humans .
the ability to use pigs from the same litter , or cloned or transgenic pigs , facilitates genetic mapping .
availability of numerous well defined cell lines , representing a broad range of tissues , will facilitate detailed testing of gene expression , drug susceptibility , etc .
for genomics it is an asset that the pig genome has high sequence and chromosome structure homology with humans . with
the swine genome sequence now well advanced there are increasingly improving genetic and proteomic tools for pigs .
table 2 highlights some of the broad array of biomedical topics now addressed using swine models . some of these studies already employ genomics approaches , such as the heart , transplantation and melanoma models ; others are still in the early stages of affirming swine physiological parameters and utility as a human biomedical model .
each model will be impacted by the availability of the functional genomic tools and swine genome sequence and maps outlined in other reviews in this issue 6 , 7 . some of the best examples of the impact of swine as a biomedical model are found with atherosclerosis and diabetes , diseases that are increasingly important today as the us faces major problems with obesity 9 , 10 .
research is underway in pigs to determine the role of genetic background and to identify nutritional , exercise , and drug approaches which will alleviate disease progression and prevent pathology .
advances in strategies to treat myocardial infarction are being pursued with cellular myoblast repair strategies 12 and tissue engineering of blood vessels 13 .
testing of emergency room treatment options , such as directed cardiopulmonary resuscitation ( cpr ) and ventricular fibrillation or cardiopulmonary bypass , which are difficult to assess in humans , are readily testable with pigs .
all aspects of reproductive function have been studied in the pig , from the basics of maternal - fetal interactions 14 , embryo development 15 - 17 and the impact of transgenesis 18 , 19 to sperm function and quality 20 , 21 .
basic sperm biology , such as chromosome positioning during spermatogenesis 22 , as well as semen transmission of infectious disease 23 , 24 are under active investigation ( table 2 ) .
major transcriptional genomic and mapping efforts are underway in the pig model 14 , 18 and should reveal important pathways regulating reproductive function . because of the size and physiologic similarity of pigs to humans , the pig has become a model of choice for tissue engineering and imaging studies .
a range of imaging techniques has been developed with pigs as an early pre - human validation model .
for example , sentinel node detection is increasingly important for cancer therapeutics ; the pig model has informed techniques for laparoscopic colon visualization and resection procedures 53 , 54 .
tissue engineering using polymer scaffolds 61 have targeted areas as diverse as alternatives for knee meniscus cartilage and artificial bladder construction 62 .
swine skin studies have been very important , the swine melanoma model has been particularly informative . targeted studies analyzing percutaneous permeation with different chemicals will influence international biodefense efforts as well as responses to biological toxins 77 .
gut physiology and intestinal development following probiotics have been pursued in pigs both as a means of decreasing antibiotic usage in pig feed as well as an important human model .
assessments have focused on probiotic strain selection , timing and dosing and the effects of these particularly on neonatal gut physiology .
the swine melanoma model is a well established spontaneous melanoma model and one of the best developed for genomic approaches .
the sinclair melanoma and melanoma - bearing libechov minipig ( melim ) have been studied in detail using immune analyses , focusing on the role of tumor infiltrating lymphocytes , the potential effects of natural killer ( nk ) and  t cells in tumor regression .
imaging and sentinel lymph node ( sln ) mapping will enhance these studies 54 . comparative studies of normal melanocytes with localized tumor cells should reveal tumor specific regulatory pathways 78 ; indeed laser capture microdissection studies revealed loss of the 13q36 - 49 chromosomal region in nodular melanoma cells 79 .
early mapping studies in the sinclair swine melanoma model determined that a single dose of a specific  b  swine leukocyte antigen ( sla ) haplotype on ssc7 was required for tumor initiator 80 ; complex segregation analysis identified a second locus 81 .
these were followed by more detailed qtl studies using the melim model which identified numerous melanoma candidate loci 40 ; interestingly human candidate genes cdk4 and braf were not susceptibility genes in this model .
zhi - qiang 41 continued these studies identifying qtl for the synthetic trait , development of melanoma on ssc1 , 2 , 13 , 15 and 17 .
their detailed phenotyping of 331 pigs revealed highly significant qtls ( p < 0.001/p < 0.05 respectively , chromosome-/genome - wide levels ) for precise disease traits .
these included ssc10 42.0 cm for ulceration ; ssc12 95.6 cm for presence of melanoma at birth ; ssc13 81.0 cm for lesion type ; ssc16 45.3 cm and ssc17 44.8 cm for number of aggressive melanomas ; and the ssc1 melim mc1r*2 allele for black coat color predisposing to melanoma .
as outlined in table 3 these studies affirmed that more exact mapping of complex traits such as tumor growth and regression are improved when very detailed phenotypic information is collected on a large group of animals .
as scientists evaluate methods to prevent infectious diseases and test new therapies and vaccines the pig is an ideal choice .
approaches include probing mucosal tissue responses in respiratory 72 , reproductive 23 , 24 , neurological 73 , and intestinal infections 74 , 75 , testing biotherapeutics and drug therapies , probing the effects of disease on development 70 , 71 and testing therapies for specific ailments , e.g. , asthma 66 , 67 .
major efforts to determine the genomics of host responses using transcription and proteomic analyses are in early stages 82 transgenic and mapping approaches 76 , 83 will help to affirm specific gene and allele involvement .
table 4 outlines some of the major issues to consider as one attempts to use swine models for biomedical studies .
regulation of immune responses and genetic resistance to infectious viral diseases is an area of concern for human and swine .
porcine reproductive and respiratory syndrome ( prrs ) is caused by the prrs virus , an enveloped , single - stranded positive - sense rna virus .
when present in a herd , prrsv causes increased abortions , stillbirths , mummies and chronic respiratory problems in pigs resulting in > $ 560 million losses in the us each year 84 . as an rna virus with an evolving genome , prrsv is particularly problematic due to slow development of protective immunity to homologous challenge and lack of protection against heterologous virus challenge .
thus it is a major target for swine research ; information gained from swine studies will inform human infectious disease studies , particularly for analyses of viral persistence and of factors relevant to prevention of congenital and seminal transmission pathways .
detailed cellular analyses have assessed gene and protein expression . as with human disease studies analyses of cultured cells ,
e.g. , infected marc cells 85 , swine macrophages 86 , 87 , or samples from infected pigs 88 , have expanded our knowledge of the impact of timing and level of viral infection on gene expression and pathway involvement .
more detailed gene expression analyses are underway using long oligo and affymetrix arrays , testing both pooled and individual animal samples , as well as mucosal samples at death .
results can be disappointing if mucosal samples are collected only after viral levels begin to resolve .
the peak of anti - viral immunity ( and relevant gene expression ) may be much earlier ; however , that may be at a time when the actual viral levels may be difficult to evaluate and thus complicate comparative analyses . therefore , it is important to affirm preliminary results with hypothesis driven repeated analyses and with translation of gene expression and array results into protein expression data .
genetic variation does exist in resistance / susceptibility to viral infections and has been proven for swine resistance / susceptibility to prrs 87 , 89 .
although to date there is limited knowledge of host genes determining prrsv resistance ; some candidate genes have been identified ( petry et al . , submitted ) .
more detailed studies are required to determine whether naturally disease resistant pigs can be identified and why do [ some ] pigs stay healthy even with prrs ? what set of factors ( detailed phenotype ) truly correlate with lower prrsv burden ? what is the potential for sampling peripheral blood cells , serum or saliva for preinfection predictive studies of genetically determined virus resistance phenotype ?
an international prrs genomics consortium , of university , government , and company based scientists , has been established to assess host genetics of prrs resistance / susceptibility .
the goal is to develop a large , publicly available disease sample and dataset from thousands of pigs from relevant commercial lines infected with prrsv and from which a detailed phenotype have been collected .
the end user performs his / her analysis on the appropriate sample and returns the data to the consortium .
it is hoped that the data generated by the consortium will verify the genetic variation in pigs responding to prrsv infection , will reveal factors influencing health , survivability and growth , and will identify the relative importance of different phenotypes , and their heritability , in predicting responses to prrsv infection .
overall this data should enable breeders to produce healthier pigs with improved resistance to prrsv and help animal health companies to develop improved vaccines and alternative anti - prrsv therapeutics .
this data should help identify new critical control factors in human responses to viral infections .
advantages of swine as a biomedical model swine biomedical models lessons learned from swine melanoma studies utilizing genomics for swine models - issues to consider
 this review is a short update on the diversity of swine biomedical models and the importance of genomics in their continued development . 
 the swine has been used as a major mammalian model for human studies because of the similarity in size and physiology , and in organ development and disease progression . 
 the pig model allows for deliberately timed studies , imaging of internal vessels and organs using standard human technologies , and collection of repeated peripheral samples and , at kill , detailed mucosal tissues . 
 the ability to use pigs from the same litter , or cloned or transgenic pigs , facilitates comparative analyses and genetic mapping . 
 the availability of numerous well defined cell lines , representing a broad range of tissues , further facilitates testing of gene expression , drug susceptibility , etc . 
 thus the pig is an excellent biomedical model for humans . for genomic applications 
 it is an asset that the pig genome has high sequence and chromosome structure homology with humans . with 
 the swine genome sequence now well advanced there are improving genetic and proteomic tools for these comparative analyses . 
 the review will discuss some of the genomic approaches used to probe these models . 
 the review will highlight genomic studies of melanoma and of infectious disease resistance , discussing issues to consider in designing such studies . 
 it will end with a short discussion of the potential for genomic approaches to develop new alternatives for control of the most economically important disease of pigs , porcine reproductive and respiratory syndrome ( prrs ) , and the potential for applying knowledge gained with this virus for human viral infectious disease studies . 
1. Introduction
2. Advantage of the Swine as a Biomedical Model
3. Swine Biomedical Models
4. Genomics and Melanoma: A case study
5. Swine as infectious disease models
6. Pig anti-Viral Responses: the response to Porcine Reproductive and Respiratory Syndrome virus
Figures and Tables