PIGS AND GENETICS AT THE EVE OF THE 21ST CENTURY
The past two decades have seen tremendous advances in the field of animal genetics but the most exciting period is still to come.
1) The 80's
In the 80s, pig genetics involved mostly quantitative genetics in selection schemes for breeding improvements (Bichard M, 1990), the study of a few geneticdiseases with an economical impact, like splayleg syndrome (Ward 1978), malignanthyperthermia (O Brien et al. 1990) or intersexuality (Hunter et al, 1988),and the investigation of the impact on reproductive performance of chromosome translocations (Popescu CP 1982).
2) The 90's
Everything changed in 1990, with the succesful launching of the europeanprogram for mapping of the pig genome (PiGMaP), coordinated byAlan Archibald at the Roslin Institute (Haley et al. 1990).
The PiGMaP project:
The aim was not to sequence the whole pig genome, since 95% of the genomeis not coding, but to find the genetic markers for economically important traits (ETLs), that could be single genes, or physiological traits thatare governed by a few genes and are measured quantitatively, the famous Quantitative Traits Loci (QTL).
The two approaches used were the physical map and the genetic map:
The physical map aimed at finding genes that are regularly spaced on each chromosome of the pig, whereas the genetic map aimed at finding genes that are transmitted together in family studies, and that could be correlated with the presence of certain QTLs (Haley C.S. & A. Archibald, 1992). Those two approaches have been very successful (Andersson et al.1993)and the PiGMaP is expanding everyday, giving the basis for DNA markers assisted selection.
Others maps (BovMaP, DoGMaP, SheepMap, etc...):
The success of the PiGMaP has triggered the interest for mapping other species, and at the XXV International Congress on Animal Genetics in Tours in July 1996, there were reports of BoVMap, SheepMap, DogMap, and other initiatives for feline, equine, chicken and fish maps, and there was the lauching at that Congress of the coordinated effort for a Rabbit map.
Comparative Gene Mapping:
Comparative Gene Mapping has revealed that in all the domestic animal species (livestock and companion animals), groups of genes are conserved when compared to the human map whereas there are more rearrangements in the mouse genome, the usual animal model. Therefore, to accelerate the process of gene mapping in any domestic animal species, a list of genes that are evenly spaced in the human genome and could be used to define a linkage group, has been developped, they are called Anchor Loci type I.
(two of the more prominents researchers in that field are Dr Stephen O'Brien from NCI in Frederick, Maryland, working in cat genetics, and Dr Jim Womack, from Texas A & M, working in cattle genetics) O'Brien etal. 1993).
Comparison of gene sequences
With the development of Bioinformatics that permits to gather DNA and protein sequences from all around the world and to compare them, it has become clear that at the gene level, the DNA sequences for a given gene is more conserved in domestic animal species compared to man than in murine species compared to man. Therefore, the whole array of human DNA probes seems available for direct application in pig gene mapping. This seems to be working since at the ISAG conference in Tours, there were reports of work done on DNA from specific human chromosomes "painted" on specific cattle or pig chromosomes ().
The development of homologous primers for Comparative Anchor Tags Sequences (CATS) that could work to amplify by Polymerase Chain Reaction (PCR) all the anchor type I genes in any domestic species, will also provide very rapidly more markers for the map ().
3) More to come
The knowledge of the list of all the genes and their products present in the body of the pig is only the first step toward the understanding of its physiology and the influence of genes on health.
Gene sequencing and expression:
The new advances will come, after isolation of each gene in the pig, by the study of its differential expression during life and in certain organs, the knowledge of all his co-factors and of the structure and function of each gene product.
Comparison of the sequence of the same gene in different families might be correlated with different physiological performances and will also help in unraveling the molecular components of the QTLs.
Sequencing of the same gene in many different animal species and comparing it to the same sequence in man, would permit to detect the coding portions of the gene that have been conserved throughout evolution and are most likely to be the active sites. This would have pharmaceutical implications.
In addition, small differences in an active site between species might explain a physiological difference. (A few years ago, it was published that the hemoglobin sequences of humans and crocodiles were compared, and a small difference in genetic sequence could be correlated with an increased binding ability. Now, synthetic human hemoglobin has been modified slightly to act more like crocodile hemoglobin, and be more efficient in treating emergencies).
Animal Models of Genetic Diseases:
This is another sector were progresses will be made. We know now that domestic animals are closer genetically to humans than are mice, the usual genetic model. In addition, it makes sense clinically to study domestic animals, since they are similar in size to newborn or adult humans, they have long lifespans, similar length of pregnancy, and some organs are known to be similar.
All the genetic diseases occuring in man, are also present in domestic animals. Detecting and characterizing spontaneous domestic animal models for human genetic diseases has been the mission of the Section of Medical Genetics at the Veterinary School of the University of Pennsylvania, since it was started in the 60's by Dr D.F. Patterson (). Through the combination of a metabolic screening lab that detects errors of metabolism for proteins, carbohydrates, and fats, an immunology lag, an hematology lab, a cytogenetic lab, and a molecular genetics lab, genetic diseases are detected and their molecular basis elucidated (). Trials for gene therapy in animals as models for humans are currently in progress. This is a rather unique setting and I had the privilege of working there for three years (Javma).
As the PiGMaP progresses, I am sure that more molecular probes will be available to study genetic problems in the pig, to identify them and to elucidate their molecular basis. Knowledge of genetic diseases in humans and animals other than pigs would also help identify these diseases in pigs.
In addition, through an animal welfare point of vue, the identification of animals that would give abnormal offspring when bred would be of help. As is the identification of animals less susceptible to stress or infections, and more adapted to the use of certain local feeds.
By knowing better all the gene products and their cofactors, it might be possible to modify the pig natural flora in order to provide essential nutrients or use more efficiently nutrition products.
In addition, the sequencing of pathogens will provide better understanding of their toxic products or their mode of penetrance, and the selection of certain pig families that could degrade harmlessly these toxins, or that lack gut receptors for attachment might be possible. The synthesis and incorporation in the feed of blockers for pathogen receptors would also help diminish the use of antibiotics. ()
Conservation of the Gene Pool and Cloning:
I could not finish without mentioning cloning.
Conservatories of very different breeds to keep the widest gene pool possible is essential because the value of a gene depends on its environment, and environment changes. Natural breeding is the most cost effective way to produce offspring and preserve genetic diversity.
However, transgenic animals expressing a specific gene (like those that might be used in xenotransplants in the future) are very costly to produce and it will make sense to clone enough of those animals to get rapidly a critical mass that is economically viable.
A BRIGHT FUTURE
In conclusion, tremendous progresses have already been made, but most of the exciting discoveries and applications in pig genetics and the understanding of pig health will come in the next century, through a combination of In Vivo, In Vitro and In Silico methods.
(I could not have been involved in Pig Gene Mapping and Comparative Medical Genetics, without the financial support of the Pig Science Project during my stay in England, and the support of the Kleberg Foundation during my stay at the University of Pennsylvania).
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