PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
PostGenetics Medicine Đurđica Ugarković Ruđer Bošković Institute Zagreb, Croatia
The age of classical genetics in the first half of the 20th Century yielded to t he Modern era of molecular genetics by discovery of the structure of DNA (1953). The term ‘Genetics’ was coined by William Bateson on 1905 T he pre-classical era of Genetics began with Mendel 40 years earlier (1865). Then followed two decades of intensified focus on protein coding DNA .
The term “Junk” DNA , originally coined by Susumu Ohno (1972) to describe repetitive satellite DNA elements, became a generic term for non-protein coding DNA. With protein coding regions appearing to occupy <5% of the human genome, the majority of approx. 95% of DNA, reffered as “Junk” DNA , was largely ignored as u npromising terrain for inquiry With completion of the Human Genome Project, first announced in 2000, “ Junk” DNA was found to comprise 98.7% of the sequenced genome, with only an estimated 26,000-30,000 genes comprising the 1.3% protein coding sequence
In the 20th Century it was believed that genetic associations with diseases would be explained by ‘mutations’ in protein-coding genes, and would be ‘solved’ by complete sequencing of genic DNA. All higher organisms have a similar number of genes. The main DNA d ifference between species across this broad evolutionary time-scale is their non-protein coding genetic content. The Human Genome Project failed to meet the expectations of those who sought a genic explanation of genetic risk to many common diseases.
There are about 25 ,000 genes in the human genome, but there are at least 150,000 different genetic disorders . We can't just look at the genes that code for proteins, you've got to look at the surrounding regulatory regions, as w ell in the 'junk ” . The challenge for the 21st century is to accept that gene typing alone has been unable to explain genetic associations between many, perhaps most, diseases and genes. New paradigms are needed.
In this PostGene era, we have established I nternational P ostGenetics Society (IPGS) to promote awareness of Junk DNA’s central role in an integrative view of the genome, much broader than protein genes alone. T he International PostGenetics Society (IPGS) was established in 2005, to give priority by an International Organization to inquiry beyond protein-coding g enes http://www.junkdna.com/postgenetics/ IPGS also serves to inform government and the private sector of the utility of total genome information in all aspects of PostGenetics; “ PostGenetics Medicine” , and the integration of "biotechnology, n anotechnology and information technology".
At European Inaugural Conference 2006, IPGS asserted that Genetics had moved beyond Genes, opening the gateway towards unravelling diseases beyond the gene definition as priority by funding agencies and other organizations. This paradigm shift (Gene-PostGene) affects “PostGenetics Medicine” – vital for a vast segment of humanity
Policy towards PostGenetics Medicine . The new domain, proposed as “PostGenet ics Medicine”, targets “Junk” DNA Diseases as “PostGene Diseases” in which hereditary / genetic elements are involved in formerly “Junk” DNA. Increasing evidence for diseases originating in non-protein coding DNA requires an urgent PostGenetics Study Program , leading to substantial increase in organizational and funding support for R&D in the field . The IPGS wants to generate scientific, political and community awareness of the potential of PostGenetics research to throw new light on common and rare “non-coding DNA” diseases .
Powerful tools of gene discovery and analysis developed over the past 35 years h ave transformed medicine ; P ost-genetics now promises to give the revolution new impetus.
MHC/HLA . The inadequacy of the gene paradigm is most evident in the Major Histocompatibility Complex and its association with allergy and autoimmunity . MHC comprises 220 genes with so far about 100 human diseases associated with the MHC/HLA complex. For all, with one possible exception (celiac disease), the mechanisms underlying the associations remain unknown
Intensifying search for only coding sequencing may be insufficient, if not misguided. A new emerging paradigm is that non-coding sequences and “Junk DNA” through regulating higher order DNA s tructure contributes together with HLA gene polymorphisms in regulat ing T cell function in allergy and autoimmunity
<ul><li>The role of non-coding (nc)RNAs </li></ul><ul><li>(ranging from microRNAs of 21-25 bp to small RNAs of 100-200 bp to large RNAs </li></ul><ul><li>of 10,000 bp or more), involved in RNA interference, gene co-suppression, gene </li></ul><ul><li>silencing, imprinting, and DNA methylation - epigenetics </li></ul>Non-coding DNA/RNA in Cancer Non-coding RNA has made an appearance as a critical factor in cancer initiation and p rogression . Three key areas are emerging:
Literally “on” genes, refers to all modifications to genes other than changes in the DNA sequene itself B iological complexity depends less on gene number, and more on how those genes are used (expressed), which is largely due to epigenetic mechanisms Epigenetic changes are heritable and effect gene expression Most cancers involve epigenetic modifications Different biological molecules might bind to chromatin elements, influencing function by altering structure. Non- coding RNA in Epigenetics
microRNAs D eregulation of microRNAs in cancer is associated with loss of suppressor gene function or gain of oncogene function that are associated with patient prognosis In addition, non-coding RNAs have been shown to contribute to embryonic and tissue stem cell fate, and we predict that they will also be found to regulate the fate of tumor stem cells or “tumor-initiating cells” in cancer. A microRNA directly regulates a gene implicated in human cancers . Human cancers are characterized by widespread reduction in microRNA gene expression, but what role does this have in the pathobiology of the disease? A new study proves that reduction in microRNA expression does indeed promote tumorigenesis, changing the way we think about cancer. MicroRNAs act as tumor suppressors
microRNA knockout uncovers critical roles in immune system Cells of the immune system in the knockout mice do not work as well as normal cells and the mice develop symptoms similar to those of human autoimmune disease. They develop changes to lung tissue, with scarring that is similar to some human systemic autoimmune disorders. Knockout mice are also less able to resist infection by bacteria, such as Salmonella
(3) Polymorphisms in non-coding regions sometimes far upstream of exons that regulate gene expression and translational initiation. (2) Mutations and rearrangements in non-coding mitochondrial DNA such the mtDNA D loop are found in some carcinomas that may regulate apoptosis susceptibility Non-coding DNA in Cancer
Prostate Cancer Three separate groups of scientists have pinpointed seven variations in DNA that definitely increase a person's risk of prostate cancer. All of the variants are found on the same chromosome. But don't call them "prostate cancer genes" —the reason scientists couldn't find those before, it seems, is that the culprits turned out not to be genes at all. Instead, they are found in so-called "junk DNA," portions of the genome that don't make proteins . "What these variants are doing inside the cell is still a big question,"
Alzheimer’s disease (AD) , a major cause of dementia affecting 4 million people in the USA, may have a PostGenetic s component . While malfunctions of the beta-Amyloid precursor, presenilin-1 and -2 genes, a nd the presence of epsilon4 allele of apolipoprotein E, are known risk factors for s usceptibility to AD, not all studies support gene associations with A D There have been suggestions of evidence for a link between AD and anterior-pharynx defective-1 genes polymorphisms .
Time to Act . The burgeoning evidence for non-coding DNA/RNA governing growth and differentiation clearly indicates that it is time for the world agencies to develop focused PostGenetics R&D policies, such as the IPGS-proposed “ PostGenetics Study Program”, Journal and Conferences , to propel the former field of “Junk DNA” into a new functional realm, coordinating individuals, organizations and disease awareness advocacy groups. This PostModern expansion of Modern Genetics will accelerate understanding of human diseases and benefit the world.
It is certainly a fact of today, that a good number of deadly diseases (e.g. types of cancer) originate from "regulatory DNA", for which no "gene discovery" is likely to find a solution - as there may be no "gene“ to look for, but rathe r “non-gene discovery" appears to be a "must" Conclusion In all likelihood, "Genetics", having turned 100 years old in 2005 may wishes to redefine itself in the parent field of Genomics and in an establishment of PostGenetics as the most rapidly advancing sub-field of Genomics