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Dear Reader

of the news column on "junkDNA", http://www.junkdna.com/new_citations.html :

You are very welcome to make your comment for "equal time" - or a lively debate.

Dr. Andras J. Pellionisz
postgenetics_AT_junkdna_DOT_com
pellionisz_AT_junkdna_DOT_com

GPS on the shovel when digging for gold?

[See full posting at http://www.junkdna.com/new_citations.html ]

Genomics study highlights the importance of "junk" DNA in higher eukaryotes

A landmark comparative genomics study appears online today in the journal Genome Research. Led by Adam Siepel, graduate student in Dr. David Haussler's laboratory at the University of California, Santa Cruz, the study describes the most comprehensive comparison of conserved DNA sequences in the genomes of vertebrates, insects, worms, and yeast to date. One of their major findings was that as organism complexity increases, so too does the proportion of conserved bases in the non-protein-coding (or "junk") DNA sequences. This underscores the importance of gene regulation in more complex species. The manuscript also reports exciting biological findings regarding highly conserved DNA elements and the development of a new computational tool for comparing several whole-genome sequences. .... Such approaches are particularly useful for analyzing non-protein-coding sequences - sometimes called "junk" DNA. Although "junk" DNA is poorly understood, the increasing availability of whole-genome sequences is rapidly enhancing the ability of scientists to ascertain the biological significance of these non-protein-coding regions. ...The vertebrates included human, mouse, rat, chicken, and pufferfish, and the insects included three species of fruit fly and one species of mosquito. .. the researchers developed a new computational tool called phastCons. ...The scientists also observed that the proportion of conserved sequences located outside of protein-coding regions tended to increase with genome length and with the species' general biological complexity.
Most strikingly, the researchers discovered that two-thirds or more of the conserved DNA sequences in vertebrate and insect species were located outside the exons of protein-coding genes, while non-protein-coding sequences accounted for only about 40% and 15% of the conserved elements in the genomes of worms and yeast, respectively. ... "These findings support the hypothesis that increased biological complexity in vertebrates and insects derives more from elaborate forms of regulation than from a larger number of protein-coding genes." ... Some of the strongest sequence conservation in vertebrates was observed in the 3' untranslated regions (3'UTRs) of genes, which indicates that post-transcriptional regulation may be a widespread and important phenomenon in more complex species. .."There really does seem to be a lot more going on at the RNA level than people would have guessed a few years ago," commented Siepel. ... some of the conserved elements may function as long-range transcriptional regulatory elements. ... Not only will the new bioinformatics tool phastCons help researchers identify evolutionarily conserved DNA elements, the reported conserved elements are represented as conservation tracks in the widely used UCSC Genome Browser. "With phastCons and with the conservation tracks in the browser," says Siepel, "we're trying to make it as easy as possible for researchers to home in on functionally important DNA sequences."

California Gold Rush Sold Shovels

[See the full posting at http://www.junkdna.com/new_citations.html ]

Dueling Databases

Can companies still make money selling genomic and molecular information?

[The reader can skip the article if lacking time. The answer is "NO money for data, $$$ for proprietary tools" - AJP]

BIOBUSINESS
Volume 19 Issue 13 Page 42 Jul. 4, 2005 By Ted Agres

Celera Genomics made hundreds of millions of dollars by selling access to its proprietary genome sequence information. But this month, Celera discontinued its database subscription service and made its 30 billion base pairs of genomic data of humans, rats, and mice freely available through GenBank, operated by the US National Center for Biotechnology Information.

Some see Celera's decision to exit the sequence business as proof of the adage that information wants to be free, and yet another sign that selling access to data is no longer a viable business model. ...

During the past few years some database companies (such as Incyte Genomics and Celera) have transitioned to drug discovery and development, while others (such as DoubleTwist) have simply gone out of business. Still, dozens of large and small companies worldwide continue to sell subscriptions to genome databases and molecular libraries, either alone or in combination with other services.

Some of these companies are information providers, such as the American Chemical Society's Chemical Abstracts Service (CAS) and Biobase, a commercial biological database vendor in Germany. Others, such as Integrated Genomics in Chicago and Inpharmatica in London, combine databases with proprietary software and other informatics tools to facilitate discovery of drug candidates.

Making a profit from research-generated data is not an easy matter, says Frank Allen, executive director of Cambridge Crystallographic Data Center, a nonprofit institute spun off from the University of Cambridge. "Some people sit back in their chairs and say, 'It's my divine right to use data that's in the public domain.' Well, it certainly is, but there's a price involved in turning that data into something that's usable. It's either going to come from the public purse or from subscription income." The CCDC maintains the Cambridge Structural Database, a repository of small molecule crystal structures.

Dozens of large and small companies worldwide continue to sell subscriptions to genome databases and molecular libraries. Their challenge is to find ways to maintain value amid growing competition from public sources.

"Science is moving towards greater openness in terms of data," says Eric Campbell, professor of health policy at Harvard Medical School. "The issue comes down to protecting one's competitive advantage. You have to have a way to uniquely profit from discoveries and prevent free-riders from hopping in at the end."

A PERISHABLE COMMODITY

Some companies, such as Biobase in Germany, are trying to increase value by curating, annotating, and extending the reach of their databases. Others, like the American Chemical Society's Chemical Abstracts Service (CAS), are attempting to maintain market exclusivity by keeping potential competitors at bay. Novartis and Perlegen Sciences, on the other hand, believe they will generate more business if they allow other researchers access to their proprietary databases. "We don't know if it's collaboration or competition or some combination that will drive science the fastest," Campbell says. "Nobody has studied it before."
Celera knew that its genomic information was a perishable commodity. "There is a time component to the value of information," says Tony Kerlavage, Celera's senior director of online business. In the company's early days, when Celera held a near-monopoly on human genome sequences, pharmaceutical companies and research institutions paid big bucks to access the raw data to locate novel genes and drug targets.

At its height, more than 200 institutions and 25 drug and biotech companies subscribed to the Celera Discovery System (CDS), paying annual fees ranging from thousands to millions of dollars, depending on the number of researchers. Over the years, the CDS was supplanted by such resources as GenBank and Ensembl – a project of the European Bioinformatics Institute and the Sanger Institute. Today, the CDS is useful primarily as a reference source, hence the company's willingness to place it in the public domain. Kerlavage declined to say how many subscriptions expired July 1, closing the service for good.

Three years ago, Celera's parent company, Applera Corp., decided to shift from information to drug discovery and development, and to selling gene expression arrays and diagnostic tools. The move may have been prescient. "If you have complementary services, it may be better to have your data freely available so you can sell more of those other services, whether they are machines or other things," says Arti Rai, a Duke University law professor who focuses on intellectual property in the life sciences.

..."There are structural changes going on in the dissemination of scientific information because of the Internet and because everything has become computer-readable. It's not the same sort of business it used to be," says Heller. "Either you adjust or you have problems."

New developments about "JunkDNA"

News items to be discussed here are compiled on http://www.junkdna.com/new_citations.html website.

This blog was created to discuss "news items" emerging in the exploding field of "JunkDNA". Hardly anybody believes that 98.7% of the (human) DNA is "Junk". The common wisdom at the moment is that it is "regulatory DNA". My "two cents" favor FractoGene, a geometrical generalization of the almost 100 year old "Gene concept". (See www.fractogene.com website, an upcoming book, experimental support of its first prediction - and a major shift in software industry for the "Post Gene Era").

Dr. Andras J. Pellionisz
http://www.usa-siliconvalley.com

Doer of "the Human Genome Project" is ready to "re-do it all"

[See posting at http://www.junkdna.com/new_citations.html ]

'Champion of "the Human Genome Project" does it again from scratch':
Venter, Launching New Company, Hopes to Synthesize Genome to Create Bacterium

NEW YORK, June 29 (GenomeWeb News) - Nearly four years after being shown the door at Celera Genomics and creating a family of nonprofits, Craig Venter has founded a new company that aims to create an organism from synthetically crafted and oriented genes.

The company, Synthetic Genomics, is in the process of building a "minimal genome" that can be inserted into the shell of a bacterium, in this case the 517-gene Mycoplasma genitalium, which scientists may eventually genetically engineer to perform specific industrial tasks.

... After designing and producing a synthetic chromosome ... the team plans to develop a proof of concept in either of two bio-energy applications: hydrogen or ethanol.

.... At a 2003 press conference announcing results from that research, Venter stressed that his team would not commercialize PCA, nor would he file patents on it. "We'd rather wait till the next stage when there's a clear-cut application: for instance if we have something that produces hydrogen that might hold some value"

Founders of "the Human Genome Project" are ready to "re-thinking it all"...

[See posting at http://www.junkdna.com/new_citations.html ]

Founders of "the Human Genome Project" are ready to "re-thinking it all"... The Uncertain Future for Central Dogma

The ScientistVol. 19. Issue 12, pp. 20.June 20th, 2005

The Uncertain Future for Central Dogma

Uncertainty serves as a bridge from determinism and reductionism to a new picture of biology
By Arnold F. Goodman, Claudia M. Bellato and Lily Khidr

Nearly two decades ago, Paul H. Silverman testified before Congress to advocate the Human Genome Project. He later became frustrated when the exceptions to genetic determinism, discovered by this project and other investigations, were not sufficiently incorporated in current research and education.

In "Rethinking Genetic Determinism,"1 Silverman questioned one of the pillars of molecular genetics and documented the need for determinism's expansion into a far more valid and reliable representation of reality. He would receive correspondence from all over the world that reinforced this vision.

Silverman firmly believed that we needed a wider-angled model, with a new framework and terminology, to display what we know and to guide future discovery. He also viewed this model as being a catalyst for exploring uncertainty, the vast universe of chance differences on a cellular and molecular level that can considerably influence organismal variability. Uncertainty not only undermines molecular genetics' primary pillars of determinism and reductionism, but also provides a bridge to future research.

PILLARS CHALLENGED
...
Various commentaries detail deviation from determinism within the cellular cycle. Here we use the term cellular cycle not in the traditional sense, but rather to describe the cyclical program that starts with gene regulation through transcription, translation, post-processing and back into regulation.

Richard Strohman at UC-Berkeley describes the program in terms of a complex regulatory paradigm, which he calls "dynamic epigenetics." The program is dynamic because regulation occurs over time, and epigenetic because it is above genetics in level of organization.2 "We thought the program was in the genes, and then in the proteins encoded by genes," he wrote, but we need to know the rules governing protein networks in a cell, as well as the individual proteins themselves.

John S. Mattick at the University of Queensland focuses upon the hidden genetic program of complex organisms.3 "RNAs and proteins may communicate regulatory information in parallel," he writes. This would resemble the advanced information systems for network control in our brains and in computers. Indeed, recent demonstrations suggest that RNA might serve as a genetic backup copy superseding Mendelian inheritance.4

Gil Ast of Tel Aviv University writes: "Alternative splicing enables a minimal number of genes to produce and maintain highly complex organisms by orchestrating when, where, and what types of proteins they manufacture."5 About 5% of alternatively spliced human exons contain retrotransposon Alu sequences. These elements represent an engine for generating alternative splicing.

Thus we see a genetic control system regulated by protein products, RNAs, and interventions from DNA itself. Yet throughout, the consideration of genetic uncertainty as a bridge to cellular behavior is conspicuously absent.

Genetic reductionism, the other pillar of molecular genetics, has many challengers. Among them is Stephen S. Rothman at UC-Berkeley, who described the limits of reductionism in great detail within his comprehensive and well-constructed book.6

A more recent publication by Marc H.V. Van Regenmortel at France's National Center for Scientific Research updated this assessment by discussing not only the deficiencies of reductionism, but also current ways of overcoming them. "Biological systems are extremely complex and have emergent properties that cannot be explained, or even predicted, by studying their individual parts."7

NEW CELL MODEL

Molecular genetics appears to be at a crossroads, since neither determinism nor reductionism is capable of accurately representing cellular behavior. In order to transition from a passive awareness of this dilemma to its active resolution, we must move from simply loosening the constraints of determinism and reductionism toward a more mature and representative combination of determinism, reductionism, and uncertainty.

Helen M. Blau was a keynote speaker at the recent UC-Irvine stem-cell symposium in memory of Paul Silverman and Christopher Reeve.8 She observed: "Where we look and how we look determine what we see." Although only a brief prescription, we now propose an approach to the exploration for uncertainty that involves both where we look and how we look. We examine those cellular-cycle outputs having a relatively high likelihood of diversity and its frequent companion, uncertainty.

The Gene Concept is Dead. Long Live FractoGene!

[see article on http://www.junkdna.com/new_citations.html]

Rosetta Genomics identifies hundreds of novel human microRNAs
Medical Research News
Published: Tuesday, 21-Jun-2005

In a study published online this week and to be published as a cover story in the July issue of Nature Genetics, Rosetta Genomics' scientists report identification of hundreds of human microRNA genes, including the first report of primate specific microRNAs.
Using a novel methodology, the researchers successfully cloned and sequenced 89 human microRNAs, nearly doubling the number sequenced in man to date.
MicroRNAs are a recently discovered class of tiny regulatory genes, comprised in the 98% of the genome that does not encode proteins, which until recently were considered 'Junk DNA'. Numerous recent studies have shown microRNA genes, far from being 'junk', are in fact of central importance, regulating at least 30% of all proteins, and involved in a wide range of diseases, including diabetes, obesity, viral diseases, and various types of cancer.
"The finding of large numbers of primate specific microRNAs is exciting because it supports the notion that microRNAs may indeed play an important role in the evolution of complexity of higher organisms," said Aaron Ciechanover, Nobel prize laureate 2004, and Chairman of Rosetta Genomics' Scientific Advisory Board. "We believe that these genes may serve as an important basis for next generation diagnostics and therapeutics."
"We are extremely pleased to report our success in nearly doubling the number of human microRNAs sequenced to date, results which we believe establish Rosetta Genomics as a leading player in discovery of microRNA genes," said Isaac Bentwich MD, founder and chairman of Rosetta Genomics and lead investigator of the study. "We are now aggressively pursuing partnerships for development of diagnostics and therapeutics based on this huge group of novel microRNAs."
MicroRNAs are a recently discovered group of non-protein-coding regulatory genes, shown to be involved in a wide range of diseases in addition to neuronal and stem-cell differentiation. MicroRNAs currently are an intensely researched area, and are believed potentially to be the basis for a new class of therapeutic and diagnostic products

Behavior of Junkies determined by JunkDNA?

[for full article, see http://www.junkdna.com/new_citations.html]

Rodent Social Behavior Encoded in Junk DNA

A discovery that may someday help to explain human social behavior and disorders such as autism has been made in a species of pudgy rodents by researchers funded, in part, by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH) and National Center for Research Resources (NCRR).

The researchers traced social behavior traits, such as monogamy, to seeming glitches in DNA that determines when and where a gene turns on. The length of these repeating sequences — once dismissed as mere junk DNA — in the gene that codes for a key hormone receptor determined male-female relations and parenting behaviors in a species of voles. Drs. Larry Young and Elizabeth Hammock, Emory University, report on their findings in the mouse-like animals native to the American Midwest in the June 10, 2005 Science.

...“This research appears to have found one of those hotspots in the genome where small differences can have large functional impact,” explained Insel. “The Emory researchers found individual differences not in a protein-coding region, but in an area that determines a gene’s expression in the brain. This is an extraordinary example of research linking gene variation to brain receptors to behavior.”

...“It was considered junk DNA because it didn’t seem to have any function,” noted Hammock.

In addition to NIH, the research was also supported by the National Science Foundation.
NIMH and NCRR are part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

Affy/Agilent duel - mopping up Intellectual Property

[see the original article at http://www.junkdna.com/new_citations.html ]

NEW YORK, May 31 (GenomeWeb News) -

Affymetrix said today that it plans to acquire privately held ParAllele BioScience for approximately $120 million in stock...

"The potential for ParAllele's technology goes far beyond genotyping," said Stephen Fodor, CEO of Affymetrix...

In 2003, Affy began providing its GeneChip platform for use with ParAllele's genotyping assays, which are based on its Molecular Inversion Probe technology - a process that enables up to tens of thousands of reactions to be multiplexed in a single tube.

Last year, Affy and ParAllele extended the collaboration into a distribution partnership under which ParAllele agreed to design assays for Affymetrix to market for use with the GeneChip platform. ...