Genetics Central Dogma Is Dead

“The gene is dead… long live the gene,” announced subtitles to an article in Science News this week.¹ Geneticists have come to a striking conclusion over the last few years: genes are not the most important things in DNA, if they even exist as a concept.The “central dogma” of genetics, since Watson and Crick determined the structure of DNA, is that genetic information flows one-way – from the gene to the protein. In the textbooks, a gene was supposed to be a finite stretch of DNA that, when read by the translation process, produced a messenger RNA, which recruited transfer RNAs to assemble the amino acids for one protein.

As Patrick Barry described in his article “Genome 2.0,”¹ the situation in real cells is much messier. “Mountains of new data are challenging old views,” his subtitle announced, including the “modern orthodoxy” that only genes are important.

Researchers slowly realized, however, that genes occupy only about 1.5 percent of the genome.  The other 98.5 percent, dubbed “junk DNA,“ was regarded as useless scraps left over from billions of years of random genetic mutations.  As geneticists’ knowledge progressed, this basic picture remained largely unquestioned….
Closer examination of the full human genome is now causing scientists to return to some questions they thought they had settled.  For one, they’re revisiting the very notion of what a gene is.

Some of the findings in the genomic era include:

• The human genome has far fewer genes than expected.
• Some lower animals have as many genes as humans (e.g., 05/01/2007).
• Most of the human genome does not code for genes.
• The code for proteins can be split between distant parts of the genome – even on different chromosomes.²
• The non-coding DNA, once considered evolutionary junk (06/15/2007), is actually heavily involved in gene regulation (04/24/2007).
• Genetic information processing acts more like a network than a static library of genes.
• RNA transcripts vastly outnumber gene transcripts: some 74 to 93% of the genome.
• RNA is much more than a messenger in the cell. Numerous small and micro RNA transcripts are heavily involved in “fine tuning” the production of protein.
• Gene regulation appears more important than the genes themselves.
• Scientists “are finding disease-associated mutations in regions of the genome formerly regarded as junk.”
• Some genes overlap with codes for micro-RNAs or regulatory elements.
• Genes can be read in multiple ways that can yield far more than one protein (alternative splicing; see 05/20/2007)).
• Messenger-RNA transcripts undergo significant modification and regulation in the nucleus.
• The translation process can even yield transcripts from the opposing strand.³

It remains indisputable that DNA codes for proteins via messenger RNA, and that proteins perform the major structural and functional operations of the cell. But as Hui Ge of the Whitehead Institute in Cambridge, Massachusetts said, “What we thought was important before was really just the tip of the iceberg.” Barry used a homey analogy to illustrate how gene regulation can be more important than genes themselves:

Consider the difference between a one-bedroom bungalow and an ornate, three-story McMansion.  Both are made from roughly the same materials—lumber, drywall, wiring, plumbing—and are put together with the same tools—hammers, saws, nails, and screws.  What makes the mansion more complex is the way that its construction is orchestrated by rules that specify when and where each tool and material must be used.

In cells, regulation controls when and where proteins spring into action.  If the traditional genome is a set of blueprints for an organism, RNA regulatory networks are the assembly instructions. In fact, some scientists think that these additional layers of complexity in genome regulation could be the answer to a long-standing puzzle…

…that puzzle being the unexpected low number of genes in the human genome. It might explain the physical differences between humans and roundworms, which both have similar numbers of protein-coding genes.

Barry’s article provides a good summary of numerous papers that have been casting serious doubt on the Central Dogma, and even the concept of a gene itself:

More fundamentally, it muddies scientists’ conception of just what constitutes a gene. In the established definition, a gene is a discrete region of DNA that produces a single, identifiable protein in a cell. But the functioning of a protein often depends on a host of RNAs that control its activity. If a stretch of DNA known to be a protein-coding gene also produces regulatory RNAs essential for several other genes, is it somehow a part of all those other genes as well?

Some scientists are advocating changing our focus from genes to “functional RNA transcripts.” But that seems to just relocate the problem. If DNA is a passive code, what codes for its activity? If gene regulation by a network of transcripts is now more important than genes, what regulates the regulators? Come back for Genome 3.0.

Update 09/24/2007:  Colin Nickerson wrote an article for the Boston News that captures the drama of these discoveries:

The science of life is undergoing changes so jolting that even its top researchers are feeling something akin to shell-shock. Just four years after scientists finished mapping the human genome – the full sequence of 3 billion DNA “letters” folded within every cell – they find themselves confronted by a biological jungle deeper, denser, and more difficult to penetrate than anyone imagined….

….the picture now emerging is more complicated, one in which illness, health, and evolutionary change appear to be the work of almost fantastical coordination between genes and swaths of DNA previously written off as junk.

Nickerson quotes Isodore Rigoutsos, geneticist, saying “The picture that’s emerging is so immensely more complicated than anyone imagined, it’s almost depressing.”

¹ Patrick Barry, “Genome 2.0,” Science News, Week of Sept. 8, 2007; Vol. 172, No. 10 , p. 154.
² “The ENCODE project revealed that about 90 percent of protein-coding genes possessed previously unknown coding fragments that were located far from the main gene, sometimes on other chromosomes.”
³ “According to the ENCODE project results, up to 72 percent of known genes have transcripts on the facing DNA strand as well as the main strand.”

Many previous entries have dealt with these subjects (e.g., 06/15/2007, 12/29/2006 bullet 2, 11/09/2006, 07/06/2006). This is a classic case of a paradigm change in science occurring before our eyes. Even what we mean by an intuitively-obvious word like gene is being questioned: is there such a thing? Does it have physical reality, or is it a mental picture humans have imposed on a much more subtle reality? The new buzzword is network, but is that an accurate characterization? Networking is concerned more with the interactions of entities than with the entities themselves; this means that the rules of the game are more important than the nodes of the network. How could that fit within a materialistic world view?

Whatever comes in the days ahead, it appears that there is far more information processing occurring in the cell than even Watson and Crick imagined – and that was startling and elegant enough. Barry states that the raw genetic information transcribed in DNA now appears to be 62 times what genes alone would produce. The fundamental operational unit of life may, therefore, be nonphysical: information, not molecules. These are exciting times for science – troubling times for Darwinists. Don’t expect them to have any remorse over leading mankind into a “modern orthodoxy” that was mistaken.