99% of genome still a mystery, but we think science knows everything...

99% of genome still a mystery
12 Nov 2008, 0024 hrs IST, Carl Zimmer, NYT News Service



New large-scale studies of DNA are causing researchers to rethink the very nature of genes. They no longer conceive of a typical gene as a single
chunk of DNA encoding a single protein. It cannot work that way, they say. There are simply too many exceptions to the conventional rules for genes.

It turns out, for example, that several different proteins may be produced from a single stretch of DNA. Most of the molecules produced from DNA may not even be proteins, but another chemical known as RNA. The familiar double helix of DNA no longer has a monopoly on heredity. Other molecules clinging to DNA can produce striking differences between two organisms with the same genes. And those molecules can be inherited along with DNA.

The gene, in other words, is in an identity crisis. This crisis comes on the eve of the gene’s 100th birthday. The word was coined by the Danish geneticist Wilhelm Johanssen in 1909, to describe whatever it was that parents passed down to their offspring so that they developed the same traits. Johanssen had no idea what that invisible factor was. But he thought it would be useful to have a way to describe it.

Over the next six decades, experts transformed that little word from an abstraction to concrete reality. A gene, they said, was a specific stretch of DNA containing the instructions to make a protein molecule.

A gene was also the fundamental unit of heredity. Every time a cell divided, it replicated its genes, and parents passed down some of their genes to their offspring. If you inherited red hair — or a predisposition for breast cancer — from your mother, chances were that you inherited a gene that helped produce that trait.

Complications emerged in the 1980s and 1990s, though. Scientists discovered that when a cell produces an RNA transcript, it cuts out huge chunks and saves only a few small remnants. Vast stretches of noncoding DNA also lie between these protein-coding regions. The 21,000 protein-coding genes in the human genome make up just 1.2% of that genome.

In 2000, an international team of scientists finished the first rough draft of that genome — all of the genetic material in a human cell. They identified the location of many of the protein-coding genes, but they left the other 98.8% of the human genome largely unexplored.

One of the biggest of these projects is an effort called the Encyclopedia of DNA Elements, or Encode for short. The Encode team expects to have initial results on the other 99% by next year.

Encode’s results reveal the genome to be full of genes that are deeply weird, at least by the traditional standard of what a gene is supposed to be. “These are not oddities — these are the rule,” said Thomas Gingeras of Cold Spring Harbor Laboratory and one of the leaders of Encode.

A single so-called gene, for example, can make more than one protein. In a process known as alternative splicing, a cell can select different combinations of exons to make different transcripts. But it turns out that the genome is also organized in another way, one that brings into question how important genes are in heredity. Our DNA is studded with millions of proteins and other molecules, which determine which genes can produce transcripts and which cannot. New cells inherit those molecules along with DNA. In other words, heredity can flow through a second channel.

Much of the baggage in the genome comes not from dead genes but from invading viruses. Once these viruses invaded our genomes, they sometimes made new copies of themselves, and the copies were pasted in other spots in the genome. Yet some of these invaders have evolved into useful forms. Some stretches of virus DNA have evolved to make RNA genes that our cells use.

Gerstein says that in order to define a gene, scientists must start with the RNA transcript and trace it back to the DNA. These new concepts are moving the gene away from a physical snippet of DNA and back to a more abstract definition. “It’s almost a recapture of what the term was originally meant to convey,” Gingeras said. A hundred years after it was born, the gene is coming home.