How Science Is Rewriting the Book on Genes

This helps explain a mystery that emerged after researchers completed the human genome in 2001. They found 22,000 genes, but there are more than 100,000 proteins. How could that be?

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The discovery of a whole world of post-transcriptional control of a gene's instructions, which allows one gene to provide instructions for more than one protein, is a big part of the answer.

How Does Evolution Change Genes?

About 5 percent of the total human genome appears to be a "message" of one sort or another, the order of the nucleotide letters determined over the course of evolution and passed through the generations with few changes. In those stretches of DNA (there are about 500,000 of them salted through our 23 pairs of chromosomes), any addition, deletion or change of a letter is likely to have a big effect. Often the effect is death.

The function of the remaining 95 percent of the DNA chain is uncertain. Changes creep in and pile up without obvious effect. The whole mass used to be called "junk DNA," but few biologists are willing to call it that anymore.

It was long thought that the active 5 percent of our DNA consisted almost entirely of genes coding the instructions for making proteins. But it turns out that's not true.

It's now clear that more of those evolutionarily preserved stretches of DNA don't code for proteins than those that do. By one estimate, 70 percent of the conserved elements are non-coding.

"The majority of what evolution cared about is stuff we didn't know about a few years ago," says Eric S. Lander, a geneticist and head of the Broad Institute of MIT.

So what are these conserved non-coding elements? They are molecules worthy of the "Star Wars" cantina scene -- insulators, micro-RNAs, exon-splicing enhancers, 3'-untranslated hairpins and other weird characters only now emerging from the shadows.

What they have in common, other than that they are never translated into proteins, is that they regulate the activity of genes that do carry instructions to make proteins. They turn them on and off, tweak them to make one version of a protein rather than another, increase or decrease the efficiency of production, and coordinate the sequential or simultaneous action of genes.

A study in the journal Science in August found that these elements are less tolerant of mutation than protein-coding genes. That means they are more likely to be identical among people, mice, fruit flies and worms than are the genes coding for proteins. It turns out that more of evolution's survival-of-the-fittest battles occurred in writing the instruction manual for running the genes than in designing the genes themselves.

It also turns out that a huge number of proteins encoded by the classical genes are used to regulate other genes, and not to be final products such as enzymes, cartilage and hemoglobin. Nearly 1 in 10 code for transcription factors, proteins that help turn genes on and off at the right time.

In practice, many of these transcription factors act like orchestra conductors. One of them, called HIF-1, picks up the baton when a cell's demand for oxygen rises or the supply falls. Depending on the length or severity of the oxygen shortage, HIF-1 can turn on genes that make more red blood cells and blood vessels, or change the cell's metabolism so it needs less oxygen.