How Science Is Rewriting the Book on Genes

This kind of regulation may be what separates mice from men -- or, more likely, what separates mice and men from yeast and flies. Nine percent of all human genes code for transcription factors. For fruit flies, it's 5 percent; for yeast, 3 percent.

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Is Efficiency the Goal?

It used to be a rule -- actually, more of an assumption -- that the genetic machinery of living organisms was never intentionally wasteful or inaccurate. It turns out this isn't always true, either.

Three recent discoveries show that what appear to be genetic mistakes can have a purpose.

Some genes, for example, contain mutations that are thought to be "silent" and harmless because the substituted letter is synonymous with the correct letter. It's a little like spelling "skeptical" with a "c" instead of a "k" -- "sceptical" -- the meaning is still the same.

Earlier this year, however, a study in Science showed that these synonymous spellings can make a difference. That's because it can be harder to make a protein from the instruction with the unusual, but synonymous, spelling. The construction process takes longer, and the final protein folds up differently. It has a slightly different shape -- and a different function.

A second example involves the gene for the blood-clotting protein called prothrombin. In its most common form, this gene contains a stretch of nucleotides near one end that makes it hard for the cell to translate the mRNA transcript into the prothrombin protein.

Some people have a mutation that fixes this problem. Their prothrombin gene makes a transcript that pours out prothrombin. The result? Their blood clots too easily. They get clots when they don't need them.

Why would evolution favor this built-in inefficiency?

One theory is that in certain circumstances -- perhaps life-threatening bleeding -- the body can throw a switch that somehow overcomes this natural inefficiency and increases clotting at a moment's notice.

A similar goal may be behind the third example, a phenomenon called nonsense-mediated decay.

When a cell is translating a piece of mRNA into a protein, it stops when it reaches a three-nucleotide segment called a termination codon that causes the just-built protein chain to separate from the construction machinery -- like a car rolling off the assembly line. It now turns out that the mRNA instructions for a few proteins have a termination codon in the middle of the chain, not just at the end.

The protein-building machinery can sometimes "read through" this instruction and complete the protein. (How it does that is complicated and only partially understood). But most of the time, construction just stops. The half-finished protein is broken down, and all the effort goes for naught.

Why would an organism have an assembly line that builds a product partway and then tears it up time after time? This may be another strategy that allows the body to handle certain problems at a moment's notice.

Think of a cell as containing a factory that makes both tractors and tanks. In peacetime, few tanks are made, but the knowledge and capacity is never lost. Most tanks are built halfway and then broken down, with the parts sent back up the assembly line for reuse.

But then comes great stress; say the cell is experiencing too much heat or not enough oxygen or food. That's where nonsense-mediated decay (NMD) comes into play. It's suddenly wartime, but instead of refitting the factory to make tanks, all the cell has to do is give the order to take the half-made tanks to completion.

For example, when an organism is well-fed, it doesn't need a lot of machinery dedicated to capturing and transporting amino acids, the building blocks of proteins. That's because there is an abundance of amino acids floating around and within easy reach.

In starvation times, however, the cell needs all the amino-acid-capturing machinery it can get. So it turns down NMD, and the proteins whose functions are to capture and carry amino acids start rolling off the assembly line in abundance.

Just the right amount of wrong instructions and wasteful habits -- that's what evolution has built into all of us.