We certainly live in interesting times. Less than two weeks ago, on Darwins birthday, the scientists who have been sequencing the human genome — that is, deciphering all of the DNA in our chromosomes — announced to the world what they had found. The human genome contains some 3.2 billion bases, so its sequencing has presented no small challenge. The success of this effort (with much of the work done in St. Louis by an outstanding team of scientists led by Dr. Bob Waterson of the Washington University School of Medicine) will rank as one of the great scientific achievements of this century, a picture of humanity carved in a molecule of DNA.
And a very unexpected picture it is. For half a century, since Watson and Crick discovered that genes are made of DNA, biologists have been studying what genes are like. By now they thought they had a pretty good idea. Genes are arrayed on chromosomes like pearls on a necklace, one after the other, with little or no spacing between them. Each gene is the blueprint for a particular protein that the body uses in the business of living. A pretty picture, with the twin virtues of clarity and simplicity. Wrong, though.
Over the next few weeks, this column will explore three unexpected aspects of the recently-revealed human genome. Today we will consider the number of genes in the human genome, next week we will explore the strange topography of human chromosomes, and the following week we will consider what the genome tells us about what it means to be human.
Most scientists who had seriously considered the matter had come to the conclusion that the human genome probably contains about 100,000 genes. Until this month, the only way to get a firm count of the number of genes in a human cell has been to extract from the cell the RNA copies of genes it is using to make proteins. These working copies are called messenger RNA. Counting them might miss some genes not being used at the moment, but even so the number of different messenger RNA molecules in a cell should give a roughly reasonable picture of how many genes the cell uses.
Taking this approach, researcher William Haseltine, president of Human Genome Sciences, claims to have retrieved and sequenced 90,000 full-length messenger RNAs from human cells, and to have made and tested the proteins from 10,000 of them. Haseltine has estimated from results like these that there must be at least 120,000 human genes.
Now, with the human genome sequenced, we can directly count the number of genes that reside on our chromosomes. The number is far fewer than Haseltine or anyone else had anticipated, only about 30,000! This result is a very great surprise. Humans have barely a third more genes than a nematode worm and scarcely double the number of genes it takes to make a fruit fly.
We humans intuitively think of ourselves as far more complex than a nematode or fruitfly — but it seems our complexity is not so much a matter of how many genes we have, as how we use them. A Porsche and a Mack truck have pretty much all the same parts — carburetors and spark plugs and axles and wheels — put to work in very different ways.
So how did Haseltine get it so wrong? His conclusion depended upon a key assumption of the pretty picture genome, that each gene makes its own special protein. By counting the proteins (as the messenger RNAs that specify them), you count the genes.
It turns out, however, that human genes are not that simple. A typical human gene is not simply a straight sequence of DNA, the order of its units corresponding to the sequence of amino acids in a protein. Instead, a human gene is fragmented. The sequence of DNA units that specifies a protein is broken into many bits and scattered about among much longer segments of nonsense DNA. Imagine looking at an interstate highway from a satellite. Scattered randomly along the thread of concrete would be cars, some moving in clusters, others individually; most of the road would be bare. That is what a human gene is like.
When a cell uses a human gene to make a protein, it first manufactures messenger RNA copies of all the useful (protein-specifying) bits of the gene, then splices the bits together. Now heres the turn-of-events Haseltine had not anticipated. It appears that human genes are often spliced together in more than one way.
Each gene bit is not just a random fragment, it turns out, but rather a functional module. One gene bit makes a straight stretch of protein, another a curve, yet another a flat place. Like mixing tinker toy parts, you can construct quite different assemblies by employing the same parts in different orders.
With this sort of alternative messenger RNA splicing, 30,000 genes can easily encode four times as many proteins. It seems we humans achieved added complexity not by gaining more gene parts, but rather by learning new ways to put them together. Great music is made from simple tunes in much the same way.
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