Molecular biologists have long suspected that human chromosomes contain a lot of excess baggage. But no one suspected how much. The recent sequencing of the human genome, key elements of which were carried out by Bob Waterstons superb research team here in St Louis at Washington University, reveals a startling picture. Each of your cells has about six feet of DNA stuffed into it, but of that, less than one inch is devoted to genes! Thats right. Nearly 99% of the DNA in your cells has nothing to do with the instructions that make you you.
True genes are scattered about the genome in clumps among the much larger amount of non-gene DNA, like isolated hamlets in a desert. What is all this other stuff? The human genome project has revealed that there are four major sorts of non-gene DNA in our chromosomes.
Non-coding DNA within genes. As we discussed in last weeks column, a human gene is not simply a stretch of DNA, like the letters of a word. Instead, like an encrypted message, a human gene is made up of numerous fragments of information embedded within a much larger matrix of non-coding DNA. The stretches of non-coding DNA between gene fragments are called introns. Together, these introns make up about 24% of the human genome, and genes from 1% to 1.5%.
Structural material. A portion of each chromosome called a centromere is devoted to creating a solid platform to anchor the microtubules that pull the chromosome during cell division. Other portions on the tips of chromosomes, called telomeres, provide sites where polymerase enzymes can initiate chromosome replication. Called constitutive heterochromatin, these structural parts of the chromosome make up about 20% of the human genome.
Repeated sequences. Scattered about the chromosomes are simple sequence repeats (SSRs). An SSR is a two- or three-nucleotide sequence like CA or CGG, repeated like a broken record thousands and thousands of times. SSRs make up about 3% of the human genome. An addition 7% is devoted to other sorts of duplicated sequences. Overall, repeated sequences make up about 10% of the human genome.
Transposable elements. Fully 45% of the human genome consists of mobile bits of DNA called transposable elements. Discovered by Barbara McClintock in 1950 (she won the Nobel Prize for her discovery in 1983), transposable elements are bits of DNA that are able to jump from one location on a chromosome to another, tiny molecular versions of Mexican jumping beans.
How do they accomplish this remarkable feat? While the details of the transposition mechanism are complex and vary for different kinds of element, the basic process is quite simple. The two ends of a transposable element have similar DNA sequences. Because the two sequences are the
same, the strands of DNA from one end can pair up with the strands from the other. When its ends associate in this way, the element forms a loop. Mark a piece of string with black ink at two places, and let the black sections touch, and you will see how a loop forms. Now if a nick is made in the DNA of the loop, an enzyme called reverse transcriptase can make an RNA copy of the DNA in the loop, a copy which is free to move away and reenter the chromosome elsewhere.
Human chromosomes contain five sorts of transposable elements. Fully 20% of the genome consists of long interspersed elements (LINEs). An ancient and very successful element, LINEs are about 6KB (6 thousand DNA bases) long, and contain all the equipment needed for transposition, including genes for a DNA-loop-nicking enzyme and a reverse transcriptase.
Nested within the genomes LINEs are over half a million copies of a parasitic element called ALU, 10% of the human genome. ALU is only about 300 bases long, and has no transposition machinery of its own — like a flea on a dog, ALU moves with the LINE it resides within. Just as a flea sometimes jumps to a different dog, so ALU sometimes uses the enzymes of its LINE to move to a new chromosome location. Often jumping right into genes, ALU transpositions cause many harmful mutations. Imagine the consequences of randomly inserting a brick into your backbone — ALU can disrupt a gene it lands in just as severely.
Three other sorts of transposable elements are also present in the human genome: 8% of the genome is devoted to long terminal repeats (LTRs). Called retroposons, they are well on the way to becoming viruses. 3% is devoted to DNA transposons, which copy themselves as DNA rather than RNA. Some 4% is devoted to dead transposons, elements that have lost the signals for replication and so can no longer jump.
Thus we see our human genome is a dynamic place when viewed from a molecular perspective. Everywhere we see evidence that DNA elements have been jumping about. Only occasionally, here and there, do we encounter a gene that specifies a protein. Its hard to escape the impression that the genes that make us human are but a minor aspect of our DNA. You cant study the genome for very long before you start feeling that youre just a transient vehicle for making more DNA, Bob Waterston said in a Washington Post interview. Yet here you are, reading these words. Practically lost in the bizarre molecular landscape of introns, LINEs and ALUs, the 30,000 human genes that define us get the job done just fine.
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