What We Didn’t Expect from the Human Genome Project

The history of DNA research is a tale of patient researchers laboring day after day on myriad tiny problems. It is a tale of myriad answers gathering at last into profound insights. This is what happened with the Human Genome Project.nn The question the HGP set out to answer was: What are all the genes in a human being? The geneticists working on the Project already knew a lot. They knew that genes work by manufacturing proteins. They knew that genes do this indirectly: Enzymes in the cell nucleus unroll and unzip part of a DNA double helix and copy a portion of the DNA, a target gene, into molecules of messenger RNA. The messenger RNA exits the nucleus and carries the gene’s code to cell parts in the cytoplasm, to direct protein manufacture. Finally, the geneticists knew that humans have around 100,000 different types of proteins in their bodies. So researchers expected the HGP to take years, and to turn up about 100,000 genes.nnBut some Project geneticists devised new, speedier techniques for decoding DNA. A lot sooner than anticipated, the whole human genome was known. And there weren’t 100,000 genes—there were only about 30,000! Or maybe only 25,000! A humbling conundrum: How do 100,000 proteins get manufactured by only 25,000 genes?nnBefore the Human Genome Project got started, something else had come to light: After a molecule of messenger RNA is copied from a gene, and before the messenger RNA leaves the cell nucleus, it gets “edited.” Molecules called spliceosomes cut the RNA message into fragments, remove some of the fragments, and splice the rest back together again. The spliced message is what actually passes out of the cell nucleus into the cytoplasm, and gets translated into a protein. n nBut the spliced message isn’t always the same. The set of fragments that get spliced together can differ. So that alternative proteins result from the same messenger RNA, and therefore from the same gene. So this is how 25,000 genes make 100,000 proteins. nnHow did this intricate system evolve? Some biologists think the first active, reaction causing molecules of life were RNA’s, while others think they were proteins. Intriguingly, spliceosomes have some of both. Could alternative splicing be connected to the earliest molecules of life? When we investigate this editing of RNA, are we seeing far back into life’s beginnings, just as we see far back into the beginnings of the universe when we investigate the oldest light we can find with the Hubble Telescope? n