Human Genome: What's Been Most Surprising?

What surprises me most about the state of the human genome in 2011 is how much of the sequence remains to be assembled accurately and how important that achievement would be for fulfilling the Human Genome Project’s original goal: a comprehensive reading of the book of life. Achieving this aim will require conquering the most structurally ornate and dynamic regions of the genome, including the essential but elusive elements (suchas centromeres and telomeres) that are responsible for faithful transmission of the genome from one generation to the next. Students of human biology and medicine would finally be able to see the genome as an orchestra of chromosomes—not merely a ‘‘parts list’’ of genes. We would, at last, be positioned to address some of the longstanding mysteries of humanbiology andmedicine, such as the fragile and tenuous nature of human reproduction, and we would understand why a sizeable proportion of all human conceptions—and half of spontaneously lost pregnancies—display dramatic anomalies of one or more chromosomes. Just as high-resolution crystal structures of macromolecular complexes enable unforeseen insights into function in health and disease, a complete and accurate assembly of the human genome will answer questions that we do not even know to ask. Variation and Complexity