Shared Differences
The architecture of our genomes is anything but basic
Whether you like it or not, you’re a little different. If it makes you feel any better, so is everybody else. In fact, everybody is far more different than anybody had imagined.
Scientists are only beginning to discover just how different humans are from each other at the genetic level and what those personal genetic attributes mean for health, history and the human evolutionary future.
It’s true that people are 99.9 percent alike, if only minor spelling variations in the genetic instruction book are taken into account. In each person, about one in every 1,000 DNA bases — the chemical letters of the genetic alphabet — differs from the generic human construction and operating manual. So, on average, one person will differ from another at about 3 million of the 3 billion letters in the human genome. Researchers have recently mapped many of these single letter variations, called single
nucleotide polymorphisms or SNPs, looking for variants that might play a role in complex diseases such as heart disease, diabetes and high blood pressure (SN: 6/21/08, p. 20).
So far, SNPs have been associated with many diseases, but SNPs can also be protective. And those little spelling differences may contain information about a person’s geographic ancestry — just as whether people write color or colour is a clue about whether they hail from the United States or Great Britain.
But SNPs aren’t the whole story of human-to-human distinctions. Scientists now know that a different type of variation, previously thought to be rare, is surprisingly widespread.
New research shows that the human genome has undergone extensive editing, much more sweeping than the minor letter differences or spelling variations. Entire pages may be torn from, or even stuffed into, an individual’s genome. Paragraphs can be duplicated multiple times, swapped with other passages, written backward, deleted, truncated or otherwise altered in myriad ways. These differences are known collectively as structural variation, and as little as 5 percent or as much as 18 percent of the human genome may be affected.
Scientists previously knew that having extra copies of an entire chromosome could lead to disorders, such as the third copy of chromosome 21 that causes Down syndrome. Research had also identified very large deletions that remove so much of a chromosome that the void can be seen under a microscope, and had revealed nips and tucks that remove single genes or parts of genes.
But until completing the Human Genome Project, an effort to map all the genes and surrounding DNA found in people, researchers had no way to detect structural changes too small to be seen under the microscope and too big to be detected by looking at individual genes.
Because these variations cover large expanses of the genome rather than single DNA bases, current estimates suggest that structural variation may encompass four times as many bases as SNPs do, meaning that people’s genomes differ by an additional 0.5 percent. So any two people are really only about 99.4 percent alike.
New findings indicate that a substantial portion of otherwise healthy people are missing large chunks of their genomes, gaps that can predispose them to certain diseases. Already, structural variants, especially the type known as copy number variants, have been linked to neurological disorders such as schizophrenia and autism, to susceptibility to HIV infection, to Crohn’s disease and even to tendencies in weight.
“Our work in structural variation is showing that no one is really normal,” says Charles Lee, a cytogeneticist at Brigham and Women’s Hospital and Harvard Medical School in Boston. Lee was among the first to discover the broad range of structural variation in the human genome.
Not necessarily two copies