Reading Our Genome Is Tough, But Epigenetics Is Giving Us Valuable Clues

When scientists sequenced the human genome a decade ago, they hoped to unlock the code of life, the sequence of molecules lined up in every cell that, summed together, made a person a personand possibly reveal new ways to understand and treat diseases. But the resultsturned out to be opaque. Biologist Eric Lander, who helped lead the effort, famously summed up the results in seven words: Genome: Bought the book; hard to read.

So the research community went looking for CliffsNotes. A decade ago scientistsstarted looking into the epigenome, chemical modifications to DNA that tell cells which genes to turn on or turn off. This weekthat project got a huge data dump24 journal articles laying out what the genomicists know so far about 111 different cell types, the inner lives of brains, hearts, blood, and skin. It is giving us a view of the living, breathing genome in motion, as opposed to a static picture of DNA, says Manolis Kellis, a computational biologist at MIT who worked on two of the new papers.

Just about every cell in a human body has the same DNA, packaged into the same chromosomes. But cells differentiate, growing into different tissue types with different functions. The epigenome works through molecules like methyl and acetyl groups that wheedle their way into DNA, exposing different genes to the machinery that reads them and makes proteins. That helps control when or whether those proteins get made at all, and its also critical to that process of differentiation. In each cell type, it unravels just the right genes, says Brad Bernstein, a biologist at Harvard University. It unravels just the right switches.

One of the reasons the genome turned out to be so hard to read is that only about 1.5 percent of it actually consists of genes that encode for proteins. The other 98.5 percent? Scientists can read the sequenceATTATCG, or whateverbut they dont know what it actually does. Epigenomic maps like these new ones might help explain what that non-coding DNA is for. If the genome is a book, then the epigenome is like the post-it notes, dog-ears, and highlights that help you make sense of a particularly dense text. It wont tell you the meaning of Moby Dick, but it will tell you if theres a whale and wheres the boat, Kellis says.

Ideally, the epigenome will also have a lot to say about the origins and processes of some serious diseases with genetic components, like Crohns, diabetes, cancer, and Alzheimers. Scientists already know aboutgenetic variants associated with Alzheimers, but because those variants arent in the protein-coding part of the genome, no one knew what they did. Thanks to epigenomic maps from mice and human brain cells, Kellis has found that they have something to do with the immune system. Those genetic abnormalities, it seems, predispose you to Alzheimers. That basically means that the immune genes and regulatory regions are not simply a consequence of the disease, but in fact they are drivers, Kellis says. Thats something people were starting to suspect, but no one had actually shown at this level.

The epigenomic mapsmay evenhelp treatcancers. Doctors often tailor therapies to specific types of tumors, but in manycases, oncologists dontknowwhere a particular cancer originatedwhich makes treatment a crap shoot. But epigenomic maps can help them identify the origin of these mysterious cancers. Tumor cells are rife with mutations, it turns out, distributed all along the cells DNA. Healthy cells package DNAitself a long, winding strandby further winding it, packing it like an overcranked rubber band. In that form, the DNA is called chromatin. More tightly-wound parts are hidden, but looser sections are exposed and accessible to a cells normal DNA-repair machinerywhich means mutations there get fixed more often, creating a chromatin mutation pattern specific to individual cell types. In the new study, researchers discovered that mutation patterns in a cancer cell correspond with chromatin structure. That means thatif you can match a tumors mutation pattern with a knownchromatin structure, you know that the tumor came from that particular cell typeand a physician canprescribe the righttreatment.

Over a longer term, understanding epigenetic changes might even provide insight into the nature-versus-nurture debate. Everything from nutrition to chemical exposures can affect the epigenome. Yet epigenetic changesfor example, molecules like methyl groups working their way into genescan sometimes get passed on to offspring. Thats startling, and seems almost counter to basic evolutionary science. So scientists want to understand the relationship between the genome and the epigenome, and how environment and genetic predilections can intertwine.

But even with this huge set of papers, the research has a long way to go. The goal of the International Human Epigenome Consortium is to map more than 1,000 cell types and then compare how individual people varyhow one persons epigenome differs from another. Thats the job, says Kellis, that I think will occupy us for at least the next decade. The genome isnt just hard to readit also takes a long time.

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Reading Our Genome Is Tough, But Epigenetics Is Giving Us Valuable Clues