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A global effort to find all the functional elements in DNA has revealed surprising genomic complexity that will probably complicate progress toward personalized medicine. The fi ndings suggest that enormous regions of the genome once dubbed “junk DNA” are functional, even though they don’t code for proteins. The discovery — described in Nature in June and detailed in 28 companion re ports in the June issue of Genome Research — was made by the ENCODE (Encyclopedia of DNA Elements) consortium, a collection of 35 research groups from around the world headed by the National Human Genome Research Institute (NHGRI) at the National Institutes of Health. ENCODE scientists exhaustively studied 30 million base pairs of human DNA, about 1% of the genome, and found evidence of transcription in the regions that lie between individual genes. (Transcription is the process by which DNA makes RNA, the molecule from which proteins are generated.) Scientists used to think that only the protein-coding components of genes — making up just 2% of the genome at most — were involved in transcription. The rest of the genome, they assumed, was largely inert. ENCODE’s fi ndings have shown this assumption to be false. However, precisely what the noncoding regions do remains a mystery, concedes Eric Green , M.D., Ph.D., NHGRI’s scientifi c director. “We understand the language of genes and the genetic code, but I can’t stress enough how little we understand about the language of noncoding DNA,” he says. “Protein production is governed by straightforward rules, but noncoding DNA appears to have multiple functions, each coordinated by different rules. We’ve only scratched the surface in terms of our understanding of how the genome works.” Far from being a collection of tidy genes with independent effects, the genome is a vast network of genes and other regulatory elements that interact in unknown ways. As the reality of this complexity sets in, scientists are revising expectations for personalized medicine and setting projected timelines back indefi nitely. “In the short term, it makes everything more diffi cult,” asserts John Greally , M.D., Ph.D., an associate professor of medicine and molecular genetics at Albert Einstein College of Medicine. “Instead of looking only in genes for disease variations, we have to consider the entire genome. But it’s only with more complete information that we can hope to understand the whole system.” After decoding the human genome, scientists predicted that progress toward personalized medicine would advance rapidly. But despite 25,000 research reports since 2000 investigating disease associations with variations in nearly 2,500 genes, researchers have yet to identify any new variations with substantial clinical effects, according to Muin Khoury, M.D., Ph.D., who directs the National Offi ce of Public Health Genomics at the Centers for Disease Control and Prevention. At most, 10% of published associations have been validated by other researchers, Khoury says. And few of these, if any, have resulted in clinical or public health applications. Of particular signifi cance is the lack of any new “big genes with big effects,” such as the BRCA gene variations that raise breast cancer risk by up to 85%. Women who inherit the BRCA variations can benefi t from personalized care, including prophylactic surgery. Scientists hoped that the genome would yield more genes like BRCA, which would point to clear clinical opportunities. But instead, genomic research has consistently linked illnesses with networks of smaller genes, each with minor risk contributions that vary greatly from patient to patient. Validating the effects of these genes is diffi cult, in part because enormous numbers of patients are needed to boost statistical power enough to make these small changes visible. Thus, with few exceptions, gene networks have not generated drug targets or clinically useful biomarkers.

Newly Revealed Genome Complexity May Mean Personalized Medicine Is Farther Away