Mapping the brain’s genetic landscape in greater detail
For the past two decades, scientists have been exploring the genetics of schizophrenia, autism and other brain disorders, looking for a path toward causation. If the biological roots of such ailments could be identified, treatments might follow, or at least tests that could reveal a person’s risk level.
In the 1990s, researchers focused on genes that might possibly be responsible for mental distress, but then hit a wall. Choosing candidate experts said. versity School of Medicine, genes up front proved to be “The effort that has gone began by combining all those fruitless. In the 2000s, using into the collection and anal- genes, as a group, and calcunew techniques to sample ysis of these data is truly lating the combined added the entire genome, scientists i mpressive,” s aid Kevin risk they impart into a sinhit many walls: Hundreds Mitchell, an associate progle coefficient. That calculaof common gene variants fessor of genetics and neuroltion on its own barely beats seemed to contribute some ogy at Trinity College, Dub- a random guess in assessing risk, but no subset stood out. lin, who was not involved added risk.
Even considered together, in the project. The data, he Gerstein and his team then all of those potential contrib- added, “represent a hugely integrated those implicated uting genes — some 360 have valuable resource.” Whether genetic locations with other been identified for schizo- that resource will help scibiological data: patterns of phrenia — offered nothing entists determine any bio- gene expression from sinclose to a test for added risk. logical cause, Mitchell caugle cells taken from people The inherited predisposi- tioned, remains an open with a disorder. The varying tion was real, but the intri- question. ratios of different cell types, cate mechanisms by which The $50 million project, in different individuals. all those genes somehow initiated in 2015 and financed The activity of transcribled to symptoms such as by the National Institute of ing and regulating molecules, psychosis or mania were a Mental Health, involves more which moderate the exprescomplete mystery. than a dozen research cension of genes — the conver
Now, using more advanced ters and scores of specialists sion into functioning proteins tools, brain scientists have in cell biology, genetics and — over time. This combined begun to fill out the picture. bioinformatics, the applicaanalysis improved predicIn a series of 11 papers, pub- tion of advanced computer tive power to about 25 perlished in Science and related learning to huge data sets. It cent over random guessing, journals, a consortium of is an all-hands, brute-force from 4 percent in previous researchers has produced the effort, coordinating top brain models. most richly detailed model banks and brain scientists at In another report, invesof the brain’s genetic land- major research centers, led tigators delivered a clearer scape to date, one that incor- by Yale, Mount Sinai, UCLA picture of brain developporates not only genes but and the University of Califor- ment over the human lifealso gene regulators, cellunia, San Francisco. time. The brain is continular data and developmenThe new model was based ally adapting, or “rewiring,” tal information across the in part on analyses of nearly itself through life, particuhuman life span. 2,000 human brains, from larly in utero and through
The work is a testament people with and without adolescence, generating an to how far brain biology has diagnoses, collected over ever-transforming genetic, come, and how much fur- d ecades. In o ne of the cellular and genetic landther it has to go, toward propapers, a research team led scape that had defied the ducing anything of practical by Mark Gerstein, professor tools of modern science. value to doctors or patients, of bioinformatics at Yale Uni-