A time and a place: a new window on the life of the brain

A new study of remarkable size and scope offers clues to how the human brain develops, from its early stages into old age. The landmark research, led by Nenad Sestan, M.D., Ph.D., associate professor of neurobiology and a member of Yale’s Kavli Institute for Neuroscience, found that gene expression in the human brain is exquisitely choreographed across developmental periods and brain regions. This tailoring of gene expression occurs particularly during the prenatal period, during which there are rapid changes in brain structure and function. In addition to its contribution to our knowledge of normal neural development, the study may help clarify why some people are more susceptible to particular psychiatric or neurological disorders, especially autism and schizophrenia, which many scientists believe are caused by perturbations in early brain development.

Sestan has long been interested in understanding the transcriptome, the term for the totality of expressed RNA molecules, of the human brain. We share most of our genes with other animals, and in Sestan’s view, it is the spatiotemporal dynamics of the brain transcriptome—when and where genes are expressed—that underlies humans’ unique attributes.

In the new research, Sestan and colleagues measured the relative abundance of messenger RNA (mRNA) molecules in 16 important brain regions at 15 developmental stages across the lifespan. Because mRNA is the molecular middleman between genes and the protein-making machinery of the cell, with some adjustments mRNA levels are a reliable indicator of which genes are slated for translation into proteins at any given time.

Previous efforts to decipher the transcriptome of the human brain have looked at only a few brain areas and/or a few time points, so when recently developed technology made it possible to interrogate most of the human genome in one swoop, Sestan saw a chance to do the study of his dreams. Yet in thinking about the study, which would ultimately analyze more than 17,000 distinct mRNA transcripts, he decided that “this cannot be done by one person, one lab, or even one institution.”

Indeed, the study, published in the October 27 issue of Nature, involved an international team of collaborators, as well as several scientists from Sestan’s own laboratory: Hyo Jung Kang, Ph.D.; Yuka Imamura Kawasawa, Ph.D.; Feng Cheng, Ph.D.; Ying Zhu; Xuming Xu, Ph.D.; Mingfeng Li, Ph.D.; Andre Sousa; Mihovil Pletikos, M.D.; Kyle Meyer; Goran Sedmak, M.D.; Yurae Shin; Matthew Johnson, Ph.D.; Zeljka Krsnik, Ph.D.; Simone Mayer; and Sofia Fertuzinhos, Ph.D.

Thanks to the generosity of brain donors, Sestan’s team had access to 57 post-mortem human brains representing developmental stages from 40 days after conception to 82 years of age. They gathered 1,340 tissue samples for analysis, including from 11 areas of the neocortex, where the neural machinery resides for many capabilities, such as language and reasoning, that we think of as distinctively human.

This massive effort uncovered some surprising results. For starters, the study found that nearly nine of every ten genes in the human genome are expressed in the brain, “basically saying you use most of your genes to build your brain,” Sestan says. DNA “switches” can turn gene expression on or off, and expression of most of these genes varied by developmental period, brain region, or both. “What was also surprising and completely unknown before,” Sestan says, “is that most of these changes occur during prenatal and early postnatal development.”

In addition, from one brain region or time point to another, “genes switch their versions like suits,” according to Sestan. They can do so because an mRNA sequence can be spliced in different configurations, meaning a single gene can create different versions of a protein.

While mRNA expression significantly differed between brain regions and across developmental periods, it varied less by ethnicity or sex. Even so, expression of 159 genes differed between males and females. Most of these sex-based expression differences appeared before birth and vanished by adulthood, but Sestan says they “may offer some insight into why there is a difference in incidence, prevalence, and severity of brain disorders between sexes.”

Though this study excluded tissue from people with overt medical or large-scale genetic abnormalities, some of the same sex-biased genes observed in the work by Sestan and colleagues have been fingered by other researchers as increasing the risk of psychiatric and neurological disorders. They include genes suspected of contributing to schizophrenia and autism, two disorders that may start brewing early in development and affect males and females differently.

Sestan and colleagues also found 29 groups of genes that were expressed together in certain brain regions during specific developmental periods. They were able to tie some of these gene expression networks to particular biological processes, yielding clues to what the genes do. Furthermore, some of the genes at the hub of these networks have been implicated in schizophrenia, mood disorders, Rett syndrome, and intellectual disability. Now, researchers who study such disorders can look to these co-expressed genes for causal leads.

Sestan and his collaborators hope that their study will help scientists who study these conditions and others. To that end, they have made their data set publicly available. After all, as Sestan well knows, it will take a village of scientific sleuths to solve the mysteries of our most complex organ.