Development, evolution and function of the human cerebral cortex.

Dr. Walsh's lab studies the normal development of the human cerebral cortex, as well as identifying mutations that disrupt the normal development and function of the human cerebral cortex. They focus on Mendelian pediatric brain diseases, manifesting as autism, epilepsy, intellectual disability and other learning disorders. Not only are these genes vital for the normal development of the cortex, but also some have been altered evolutionarily to allow the unique aspects of the brain that underlie human cognitive abilities. Therefore these genes define in some sense what makes us uniquely human. They have identified more than two-dozen human disease genes. Most of their genetic work has benefited from worldwide collaborations, especially in Middle Eastern countries where consanguinity is common, since this enhances the effects of recessive mutations and makes them easier to map and identify. Recent work has focused notably on the role of somatic mutations in neurological disease. This has led to the characterization of somatic mutations in AKT3, MTOR, and PIK3CA that result in hemimegalencephaly (enlarged, malformed cerebral hemisphere) and focal cortical dysplasia, and they are also studying the role of somatic mutation in autism and other developmental disorders. They have pioneered “single cell genomics” at both the RNA level--to study brain progenitor cells--and at the DNA level, and have discovered that the somatic mutations that occur in dividing progenitor cells during normal human brain development cause adult human neurons to bear indelible marks of the pattern of cell divisions that produce the human brain.