Steven McCarroll, 2011
Who he is
Steve McCarroll is the Dorothy and Milton Flier Professor of Biomedical Science and Genetics, Harvard Medical School and the Director of Genomic Neurobiology, Stanley Center, Broad Institute of MIT and Harvard.
What he does
The scientific teams in our lab are working to recognize the biology that underlies human brain health and illness, and the ways in which human genes, inherited genetic variation, and somatic mutations conspire to shape this biology. The biological basis for most brain disorders is unknown today: most are understood mainly in terms of collections of symptoms, neuropathological observations – such as cortical thinning, protein aggregates, or death of a specific kind of cell – and human-genetic associations. We need to deeply understand these disorders as biological entities so that we can develop new and innovative ways to monitor and treat them.
Our lab is especially excited about (i) DNA-repeat disorders and (ii) the disruptions of mental health commonly known as “psychiatric disorders”, especially schizophrenia.
Our research team brings together people with experiences, approaches and insights from biology, human genetics, statistics, and computer science.
News from the Lab
We discovered a large constellation of gene-expression changes that are implemented together by neurons and astrocytes in a coordinated manner; that vary in magnitude among individual persons; and that are compromised in schizophrenia and in brain aging (Ling et al., Nature 2024).
Huntington Disease (HD) is a fatal genetic disease in which most of a person’s striatal projection neurons (SPNs) degenerate and die. The central biological question about HD has involved how the disease-causing inherited DNA repeat (CAGn) in the huntingtin (HTT) gene leads to neurodegeneration after a long latent period. The length of the HTT CAG repeat varies within the brain (somatic mosaicism), and many common human-genetic modifiers of HD age-at-onset are in genes that affect DNA-repeat stability. To understand how the HTT CAG repeat might underlie pathological changes in HD, we developed a method to sequence and measure the CAG repeat together with genome-wide RNA expression in the same cells. We found that the CAG repeat routinely expands from 40-45 CAGs (germline) to 100-500+ CAGs in SPNs but not in other striatal cell types, with these long expansions acquired asynchronously by individual SPNs. Surprisingly, somatic expansion from 40 to 150 CAGs had no apparent direct effect upon SPN gene expression. In contrast, sparse SPNs with 150-500+ CAGs had profound gene-expression changes – affecting hundreds of genes, escalating with further repeat expansion, eroding positive and then negative features of SPN identity, and culminating in expression of senescence/apoptosis genes. Across stages of HD, these “SLEAT” SPNs (with somatic long expansions and asynchronous toxicity) appeared in proportion to rates of SPN loss. Our experiments, analyses and simulations suggest that individual SPNs undergo decades of biologically quiet DNA-repeat expansion to a high threshold length, then asynchronously pass through a brief toxicity phase before dying. We conclude that, at any moment in the course of HD, most SPNs have an innocuous (but unstable) huntingtin gene, and that HD pathogenesis is a DNA process for almost all of a neuron’s life. (Handsaker, Kashin et al., manuscript in preparation.)