The Li lab studies the genetic basis of complex human diseases using genomic approaches. Currently our interests include analyses of gene expression patterns in postmortem brain tissues associated with major depression, bipolar disorder, and schizophrenia, sequencing-based variant discovery and analysis in rare Mendelian disorders and the bipolar disorder, integrated analysis of cancer genome alterations, intratumor heterogeneity in breast and esophageal cancers, and spontaneous mutation patterns in the human genome.
The Brain’s 24-Hour Clock
Most of our bodily functions, such as appetite and alertness, follow a regular 24-hour cycle. This daily rhythm is generated by a network of interacting proteins in our cells. Their rhythmic patterns can be studied in skin and blood cells, which are easy to collect, but they are difficult to study in the human brain, because it is not ethical to take a brain sample out of a living human once every few hours. Our team solved this problem by comparing brain tissues across people who have died at different hours of the day. If there are indeed regular rise and fall of gene activities in brain cells, we should be able to see recognizable differences between those who died at night from those who died during the day, as long as most donated brain tissues show the activity patterns typical for their hour of death, just like a clock damaged in earthquake registers the exact time of the quake. This is indeed what we found: while we still could not follow a single brain over time, by studying many people, each having died at a different point around the clock, we demonstrated that human brain cells indeed show a 24-hour rhythm in gene activity, with hundreds of genes being cyclical. Having learned these patterns, we were also able to look at a sample from someone whose time of death was unknown, and estimate this time based on its telltale gene patterns. Interestingly, for people with major depression, their estimated time of death was far off the actual time, as if they had died while living in a different time zone. This is likely because people suffering from brain disorders often experience disrupted sleep. Being able to study daily cycles of the brain this way opened up new directions to understand the relationship between sleep quality and mental health.