The origin of SARS-CoV-2, the causative virus of COVID-19, has been a mystery since the beginning of the outbreak and has been heavily debated lately. One of the main reasons for this is that RaTG13, the closest relative found to date [ 1] (in the horseshoe bat Rhinolophus affinis), has only 96.1% nucleotide similarity to SARS-CoV-2 (with ∼1200 nucleotide differences). The situation is distinct from the two previous coronavirus outbreaks that happened this century (SARS in 2003 and MERS in 2012); in both cases, a closely related virus with over 99% nucleotide similarity to the causative virus was found in wild animals shortly after the start of each outbreak [ 2, 3]. The missing intermediates between RaTG13 and SARS-CoV-2 prevent a better understanding of the spillover. Fortunately, since the viral mutation spectrum is expected to be heavily shaped by host factors, signatures left on the available viral genomes would inform the pre-outbreak history of SARS-CoV-2.

Cross-modal analysis of the same whole brain is an ideal strategy to uncover brain function and dysfunction. However, it remains challenging due to the slow speed and destructiveness of traditional whole-brain optical imaging techniques. Here we develop a new platform, termed Photoacoustic Tomography with Temporal Encoding Reconstruction (PATTERN), for non-destructive, high-speed, 3D imaging of ex vivo rodent, ferret, and non-human primate brains. Using an optimally designed image acquisition scheme and an accompanying machine-learning algorithm, PATTERN extracts signals of genetically-encoded probes from photobleaching-based temporal modulation and enables reliable visualization of neural projection in the whole central nervous system with 3D isotropic resolution. Without structural and biological perturbation to the sample, PATTERN can be combined with other whole-brain imaging modalities to acquire the whole-brain image with both high resolution and morphological fidelity. Furthermore, cross-modal transcriptome analysis of an individual brain is achieved by PATTERN imaging. Together, PATTERN provides a compatible and versatile strategy for brain-wide cross-modal analysis at the individual level.

Somatic clonal expansion refers to the proliferation and expansion of a cell clone within a multicellular organism. Since cancer also results from the uncontrolled proliferation of few cell clones, it is generally believed that aging-associated somatic clonal expansion observed in normal tissues represents a precancerous condition. For instance, hematological malignancy is often preceded by clonal hematopoiesis. However, the precise connection between cancer and somatic clonal expansion remains elusive in solid organs. In this study, we utilized a straightforward method to assess the relative quantitative degrees of clonal expansion in nine human organs. Our findings reveal that the degree of clonal expansion varies across different organs while remaining consistent among different individuals. Contrary to the general belief, we did not identify any significant correlation between lifetime cancer risk and the degree of lifetime somatic clonal expansion. For example, the lifetime risk of colorectal cancer is approximately 20 times higher than that of esophageal cancer, yet the former exhibited the lower degree of clonal expansion than the latter. Our results suggest that somatic clonal expansion represents an evolutionary process distinct from carcinogenesis in normal tissues, providing novel perspectives on precancerous conditions.