Chen Weng

Mitochondrial lineage tracing brought exciting new capabilities to single-cell genomics. However, a core problem remains: unlike classical lineage recorders, mtDNA mutations can drift and disappear as cells divide, preventing us from precisely decoding lineage history.

Last but not least—huge shoutout to @gaoteng.bsky.social So much fun working together! And thank you @bloodgenes.bsky.social and @jswlab.bsky.social for the amazing mentorship.
@whiteheadinstitute.bsky.social @broadinstitute.org @bostonchildrens.bsky.social @hhmi-science.bsky.social

Finally, we combine PATH (Landau lab) with MitoDrift to identify heritable vs plastic tumor states, linking intratumoral heterogeneity programs to therapy resistance. (6/7)

The lineage resolution of ReDeeM+MitoDrift extends beyond the capability of CNA analysis and reveals clonal diversifications within CNA-defined subclones, depicting a polyclonal reservoir for therapy resistance. (5/7)

We next applied MitoDrift to study clonal evolution of malignant plasma cells in multiple myeloma. We built massive lineage trees from longitudinal samples, revealing varying degrees of clonal remodeling among patients and branch-specific heterogeneity in drug sensitivity. (4/7)

Applied to human hematopoiesis in vivo, MitoDrift shows age-related clonality changes are strongly cell-type-specific. In aging HSCs, integrating MitoDrift lineages with multiome readouts suggests a link between clonal expansions and AP-1/stress programs. (3/7)

We validated MitoDrift against lentiviral barcodes (in vitro) and single-colony WGS trees (in vivo). By refining the tree topology using branch confidence, the MitoDrift can achieve 70–95% clade accuracy while preserving the vast majority of true clonal structures. (2/7)

Can we accurately map cell family trees using mtDNA? Excited to share MitoDrift, a high-precision single-cell lineage inference tool, enabling reliable mapping of lineage history to cell phenotypes. doi.org/10.64898/202...
Joint with @gaoteng.bsky.social. @bloodgenes.bsky.social @jswlab.bsky.social🧵