Lectures and seminars Analysis of clonal variation in lineage-resolved scRNA-seq data
Welcome to a seminar with Dr Peter Kharchenko!
About the talk
Assays that couple high-throughput lineage tracing with scRNA-seq or other single-cell assays are increasingly helpful for studying development and disease. They not only allow one to see the major routes of cell differentiation, but also inform on more subtle, continuous fate biases and the regulatory programs associated with them. Analysing such data presents some computational challenges, due to sparse sampling of clones and annotation dependencies. Most current approaches rely on discrete cell-type annotations, which can obscure shifts in subpopulations or coordinated changes among multiple cell types.
In this seminar, Dr Kharchenko will discuss his work on clone2vec — a machine-learning approach his group developed to analyze lineage-resolved scRNA-seq data. He will describe how clone2vec bypasses the need for discrete cell-type labels by learning continuous clone embeddings directly from the cellular expression manifold. The approach shows good stability, even when dealing with very sparse clonal sampling. The resulting embedding representation translates clonal variation into an interpretable geometry, allowing one to perform robust clone-gene association statistics, or align clones across entirely different datasets.
Dr Kharchenko will present applications of this approach to different types of traced data. Most obvious are its applications to developmental biology, including clonal biasing in early embryogenesis, hematopoiesis, and human cortical differentiation, where one can map out how specific developmental pathways continuously bias progenitor fates. He will also illustrate clone2vec application to TCR-sequencing data, analyzing heterogeneity of the Treg lineages in an inflammatory setting. Analysis of CD8+ T cells in the context of different cancer types identified T-cell archetypes — separating tumor-reactive clones from different bystander-like subsets, conserved across diverse cancer types. He will also discuss potential extensions of such approaches to studying perturbations and spatial tissue organization.
About the speaker
Dr Peter Kharchenko completed his PhD at Harvard University's Biophysics program, studying gene regulation under the supervision of George Church, and then went on to do a postdoctoral fellowship in the group of Peter Park, focusing on chromatin configuration.
Dr Kharchenko's own group at the Harvard Medical School has developed computational methods for genomic analysis of single cells, enabling statistical separation of distinct cellular states, detection of genomic aberrations in transcriptional data, and inference of cellular dynamics from snapshots of cellular state. His group has also applied these approaches to study the organization of different tissues and the impact of diseases ranging from cancer to schizophrenia. He then joined Altos Labs as a Principal Investigator in 2022, focusing his group’s efforts on mechanisms of cell and tissue resilience. Kharchenko is currently a Visiting Fellow at the Institute of Molecular Biotechnology, Austria.
Selected (recent) publications
- Mitchell J, Gao T, Petukhov V, Cole E, Kharchenko PV. Impact and correction of segmentation errors in spatial transcriptomics. Nature Genetics. 2026 Jan 20. doi: 10.1038/s41588-025-02497-4.
- Mitchel J, Gordon MG, Perez RK, Biederstedt E, Bueno R, Ye CJ, Kharchenko PV. Coordinated, multicellular patterns of transcriptional variation that stratify patient cohorts are revealed by tensor decomposition. Nature Biotechnology. 2025 Jul;43(7):1192-1201. doi: 10.1038/s41587-024-02411-z.
- Gao T, Kastriti ME, Ljungström V, Heinzel A, Tischler AS, Oberbauer R, Loh PR, Adameyko I, Park PJ, Kharchenko PV. A pan-tissue survey of mosaic chromosomal alterations in 948 individuals. Nature Genetics. 2023 Nov;55(11):1901-1911.
- Gao T, Soldatov R, Sarkar H, Kurkiewicz A, Biederstedt E, Loh PR, Kharchenko PV. Haplotype-aware analysis of somatic copy number variations from single-cell transcriptomes. Nature Biotechnology 2023 Mar;41(3):417-426. doi: 10.1038/s41587-022-01468-y
- Kfoury Y, Baryawno N, Severe N, Mei S, Gustafsson K, Hirz T, Brouse T, Scadden EW, Igolkina AA, Kokkaliaris K, Choi BD, Barkas N, Randolph MA, Shin JH, Saylor PJ, Scadden DT, Sykes DB, Kharchenko PV. Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment. Cancer Cell. 2021 Oct 15:S1535-6108(21)00494-3.
- Petukhov V, Xu RJ, Soldatov RA, Cadinu P, Khodosevich K, Moffitt JR, Kharchenko PV. Cell segmentation in imaging-based spatial transcriptomics. Nature Biotechnology. 2021 Oct 14. doi: 10.1038/s41587-021-01044-w
Host
Department of Medical Biochemistry and Biophysics (contact: tamsinlindstrom@ki.se)