About

Welcome! I'm an assistant professor (chaire de professeur junior) at Inserm and I head a research group at Institut Imagine in Paris.

Research

Genomic sequencing reveals genetic variation at many scales: divergence between species, heritable differences among individuals, and the mosaic makeup of somatic tissues. My research focuses on analyzing recent and rare genetic variants, which are informative about the sources of genetic variability and at the root of many genetic diseases and cancers. I develop mathematical models and statistical inference methods to learn about the biology of mutation and genetic disease from sequencing data.

Toward a comprehensive model of mutation. Mutations are the original source of genetic variation, yet we know surprisingly little about how they arise in vivo and what determines their rate and spectrum across cell types. The sequencing of large tumor cohorts has revealed repeatable patterns, termed mutational signatures, and helped link some of them to specific mutagenic processes. However, the implicit model treats each process as producing a single, invariant signature, largely ignoring that signatures reflect the net result of DNA damage and repair. When repair is compromised, as in individuals with constitutional repair defects or in certain tumors, underlying damage is exposed more directly. Such cases carry information that current approaches do not fully capture. The goal is to develop a model that makes it possible to learn from them systematically.

In a complementary direction, I collaborate with Thomas Dupic on somatic hypermutation in B cells, where targeted damage and error-prone repair locally elevate the mutation rate by a few orders of magnitude. The fast pace, and a well-characterized source of damage, make it a natural model system to study the kinetics of mutagenesis.
We're recruiting a PhD student to start in Fall 2026. See more details here. Informal enquiries are welcome.

Somatic variation and the genetics of disease. A large fraction of suspected genetic diseases cannot be linked to a causal variant. What are we missing? The answer likely involves regulatory variation, which remains difficult to interpret, and somatic mutations present in a fraction of cells only. I am interested in estimating how often somatic variants play a role in genetic disorders. De novo germline mutations known to contribute to disease provide a point of reference: what do the variants with known effects imply about those we have yet to identify? On the data side, I work on identifying somatic mutations from long-read sequencing, where single-molecule resolution makes it possible to call somatic variants reliably at scale.

Publications

All papers can be found via my Google Scholar profile.
Latest preprints:

Teaching

Fall 2026: TBA

Contact

E-mail natanael.spisak@gmail.com
Bluesky @natanaels.bsky.social