Systems Genetics of Evolution

Frank Chan

FrankChanNov2012-05 crop2
  • PhD in the Department of Developmental Biology, Stanford University, 2003-09
  • Postdoctoral training, Max Planck Institute for Evolutionary Biology, Plön, 2009-12
  • Max Planck Research Group Leader at the FML since 2012

Research Interest

The genome is in constant evolution. Despite this on-going change, the genome also has to maintain essential functions. Discovering the evolutionary process underlying genome evolution is thus a central goal not only in evolutionary genetics, but also in medicine. Using the house mouse as our model organism, we aim to connect molecular mutations to their phenotype consequences and track their fate through evolution.

We have pioneered an innovative system to induce mitotic recombination in mouse embryonic stem cells, which allows us to perform genetic mapping for the first time between sister mouse species in a cellular context. By creating interspecific hybrids between mice with increasing divergence, we can study how traits evolve across species boundaries. Using the in vitro cross system, we can now generate diversity in a single petri dish and directly track how different genetic combinations may lead to gene expression or cell fate differences between cells. Our in vitro cross approach creates “Impossible Hybrids” – advanced recombinant cell lines that circumvent conventional species barriers.

This project uses the latest functional genomics and tissue culture techniques, including single-cell sorting and droplet microfluidics techniques, as well as RNA- or ChIP-seq methods to interrogate each cell. Our aim is to construct gene networks across evolutionary divergences and connect the dots between individual genetic changes and their evolutionary impacts.

The ultimate goal of our research is to understand how evolution has shaped gene regulatory networks to be tightly interwoven, yet still allow flexible response to allow rapid adaptation.

  • Frank Chan Fig2 2016 01
    click to enlarge

HybridMiX: for the first time we can now directly study the genetic changes between species by performing “in vitro crosses” between evolutionarily distant mouse species. By studying these “impossible hybrid” cell lines using genomics, organ-on-a-chip and organoid techniques we aim to reveal how gene regulatory networks change through six million years of evolution.

  • IVR colonies
    click to enlarge

Breeding mice in a dish: Using our in vitro recombinant method, we can now generate genetic diversity within a single petri dish. F1 hybrid ES cells carrying a single copy of GFP transgene were grown into colonies. Under control conditions, the whole colony should be uniformly green fluorescent. In contrast, after inducing in vitro recombination, random mitotic recombination gave rise to daughter cells inheriting two or no copies of the GFP transgene, resulting in mixed colonies with variegated GFP expression (right).

   

Available PhD Projects

HybridMiX: Systems genetics of species differences using in vitro crosses in mouse ES cells.

Selected Reading

1) Lazzarano S, Kučka M, Castro JPL, Naumann R, Medina P, Fletcher MNC, Wombacher R, Gribnau J, Hochepied T, Libert C, Chan YF (2017) Genetic mapping of species differences via “in vitro crosses” in mouse embryonic stem cells. bioRxiv https://doi.org/10.1101/148486.

2) Chan YF, Jones FC, McConnell E, Bryk J, Bünger L, Tautz D (2012) Parallel selection mapping using artificially selected mice reveals body weight control loci. Current Biology 22, 794-800.

 3) Chan YF, Marks ME, Jones FC, Villarreal Jr G et al. (2010) Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 327, 302-305.