People

michel.milinkovitch@unige.ch

+41 22 379 33 38

Michel C. Milinkovitch is Full Professor in the Department of Genetics & Evolution at the University of Geneva (Switzerland) and President of the Division of Biology since 2019. He is also a member of the Institute of Genetics and Genomics in Geneva (iGE3) since its foundation (2011) and a Group leader of the Swiss Institute of Bioinformatics (SIB) since 2014. In his ‘previous life’ as an evolutionary geneticist, he contributed to quantitative analysis and modelling in Molecular Phylogenomics and Applied Evolutionary Genetics. He has developed concepts, analytical tools, and algorithms/models for multiple sequence alignments, phylogeny inference and haplotypic network building. His recent focus (since 2008) is on Evolutionary Developmental Genetics (Evo-Devo) and the Physics of Biology. He specialises on non-classical model species in reptiles and mammals and integrates data and analyses from comparative genomics, molecular developmental genetics, as well as mathematical modelling and numerical simulations. He has published over 120 papers in international peer-reviewed journals (including Nature, Nature Communications, Science, Science Advances, PNAS, PRL, PRX, Mathematics). He has given 150 invited talks and conferences around the world (Europe, USA and Asia). He has been reviewer for over 50 peer-reviewed international biology and physics journals and has served as external reviewer for academic promotions, grant proposals, and PhD committees in Switzerland, Europe, UK, Israël and the USA. He has served on the Editorial Board of scientific journals and has supervised >20 Ph.D. theses. He has been a member of the ERC (European Research Council) evaluation committee and has chaired one of its panels. His work has made on multiple occasions the headlines in the media (BBC; National Geographic; Swiss, European and US Televisions and radios; Le Monde, The New York Times, The Washington Post). He is the co-founder (November 2001) of the spin-off Delphi Genetics which was acquired in 2021 by Catalent, a giant in innovative drug development and delivery. He is married and has 4 children.

ORCID ID: 0000-0002-2553-0724

Google Scholar ID byH9cPoAAAAJ

Self-organized patterning of crocodile head scales by compressive folding

Gabriel N. Santos-Durán, Rory L. Cooper, Ebrahim Jahanbakhsh, Grigorii Timin, Michel C. Milinkovitch

Nature 637 : 375-383 (2025-01-09)

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Abstract

Self-organized patterning of crocodile head scales by compressive folding

Gabriel N. Santos-Durán, Rory L. Cooper, Ebrahim Jahanbakhsh, Grigorii Timin, Michel C. Milinkovitch

Amniote integumentary appendages constitute a diverse group of micro-organs, including feathers, hair and scales. These structures typically develop as genetically controlled units1, the spatial patterning of which emerges from a self-organized chemical Turing system2,3 with integrated mechanical feedback4,5. The seemingly purely mechanical patterning of polygonal crocodile head scales provides an exception to this paradigm6. However, the nature and origin of the mechanical stress field driving this patterning remain unclear. Here, using precise in ovo intravenous injections of epidermal growth factor protein, we generate Nile crocodile embryos with substantially convoluted head skin, as well as hatchlings with smaller polygonal head scales resembling those of caimans. We then use light-sheet fluorescence microscopy to quantify embryonic tissue-layer geometry, collagen architecture and the spatial distribution of proliferating cells. Using these data, we build a phenomenological three-dimensional mechanical growth model that recapitulates both normal and experimentally modified patterning of crocodile head scales. Our experiments and numerical simulations demonstrate that crocodile head scales self-organize through compressive folding, originating from near-homogeneous skin growth with differential stiffness of the dermis versus the epidermis. Our experiments and theoretical morphospace analyses indicate that variation in embryonic growth and material properties of skin layers provides a simple evolutionary mechanism that produces a diversity of head-scale patterns among crocodilian species.
Simple Reaction-Diffusion Modeling Predicts Inconspicuous Neighborhood-Dependent Color Subclustering of Lizard Scales

Szabolcs Zakany and Michel C. Milinkovitch

Physical Review X 13 , 41011 (2023-10-20)

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Abstract

Simple Reaction-Diffusion Modeling Predicts Inconspicuous Neighborhood-Dependent Color Subclustering of Lizard Scales

Szabolcs Zakany and Michel C. Milinkovitch

Turing proposed a reaction-diffusion (RD) process as the chemical basis of morphogenesis. Despite the elegance of this model, its relevance for the precise description of morphogenesis in real organisms is largely disputed. Here, we show that a simple RD system, predicting the cellular-automaton-like patterning of ocellated lizards’ skin into green and black labyrinthine chains of scales, additionally predicts unsuspected subtle color subclustering that correlates with the colors of the scales’ neighbors. Hyperspectral imaging indicates that color subclustering is present in real lizards, confirming the numerical model nontrivial prediction. In addition, extensive histological analyses show that melanophores’ spatial distribution correlates with scale neighborhood, confirming that color subclustering is associated to the underlying microscopic system of chromatophore interactions. We then show that the observed subclustering is efficiently captured by RD models, irrespective of their form, discretization, and spatial dimensionality. We also show that sets of values can be identified in the 12-dimensional RD parameter space to yield the correct direction of correlation (i.e., observed in real lizards) between green-scale blackness and their neighborhood configuration, hence instructing the mathematical model. More generally, our results show that subtle mesoscopic properties of biological dynamical systems, as well as some of the underlying microscopic features, are quantitatively captured by simple RD models without integrating the unmanageable profusion of variables at lower scales.
The Unreasonable Effectiveness of Reaction Diffusion in Vertebrate Skin Color Patterning

Michel C. Milinkovitch, Ebrahim Jahanbakhsh, Szabolcs Zakany

Annual Review of Cell and Developmental Biology 39 : 145-174 (2023-10-18)

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Abstract

The Unreasonable Effectiveness of Reaction Diffusion in Vertebrate Skin Color Patterning

Michel C. Milinkovitch, Ebrahim Jahanbakhsh, Szabolcs Zakany

In 1952, Alan Turing published the reaction-diffusion (RD) mathematical framework, laying the foundations of morphogenesis as a self-organized process emerging from physicochemical first principles. Regrettably, this approach has been widely doubted in the field of developmental biology. First, we summarize Turing's line of thoughts to alleviate the misconception that RD is an artificial mathematical construct. Second, we discuss why phenomenological RD models are particularly effective for understanding skin color patterning at the meso/macroscopic scales, without the need to parameterize the profusion of variables at lower scales. More specifically, we discuss how RD models (a) recapitulate the diversity of actual skin patterns, (b) capture the underlying dynamics of cellular interactions, (c) interact with tissue size and shape, (d) can lead to ordered sequential patterning, (e) generate cellular automaton dynamics in lizards and snakes, (f) predict actual patterns beyond their statistical features, and (g) are robust to model variations. Third, we discuss the utility of linear stability analysis and perform numerical simulations to demonstrate how deterministic RD emerges from the underlying chaotic microscopic agents.
Transient agonism of the sonic hedgehog pathway triggers a permanent transition of skin appendage fate in the chicken embryo

Rory L. Cooper and Michel C. Milinkovitch

Science Advances 9 , 20 (2023-05-17)

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Abstract

Transient agonism of the sonic hedgehog pathway triggers a permanent transition of skin appendage fate in the chicken embryo

Rory L. Cooper and Michel C. Milinkovitch

Vertebrate skin appendage early development is mediated by conserved molecular signaling composing a dynamical reaction-diffusion–like system. Variations to such systems contribute to the remarkable diversity of skin appendage forms within and among species. Here, we demonstrate that stage-specific transient agonism of sonic hedgehog (Shh) pathway signaling in chicken triggers a complete and permanent transition from reticulate scales to feathers on the ventral surfaces of the foot and digits. Resulting ectopic feathers are developmentally comparable to feathers adorning the body, with down-type feathers transitioning into regenerative, bilaterally symmetric contour feathers in adult chickens. Crucially, this spectacular transition of skin appendage fate (from nodular reticulate scales to bona fide adult feathers) does not require sustained treatment. Our RNA sequencing analyses confirm that smoothened agonist treatment specifically promotes the expression of key Shh pathway–associated genes. These results indicate that variations in Shh pathway signaling likely contribute to the natural diversity and regionalization of avian integumentary appendages.
Modeling convergent scale-by-scale skin color patterning in multiple species of lizards

Ebrahim Jahanbakhsh, Michel C Milinkovitch

Current biology 32 : 5069-5082.e13 (2022-12-05)

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Abstract

Modeling convergent scale-by-scale skin color patterning in multiple species of lizards

Ebrahim Jahanbakhsh, Michel C Milinkovitch

Skin color patterning in vertebrates emerges at the macroscale from microscopic cell-cell interactions among chromatophores. Taking advantage of the convergent scale-by-scale skin color patterning dynamics in five divergent species of lizards, we quantify the respective efficiencies of stochastic (Lenz-Ising and cellular automata, sCA) and deterministic reaction-diffusion (RD) models to predict individual patterns and their statistical attributes. First, we show that all models capture the underlying microscopic system well enough to predict, with similar efficiencies, neighborhood statistics of adult patterns. Second, we show that RD robustly generates, in all species, a substantial gain in scale-by-scale predictability of individual adult patterns without the need to parametrize the system down to its many cellular and molecular variables. Third, using 3D numerical simulations and Lyapunov spectrum analyses, we quantitatively demonstrate that, given the non-linearity of the dynamical system, uncertainties in color measurements at the juvenile stage and in skin geometry variation explain most, if not all, of the residual unpredictability of adult individual scale-by-scale patterns. We suggest that the efficiency of RD is due to its intrinsic ability to exploit mesoscopic information such as continuous scale colors and the relations among growth, scales geometries, and the pattern length scale. Our results indicate that convergent evolution of CA patterning dynamics, leading to dissimilar macroscopic patterns in different species, is facilitated by their spontaneous emergence under a large range of RD parameters, as long as a Turing instability occurs in a skin domain with periodic thickness.
Lizard Skin Patterns and the Ising Model

Szabolcs Zakany, Stanislav Smirnov, Michel C. Milinkovitch

Physical Review Letters 128 , 48102 (2022-01-27)

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Abstract

Lizard Skin Patterns and the Ising Model

Szabolcs Zakany, Stanislav Smirnov, Michel C. Milinkovitch

The ocellated lizard (Timon lepidus) exhibits an intricate skin color pattern made of monochromatic black and green skin scales, whose dynamics of color flipping are known to be well modeled by a stochastic cellular automaton. We show that the late-time probability distribution of the pattern corresponds to the canonical probability distribution of the antiferromagnetic Ising model and can be generated by dynamics different from the commonly-used Glauber. We comment on skin scale patterns generated by the Ising model on the triangular lattice in the low-temperature limit.
Reaction-diffusion in a growing 3D domain of skin scales generates a discrete cellular automaton

Fofonjka, A., Milinkovitch, M.C.

Nature Communications 12 : 2433 (2021-04-23)

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Abstract

Reaction-diffusion in a growing 3D domain of skin scales generates a discrete cellular automaton

Fofonjka, A., Milinkovitch, M.C.
A Living Mesoscopic Cellular Automaton Made of Skin Scales

Manukyan L., Montandon S.A., Fofonjka A., Smirnov S., M.C. Milinkovitch

Nature 544 , 7649 : 173–179 (2017-04-13)

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Abstract

A Living Mesoscopic Cellular Automaton Made of Skin Scales

Manukyan L., Montandon S.A., Fofonjka A., Smirnov S., M.C. Milinkovitch

In vertebrates, skin colour patterns emerge from nonlinear dynamical microscopic systems of cell interactions. Here we show that in ocellated lizards a quasi-hexagonal lattice of skin scales, rather than individual chromatophore cells, establishes a green and black labyrinthine pattern of skin colour. We analysed time series of lizard scale colour dynamics over four years of their development and demonstrate that this pattern is produced by a cellular automaton (a grid of elements whose states are iterated according to a set of rules based on the states of neighbouring elements) that dynamically computes the colour states of individual mesoscopic skin scales to produce the corresponding macroscopic colour pattern. Using numerical simulations and mathematical derivation, we identify how a discrete von Neumann cellular automaton emerges from a continuous Turing reaction–diffusion system. Skin thickness variation generated by three-dimensional morphogenesis of skin scales causes the underlying reaction–diffusion dynamics to separate into microscopic and mesoscopic spatial scales, the latter generating a cellular automaton. Our study indicates that cellular automata are not merely abstract computational systems, but can directly correspond to processes generated by biological evolution.
The Anatomical Placode in Reptile Scale Morphogenesis Indicates Shared Ancestry Among Skin Appendages in Amniotes

Di-Poï N., M. C. Milinkovitch

Science Advances 2 , 6 : e1600708 (2016-06-24)

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Abstract

The Anatomical Placode in Reptile Scale Morphogenesis Indicates Shared Ancestry Among Skin Appendages in Amniotes

Di-Poï N., M. C. Milinkovitch

Most mammals, birds, and reptiles are readily recognized by their hairs, feathers, and scales, respectively. However, the lack of fossil intermediate forms between scales and hairs and substantial differences in their morphogenesis and protein composition have fueled the controversy pertaining to their potential common ancestry for decades. Central to this debate is the apparent lack of an “anatomical placode” (that is, a local epidermal thickening characteristic of feathers’ and hairs’ early morphogenesis) in reptile scale development. Hence, scenarios have been proposed for the independent development of the anatomical placode in birds and mammals and parallel co-option of similar signaling pathways for their morphogenesis. Using histological and molecular techniques on developmental series of crocodiles and snakes, as well as of unique wild-type and EDA (ectodysplasin A)–deficient scaleless mutant lizards, we show for the first time that reptiles, including crocodiles and squamates, develop all the characteristics of an anatomical placode: columnar cells with reduced proliferation rate, as well as canonical spatial expression of placode and underlying dermal molecular markers. These results reveal a new evolutionary scenario where hairs, feathers, and scales of extant species are homologous structures inherited, with modification, from their shared reptilian ancestor’s skin appendages already characterized by an anatomical placode and associated signaling molecules.
Photonic Crystals Cause Active Colour Change in Chameleons

Teyssier J., Saenko S.V., van der Marel D., M.C. Milinkovitch

Nature Communications 6 , 6368 (2015-03-10)

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Abstract

Photonic Crystals Cause Active Colour Change in Chameleons

Teyssier J., Saenko S.V., van der Marel D., M.C. Milinkovitch

Many chameleons, and panther chameleons in particular, have the remarkable ability to exhibit complex and rapid colour changes during social interactions such as male contests or courtship. It is generally interpreted that these changes are due to dispersion/aggregation of pigment-containing organelles within dermal chromatophores. Here, combining microscopy, photometric videography and photonic band-gap modelling, we show that chameleons shift colour through active tuning of a lattice of guanine nanocrystals within a superficial thick layer of dermal iridophores. In addition, we show that a deeper population of iridophores with larger crystals reflects a substantial proportion of sunlight especially in the near-infrared range. The organization of iridophores into two superposed layers constitutes an evolutionary novelty for chameleons, which allows some species to combine efficient camouflage with spectacular display, while potentially providing passive thermal protection.
Crocodile Head Scales Are Not Developmental Units But Emerge from Physical Cracking

Milinkovitch M.C., Manukyan L., Debry A., Di-Poï N., Martin S., Singh D., Lambert D., Zwicker M.

Science 339 , 6115 : 78-81 (2013-04-01)

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Abstract

Crocodile Head Scales Are Not Developmental Units But Emerge from Physical Cracking

Milinkovitch M.C., Manukyan L., Debry A., Di-Poï N., Martin S., Singh D., Lambert D., Zwicker M.

Various lineages of amniotes display keratinized skin appendages (feathers, hairs, and scales) that differentiate in the embryo from genetically controlled developmental units whose spatial organization is patterned by reaction-diffusion mechanisms (RDMs). We show that, contrary to skin appendages in other amniotes (as well as body scales in crocodiles), face and jaws scales of crocodiles are random polygonal domains of highly keratinized skin, rather than genetically controlled elements, and emerge from a physical self-organizing stochastic process distinct from RDMs: cracking of the developing skin in a stress field. We suggest that the rapid growth of the crocodile embryonic facial and jaw skeleton, combined with the development of a very keratinized skin, generates the mechanical stress that causes cracking.
2X genomes - depth does matter

Milinkovitch M.C., Helaers R., Depiereux E., Tzika A.C., & T. Gabaldon

Genome Biology 11 , 16 (2010-02-09)

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Abstract

2X genomes - depth does matter

Milinkovitch M.C., Helaers R., Depiereux E., Tzika A.C., & T. Gabaldon

Background. Given the availability of full genome sequences, mapping gene gains, duplications, and losses during evolution should theoretically be straightforward. However, this endeavor suffers from overemphasis on detecting conserved genome features, which in turn has led to sequencing multiple eutherian genomes with low coverage rather than fewer genomes with high-coverage and more even distribution in the phylogeny. Although limitations associated with analysis of low coverage genomes are recognized, they have not been quantified. Results. Here, using recently developed comparative genomic application systems, we evaluate the impact of low-coverage genomes on inferences pertaining to gene gains and losses when analyzing eukaryote genome evolution through gene duplication. We demonstrate that, when performing inference of genome content evolution, low-coverage genomes generate not only a massive number of false gene losses, but also striking artifacts in gene duplication inference, especially at the most recent common ancestor of low-coverage genomes. We show that the artifactual gains are caused by the low coverage of genome sequence per se rather than by the increased taxon sampling in a biased portion of the species tree. Conclusions. We argue that it will remain difficult to differentiate artifacts from true changes in modes and tempo of genome evolution until there is better homogeneity in both taxon sampling and high-coverage sequencing. This is important for broadening the utility of full genome data to the community of evolutionary biologists, whose interests go well beyond widely conserved physiologies and developmental patterns as they seek to understand the generative mechanisms underlying biological diversity.
A nonlinear optimization procedure to estimate distances and instantaneous substitution rate matrices under the GTR model

Catanzaro D., Pesenti R. & M. C. Milinkovitch

Bioinformatics 6 , 22 : 708-715 (2006-01-05)

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Abstract

A nonlinear optimization procedure to estimate distances and instantaneous substitution rate matrices under the GTR model

Catanzaro D., Pesenti R. & M. C. Milinkovitch

Motivation: The general-time-reversible (GTR) model is one of the most popular models of nucleotide substitution because it constitutes a good trade-off between mathematical tractability and biological reality. However, when it is applied for inferring evolutionary distances and/or instantaneous rate matrices, the GTR model seems more prone to inapplicability than more restrictive time-reversible models. Although it has been previously noted that the causes for intractability are caused by the impossibility of computing the logarithm of a matrix characterised by negative eigenvalues, the issue has not been investigated further. Results: Here, we formally characterize the mathematical conditions, and discuss their biological interpretation, which lead to the inapplicability of the GTR model. We investigate the relations between, on one hand, the occurrence of negative eigenvalues and, on the other hand, both sequence length and sequence divergence. We then propose a possible re-formulation of previous procedures in terms of a non-linear optimization problem. We analytically investigate the effect of our approach on the estimated evolutionary distances and transition probability matrix. Finally, we provide an analysis on the goodness of the solution we propose. A numerical example is discussed.

For publications prior to 2006 (1992‑2005), please click this link.