Frank Jacobs lab                                                                                                               

University of Amsterdam                                                                                                                   

The impact of primate genome evolution on human gene-regulatory networks

This is the main research interest in my group. In particular, how has the evolution of the human genome shaped gene regulatory networks involved in human brain development.



Genomic changes can be small, such as retrotransposon insertions, or big, such as segmental duplications of whole segments of the genome. Genomic modifications happened frequently during primate evolution, but the extent to which individual evolutionary genomic events accounted for changes in gene expression and contributed to the evolution of species remains unclear. 








 


In previous work (Jacobs et al., 2014; Nature) we showed how KRAB zinc finger genes in our genome are in a continuous battle against retrotransposon invasions, revealing how our genome is actually in a war against itself. As a result of this evolutionary armsrace, both retrotransposons and KRAB zinc finger genes become heavily integrated in pre-existing gene regulatory networks, adding an extra level of complexity to how, where and when genes in our genome are shut on or off.

Evolutionary arms race between KRAB zinc finger genes and Retrotransposons. The ongoing battle within ourselves, driving genomes to become increasingly complex, as they evolve mechanisms to fight off ever-changing elements of their own DNA.


Our lab currently investigates how this extra layer of retrotransposon-mediated gene control has re-shaped gene regulatory networks involved in human brain development. My research aims to pinpoint how specific genomic changes have contributed to the evolutionary increase in size and complexity of the human neocortex and understand how these changes may relate to human's increased susceptibility to neurodevelopmental disorders such as Autism and Schizophrenia and human neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

To study primate genome evolution in the context of brain development, we use human and primate stem cells as a source for cortical neurons. Upon culturing of these cells in specialized medium and subjecting them to multiple developmental signals, these cells can be directed into highly organized cortical tissues. We call these tissues 'cortical organoids' or 'minibrains' and showed that they recapitulate key aspects of human brain development as observed during early stages of embryonic development. The opportunity to generate cortical tissues that mimic early developmental stages of brain development, allows us to investigate the functionality of genomic novelties in the context of the development and evolution of the primate and human neocortex.


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Human stem cell-derived Cortical Organoid (minibrain), showing the radially organized distribution of PAX6 positive neural stem cells and TBR1-positive cortical neurons









 The Jacobs Lab 2017