The impact of recent retrotransposon invasions on the evolution of human neural gene expression

Informations projet

Evolutionary Neurogenomics

N° de convention de subvention: 659193

DOI

10.3030/659193

Projet clôturé

Date de signature de la CE 5 Mai 2015

Date de début 1 Juin 2015

Date de fin 31 Mai 2017

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 177 598,80

Contribution de l’UE

€ 177 598,80

Coordonné par

UNIVERSITEIT VAN AMSTERDAM
Netherlands

Periodic Reporting for period 1 - Evolutionary Neurogenomics (The impact of recent retrotransposon invasions on the evolution of human neural gene expression)

Période du rapport: 2015-06-01 au 2017-05-31

Résumé du contexte et des objectifs généraux du projet

In this research program, I made the first steps to determine how recent retrotransposon insertions have shaped gene-regulatory pathways involved in human brain development. Through a combination of bioinformatics and human and non-human primate stem cell cortical neuron differentiation protocols, I aimed to identify neuronally expressed genes that have become under the control of retrotransposons. Knowing exactly how each class of retrotransposons have impacted human gene expression will allow us to explore these novel gene-regulatory properties may have come indispensable for the human brain and possibly contain clues to the increased susceptibility of humans to some neurological disorders. The long term goal of my research program is to investigate how waves of retrotransposon insertions have contributed to the evolution of human gene expression patterns and how these changes relate to human-specific aspects of brain development in health and disease.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

I finalized the goals set out in work package 1 for one type of retrotransposon and obtained promising preliminary outcomes. Even though it needs to be further supported by other complementary strategies, the position of human specific retrotransposons seems to be correlated to increased inter-species gene expression differences. This is in line with what we expected. For work package 2, I setup shRNA-lentiviral transduction protocols in my lab in order to manipulate the expression of specific zinc finger genes and successfully made human ESC lines with knock down of some of them. We have performed RNA-seq analysis as planned and are now working on the analysis of the data. Finally, we have started to create CRISPR-Cas9 knock out hESC lines for some of the KRAB Zinc fingers involved in important retrotransposon repressive activities. The functional analysis of in vitro brain tissues derived from these KRAB zinc finger gene mutated stem cell lines will help us understand the genomic and genome-functional impact of each of these retrotransposon invasions and the evolutionary arms race with KRAB zinc fingers that was elicited by it.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Even though it remains hard to predict the societal impact of this research program at this time, we have uncovered a number of exciting patterns and features of some specific retrotransposon-classes, that could potentially lead us to unravel at least one of the multiple genetic causes that underly the differential susceptibility to neurological diseases observed in the human population. Future research, building on the solid technical and intellectual foundations that I was able to lay down because of the Marie Curie Reintegration grant will allow me to assess the impact of these phenomena for the human species, in the past and today’s populations.

Evolutionary arms race between KRAB zinc finger genes (predator) and Retrotransposons (prey).