Are you interested in the non-coding genome and how alterations of it can cause human disease? Would you like to work in a highly dynamic environment between the interphase of fundamental science and applied human clinical genetics, directly benefiting patients? And all of that in a fun, young and international team at a top university? Then join our expanding research team as our new PhD student!

The current position is funded by a ZonMw Vidi project, which aims to solve missing heritability in epileptic encephalopathies. These are severely devastating disorders that present with intractable epileptic seizures at early age. Severely affecting brain development of affected individuals and thereby imposing a large burden on patients, their families and the health care system. Many epileptic encephalopathies are caused by mutations in a large number of coding genes. But still around 50% of patients cannot be genetically diagnosed despite the high suspicion that it must be a genetic disorder.

We hypothesis that some of this “missing heritability” is caused by genetic alterations in the non-coding genome, which contains important gene regulatory elements, such as enhancers. Our previous work, using computational analysis and massively parallel reporter assays has resulted in an atlas of such regulatory elements, of which we find many to regulate medically relevant human genes.

In this project, we will explore how mutations in these regulatory elements might cause epileptic encephalopathy and other neurodevelopmental disorders. For this we will use:

• Analysis of patient whole genome sequencing data (short read and long read, both from our local patient cohort, our large network of international collaborators as well as from the Genomics England 100,000 Genomes Project and other repositories).
• Patient derived RNA-seq data.
• Data obtained in the wet-lab including massively parallel reporter assays, single cell analysis and chromatin conformation capture analysis in various cell models. Including brain organoids and zebrafish, combined with computational approaches including machine learning.

Tight interplay with the wet-lab will allow functional validation of the various obtained findings, and close links to clinic and diagnostics will ensure immediate translation of findings to improve patient care.

• You are a highly-motivated, creative and actively participating, hardworking team player with strong problem solving skills and broad interests.
• You have successfully obtained a MSc degree (or will shortly graduate), in the field of Bioinformatics, Computational Sciences, Health Science, Life Science, or related field.
• You gained previous experience in computational data analysis including next generation sequencing data. Affinity with gene regulation mechanisms and related technologies to study them such as functional genomics assays, RNA-seq, ChIP-seq, and ATAC-seq data analysis would be a strong plus. As would be previously obtained co-authorships on peer reviewed publications.
• Proficiency in widely used programming languages (R, Python, command line language) is a condition for the appointment.
• You are highly communicative with outstanding verbal and written English language skills (minimal IELTS 7.0, TOEFL 100 or equivalent) and you are willing to share your knowledge with other group members.
• You are preferably directly available (the latest per February 1st, 2024).

• You will receive a temporary position for 4 years. The gross monthly salary is € 2.901,- in the 1st year and increases to € 3.677,- in the 4th year (scale OIO).
• Excellent fringe benefits, such as a 13th month that is already paid out in November and a individual travel expense package.
• Pension insurance with ABP. We take care of approximately 2/3 of the monthly contribution.
• Special benefits, such as a incompany physiotherapist and bicycle repairer. And there is also a gym where you can work on your fitness after work.

Erasmus MC

You will be part of a highly international working environment in an inspiring, dynamic and productive team at the Barakat lab at the Clinical Genetics department of Erasmus MC. With access to a broad range of disease models and high-throughput next generation sequencing data, both from wet lab experiments as well as patient samples.

The Barakat lab was established in 2017 at Erasmus MC, and focusses on deciphering molecular mechanisms leading to neurodevelopmental disorders, with a particular interest in the role of the non-coding genome. Using functional-genomics and computational approaches we aim to understand the gene-regulatory-landscape in cells representing neurodevelopment.

Our long-term goal is to translate our research findings to the clinic, where we aim to develop novel diagnostics and therapies focusing on the so far, so often, neglected non-coding regions of the human genome. Next to our interest in fundamental gene-regulation, we apply disease-modelling for neurodevelopmental disorders using genome-engineering, induced pluripotent stem-cells, brain-organoids, and zebrafish.

Our group, currently consisting of 12 members, is strongly embedded in the department, and forms an important bridge between research and clinic, ultimately leading to advancements for patients. Since 2017 we have published 33 papers (majority in top-10 journals). Describing new disease entities and mechanisms, have obtained > 3.8 million euro funding (including competitive grants from CURE Epilepsy, EpilepsieNL, ZonMw Veni, ZonMw Vidi). We have been awarded a number of prizes, including an KNAW Early Career Award 2021.

Full publication record of the PI (including previous publications in Cell, Nature and Cell Stem Cell) can be found here and here. Relevant publications related to this project include:

Yousefi S et al: “Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance”.
Genome Med. 2021 Oct 19;13(1):162. doi: 10.1186/s13073-021-00980-1. PMID: 34663447
Barakat TS, Halbritter F, Zhang M, Rendeiro AF, Perenthaler E, Bock C, Chambers I: “Functional Dissection of the Enhancer Repertoire in Human Embryonic Stem Cells”. Cell Stem Cell. 2018 Aug 2;23(2):276-288.e8. doi: 10.1016/j.stem.2018.06.014.

Perenthaler E, et al : “Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases”.
Acta Neuropathol. 2020 Mar;139(3):415-442. doi: 10.1007/s00401-019-02109-6.

Sanderson et al: “Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking” Brain. 2021 Apr 12;144(3):769-780. doi: 10.1093/brain/awaa459.