[CPM-SPIRE-L] Postdoc at Paris Sorbonne

Tue Nov 9 04:19:51 PST 2021

Call for a postdoctoral position at the Analytical Genomics Lab
Department of Computational and Quantitative Biology, Sorbonne Université
A.Carbone –alessandra.carbone at sorbonne-universite.fr

We offera postdoctoral position in the Analytical Genomics lab, at the 
LCQB in Sorbonne Université(SU). The goal
of the project is to provide a proof of concept that for a given gene, 
using combined results of known synthetic
biology, DNA-bar coding, NGS and computational biology, one can 
determine the pathogenicity of all variants
generated by single nucleotide mutations.Theconsortium involves SU, CIRI 
-ENS Lyon, IRMB –U.de Montpellier.

Description. Monogenic diseases are due to mutations that can affect up 
to 4,000 different genes. Due to a
substantial number of genes for which mutations trigger different 
diseases, more than 6,000 monogenic diseases
have been characterized (https://www.omim.org/statistics/geneMap). The 
major roadblock in genetic diagnosis
is the number of variants of uncertain significance (VUS). Identifying a 
VUS in a patient leaves the practitioner with
no actionable diagnosis (decision to treat or search for an alternative 
diagnosis), leading to a stressful and costly
diagnostic wandering and a loss of chance for the patient.By providing 
in vitropathogenicity score and novel in
silicopredictions for each coding sequence variant described in a 
specific gene, this project should, ultimately,
provide a way to greatly reduce the number of VUS.

We shall focus on a specific gene, MEFV: i) this gene carries a large 
proportion of VUS (≈50%) (despite intense
studies on this gene and its variants since its discovery 25 years ago), 
ii) mutations of this gene can cause three
different diseases: familial Mediterranean fever (FMF), FMF-like disease 
and Pyrin-Associated Autoinflammation
with neutrophilic dermatosis (PAAND) with different inheritance 
patterns, iii) FMF is the most common hereditary
autoinflammatory disease (AID) and MEFVgene is thusvery frequently 
sequenced in AID patients. Importantly,
the technological and computational approaches developed in this "proof 
of concept" project should be
transferable to all the genes involved in genetic diseases for which 
functional assays exist or can be designed.

The postdoc will be involved in the in silicopart of the project and 
will work in collaboration with themembers of
the consortium. (S)he will develop novel computational methods leading 
to thereconstruction of the protein
mutational landscapes and the evaluation of protein mutations in 
multimeric proteins.

(S)he will apply the new tools to the studyof the behavior of the 
multimeric protein Pyrin, coded in the MEFV
gene. For Pyrin, we wish to decrypt the surfaces at the amino-acid 
residue level and gain novel insights into the
mechanisms underlying the pathogenicity of the different variants. In 
addition to providing novel hypotheses on
Pyrin functions and dysfunctions, aback-and-forth approach between 
biological data and in silicomodelling is
expected toimprove the performance of in silicoprediction of pathogenic 
mutations. Five computational
approaches will be performed. Their aim is threefold and concern: 1. the 
protein structure: the interaction of the
different domains, the potential conformational changes of the protein 
and the identification of unstructured
regions; 2. the interaction of the protein with other partners: the 
binding sites of the protein and the modelling
of the physical interaction of the pyrin domains with known protein 
partners; 3. the reconstruction of the protein
mutational landscape. Multiplepotential novel insights generated by 
thefiveapproaches were highlighted
although fully unexpected hypotheses might emerge from the analyses:
1.Reconstruction of the landscape of phenotypic effects from 
evolutionary conservation and epistatic signals.
2. Prediction of protein interaction siteswithout knowledge of the partner.
3.3D modelling and molecular dynamic simulationsof the known pyrin 
protein partners.
4. Intra and inter-molecular analyses of the co-evolution of amino-acid 
residues.
5.Docking experiments.

Profile of the postdoctoral candidate: we look for a postdoctoral 
candidate from the field of bioinformatics,
computer scienceor physicswith an experience in protein structures 
and/or genomics.

General information on the scientific environment.The Analytical 
Genomicsteam at LCQBworks on various
problems connected with the functioning and evolution of biological 
systems. We use mathematical concepts,
coming from statistics and combinatorics, algorithms(deep learning and 
optimisation) and molecular physics
approaches to study basic principles of cellular functioning starting 
from genomic data. Our projects aim at understanding the basic 
principles of evolution and co-evolution of molecular structures in the 
cell. They are intimately linked to each other. Applications are 
inmedicineandenvironment.
See www.lcqb.upmc.fr/AnalGenom/projects.html

The Computational and Quantitative Biology unit,SU-CNRS UMR7238, offers 
a multidisciplinary work
environment made up of a part of experimentalists (genetics and 
synthetic biology) and a part of theoreticians
(computer science, mathematics, physics), around several themes: 
evolution, genome and population dynamics,
regulatory networks, structural bioinformatics, environment, modeling of 
complex biological systems, synthetic
biology and protein engineering. Further information can be found at 
www.lcqb.upmc.fr

Sorbonne Université(SU, www.sorbonne-universite.fr) is a fully 
multidisciplinary research-intensive university,
located in several campuses at the heart of Paris. Sorbonne Université 
covers all major disciplinary fields and
offers transversal academic and research programs with three faculties: 
Humanitiesand Social Sciences, Medicine
and Sciences & Engineering, bringing together the best talents in a wide 
array of these disciplines. With more
than 55 600 students (among 10 200 international students), 4700 
doctoral students and 6400 researchers,
Sorbonne Université is one of the leading French universities.

Location:the Pierre and Marie Campus is located in the heart of Paris, 
the 5thquarter, in front of the Seine river.

Position: 2 years postdoctoral position possibly starting from January 2022.

Contact:Alessandra Carbone, alessandra.carbone at sorbonne-universite.fr

-- 
___________________________________
Analytical Genomics Lab
Department of Computational and Quantitative Biology
UMR 7238 Sorbonne Université-CNRS
Campus Pierre et Marie Curie
Building C - 4th floor
4, place Jussieu, 75005 Paris

+33(0)1.44.27.73.45
Alessandra.Carbone at lip6.fr
http://www.ihes.fr/~carbone/
http://www.lcqb.upmc.fr/AnalGenom/home.html
http://www.lcqb.upmc.fr/Contact   (for directions)

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