Meet the team
If you're interested in joining the LMS
The Genomic Variation and Disease team at the LMS started in 2024. Led by Lila Allou, it aims to understand the molecular consequences of SVs affecting noncoding regions in development and disease, thereby improving rare disease diagnosis and identifying potential therapeutic targets in cancer.
“How do changes in the structure of chromosomes affect health and development?”
In the nucleus of each cell, a DNA molecule forms thread-like structures called chromosomes. Chromosomes are thus a collection of genes carrying genetic information (DNA).
Chromosome mutations, which can modify the number or structure of chromosomes in a cell, are a complex phenomenon. While a gene mutation affects only a single gene or a segment of DNA on a chromosome, a chromosomal mutation alters the entire gene on that chromosome. These structural changes can lead to issues with the growth, development, and function of body systems. They can also disrupt the proteins produced by many genes along the chromosome and impact the noncoding DNA sequences located between genes.
Our team is researching exactly how changes that affect chromosome structure can cause problems with the growth, development, and function of systems in the body. We are also researching novel therapeutic targets in cancer derived from changes that affect chromosome structure.
We investigate this using synthetic genomics – where we can synthesize large DNA fragments and insert them into chromosomes within cells.
By deepening our understanding of the consequences of changes that affect chromosome structure, we have the potential to make a significant impact. This knowledge could lead to the diagnosis of a substantial portion of the 300 million undiagnosed patients with rare diseases and the development of innovative therapeutic strategies for cancer patients.
“Intergenic structural variation is a critically understudied class of mutation, although it is likely to contribute significantly to unsolved genetic disease.”
Structural variants (SVs) are changes in the genome structure with a minimum size of 50 bp. They can include inversions, balanced translocations, or genomic imbalances (insertions, deletions, and duplications). Interpreting the impact of SVs, particularly intergenic SVs, on human health and disease is challenging. However, this is of particular importance to diagnose at least a subset of the 300 million undiagnosed patients with a rare disease and to develop novel therapeutic strategies for cancer patients.
We aim to unravel the molecular consequences of SVs in development and disease. We investigate the functional consequences of SVs in rare diseases and identify new SV-derived therapeutic targets in cancer. We use synthetic genomics for mouse or human genome rewriting to study the functional consequences of SVs. This powerful tool allows us to better understand human pathologies and develop novel therapies by faithfully recapitulating human diseases in mice.
Allou L, Mundlos S. Disruption of regulatory domains and novel transcripts as disease-causing mechanisms. Bioessays. 2023 Oct;45(10):e2300010. doi: 10.1002/bies.202300010. Epub 2023 Jun 29. PMID: 37381881.
Allou L, Balzano S, Magg A, Quinodoz M, Royer-Bertrand B, Schöpflin R, Chan WL, Speck-Martins CE, Carvalho DR, Farage L, Lourenço CM, Albuquerque R, Rajagopal S, Nampoothiri S, Campos-Xavier B, Chiesa C, Niel-Bütschi F, Wittler L, Timmermann B, Spielmann M, Robson MI, Ringel A, Heinrich V, Cova G, Andrey G, Prada-Medina CA, Pescini-Gobert R, Unger S, Bonafé L, Grote P, Rivolta C, Mundlos S, Superti-Furga A. Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator. Nature. 2021 Apr;592(7852):93-98. doi: 10.1038/s41586-021-03208-9. Epub 2021 Feb 10. PMID: 33568816.
Allou L, Julia S, Amsallem D, El Chehadeh S, Lambert L, Thevenon J, Duffourd Y, Saunier A, Bouquet P, Pere S, Moustaïne A, Ruaud L, Roth V, Jonveaux P, Philippe C. Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease. Clin Genet. 2017 Mar;91(3):431-440. doi: 10.1111/cge.12784. Epub 2016 May 11. PMID: 27062609.
Allou L, Lambert L, Amsallem D, Bieth E, Edery P, Destrée A, Rivier F, Amor D, Thompson E, Nicholl J, Harbord M, Nemos C, Saunier A, Moustaïne A, Vigouroux A, Jonveaux P, Philippe C. 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements. Eur J Hum Genet. 2012 Dec;20(12):1216-23. doi: 10.1038/ejhg.2012.127. Epub 2012 Jun 27. PMID: 22739344; PMCID: PMC3499785.