Non-coding Genome Alterations in Development Anomalies

Event Details

Type

Special Seminar Series

Speaker(s)

Stanislas Lyonnet, M.D., Ph.D., professor of genetics, Paris Descartes University Medical School; clinical geneticist, department of medical genetics, Necker Hospital for Sick Children; principal investigator, INSERM, Imagine Foundation

Speaker bio(s)

One of the key discoveries of vertebrate genome sequencing projects was the unexpected amount of DNA that remained evolutionarily conserved under selective pressure, and thus likely functional. Two-thirds of it does not correspond to coding sequences (exons and UTRs); these sequences have been named conserved non-coding sequences and represent a vast amount of DNA (three percent of the human genome). Interestingly, enrichment for conserved non-coding sequences has been demonstrated within gene deserts nearest to physically isolated genes known or suspected to be important developmental regulators. It has been thus suggested that, in these cases, conserved non-coding sequences may represent regulatory elements (enhancers or suppressors) necessary for the correct spatiotemporal expression of these genes needed for embryonic development, and acting as modular, sometimes combinatorial, tissue-specific enhancers of gene transcription.

In that context, Dr. Lyonnet will discuss a number of findings, following the seminal discovery of long-distance genomic alterations altering the expression of the SHH (Sonic Hedgehog) gene. Recent examples involve:

- Mutation of non-coding RNA genes, such as the deletions observed at the mir17-92 cluster in Feingold syndrome, or mutation of a long non-coding RNA in RAVINE encephalopathy.

- Enhancer variants located within or close to a gene, such as a genomic variant in a highly conserved sequence located in a non-coding region of the RET gene, altering the binding of a transcription factor expressed in neural crest cell precursors to the enteric nervous system, which predispose to Hirschsprung disease.

- Long-distance disruption of CNCs, whatever their function, such as those observed on both sides of the SOX9 gene coding sequences in either Pierre Robin sequence, a common orofacial cleft anomaly with mandibular hypoplasia, or isolated disorders of sex determination. In these cases, the disruption of distant tissue-specific regulatory elements, required for the normal development of either the mandibula or the gonads, perturbs embryonic expression of SOX9 and could account for the Pierre Robin sequence or disorders of sex determination phenotypes respectively, as these evolutionarily constrained regions may be disrupted in a modular fashion.

Collectively, these observations suggest that the domains to study for genomic alterations, resulting in tissue-specific misregulation of a developmental gene and a subsequent malformation, should be much broader than traditionally investigated.

After training in pediatrics and genetics, Dr. Lyonnet became a full professor of genetics at Paris Descartes University Medical School in 1995. He is a clinical geneticist in the department of medical genetics at Necker Hospital for Sick Children. As a principal investigator of an INSERM research group, "Genetics and embryology of congenital malformations," Dr. Lyonnet has conducted several studies aiming to localize and identify the genes involved in congenital malformation and inborn errors of development, mostly neurocristopathies. This group belongs to the recently created Imagine Foundation, Institute for Genetic Diseases (Necker campus). Dr. Lyonnet is responsible for the Master of Genetics (Paris Descartes-Paris Diderot Universities). He is a member of the INSERM Scientific Advisory Board, and has been a member of the board of the European Society of Human Genetics and its scientific programme committee. He is a section editor of the European Journal of Human Genetics, and belongs to the editorial boards of Human Molecular Genetics and Clinical Dysmorphology. He was awarded the Jean Hamburger prize of Ville de Paris in 2006 and the INSERM Research Price in 2009. He is the elected president of the European Society of Human Genetics.

Open to

Public

Reception

Refreshments, 3:45 p.m. - 4:00 p.m., Lower Level Greenberg Building (CRC)

Contact

Jill Benz

Phone

(212) 327-7244

Sponsor

Jill Benz
(212) 327-7244
benzj@rockefeller.edu