Niels Tommerup

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Primary fields of research

The research focus of Tommerup Group is mapping of balanced chromosomal rearrangements (BCR) to identify and characterize novel disease and phenotype genes, regulatory domains (Topological Associating Domains (TADs)) of disease genes and novel genetic mechanisms. Characterization of germline chromothripsis and functional studies of non-coding RNA genes. Sex differential responses to Sars-Cov-2-, influenza-  and RSV-infections.

Current research

Recent highlights

The first study of long-term risk of prenatally diagnosed de novo BCRs increases the risk from 7% to appr. 20% and lead to new guidelines (Am J Hum Genet 2018;102:1090-1103); the multiple breakpoints in germline chromothripsis may predispose to complex multigenic disorders (Hum Mutat 2019;40:1057-62); haploinsufficiency of ARHGAP42 leads to age-dependent hypertension (Eur J Hum Genet 2019;27:1296-1303). The latter study also provides support for an obesity locus in the CELF4 regulatory domain on chromosome 18. Combining DNA-DNA-interaction (Hi-C) studies with short and long read sequencing improve the dissection of germline complex chromosomal rearrangements (Nat Commun. 2022;13:6470).

 

Ongoing projects

• Coordination of International Breakpoint Mapping Consortium (2014-), involving multiple diagnostic cytogenetic laboratories from >50 countries/6 continents.
• In collaboration with the group of Michael Talkowksi, Harvard, we have accumulated the largest number (>700) of sequence resolved germline BCRs, including the first large control BCR cohort. Direct gene truncation may explain ~18% of BCR-associated early developmental disorders (DD). We provide the first ranked list of TADs as genomic units for BCR-mediated long-range-position effects (LRPE). We define novel LRPE-loci (e.g. BCL11A, BCL11B) and our data suggest that LRPE may be at least as frequent a cause of DD as gene truncation. This window into the developmental regulome establish links to multiple disorders, incl. intellectual disability, autism, epilepsy, narcolepsy, speech defects and congenital brain malformations (in revision for Nature Genet).
• We have initiated the first systematic X-inactivation study of sequence resolved X;autosomal translocations and X-inversions. 
• Studies of extremely complex germline chromothripsis.  
• Search for host genetic factors that may be underly sex differential responses to Sars-Cov-2, influenza and RSV-infections, with a particular focus on the X-chromosome.
• Linking anatomical variation to genetic variation.
• Development of methods for visualization of nuclear genome organization.