Functional characterization of non-coding mutations in CLL




Principal Investigator:

Robert Mansson


Karolinska Institutet

Start Date:


End Date:


Primary Classification:

30107: Medical Genetics



  • Castor /proj/nobackup at UPPMAX: 29000 GiB
  • Cygnus /proj/nobackup at UPPMAX: 29000 GiB
  • Castor /proj at UPPMAX: 28000 GiB
  • Cygnus /proj at UPPMAX: 28000 GiB
  • Bianca at UPPMAX: 2 x 1000 core-h/month


Whole-genome sequencing (WGS) has provided a powerful tool for the identification of underlying genetic alterations in chronic lymphocytic leukemia (CLL). While major focus has been put on coding mutations, the significant fraction of mutations occurs in non-coding regions and remains minimally explored. Substantial numbers of these mutations are localized within regulatory elements, Thus, it is compelling to hypothesize that these mutations contribute to the development of disease by causing transcriptional dysregulation. To test this hypothesis,, non-coding mutations will be identified using WGS. For non-coding mutations to effect transcription, they have to alter transcription factor (TF) binding which in turn changes the regulatory effect of the element. TFs typically bind regulatory elements in small areas of open chromatin. ATACseq will be utilized to identify such open regions overlapping with mutations. Further, the sequence variant introduced by the mutations allow for directly comparing DNA accessibility and binding on the mutated and unmutated sister chromosomes. Together this will allow for identifying non-coding mutations causing functional changes in regulatory elements. As mamalian regulatory elements physically interact over long genomic distances , target promoters cannot be predicted simply by genomic localization. We will map these interactions using genome-wide chromosome conformation capture (HiC). Mutated enhancers can thus be linked to specific promoter-enhancer dependencies and as such directly provide a mechanism for how these mutations contribution to leukemogenesis through a transcriptional target. Taken together this will further our understanding of the gene regulatory mechanisms underpinning the CLL phenotype and the extent to which non-coding mutations impact leukemic transformation.