Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Characteristics and Sample Acquisition
2.1.1. Library Preparation and Sequencing
2.1.2. Sequence Alignment and Variant Calling
2.1.3. Mutational Signatures Analysis
- 1.
- Variant classification in 96 contexts: Every single nucleotide variant (SNV) was represented for example, as C>A, C>T (by convention beginning with the pyrimidine) within a trinucleotide context (e.g., “GCT>GAT”). This approach yields 96 different possible contexts (six substitution type C>A, C>G, C>T, T>A, T>G, T>C with four possible bases immediately 5’ and 3’ to each substitution). This classification annotation was performed for mutations within localized regions (IG loci) as well as for genome-wide mutations (WES) (Figure 1).
- 2.
- Signature extraction, similarity and fitting: Global and localized mutational signatures were defined by a workflow encompassing a three-step procedure, starting with a de novo signature extraction, followed by an similarity analysis, to allow a final fitting approach. de novo mutational signature extraction was generated by a non-negative matrix factorization (NMF) using R-package SigProfiler [33]. One of the practical drawbacks of the multiplicative NMF algorithm is that the task of selecting the appropriate number of sources is left to the user. Using this tool automatically allows the identification of the optimal number of operative signatures in our dataset (Figure 1, Supplementary Figure S1).
2.1.4. Unsupervised Clustering Analysis
2.1.5. Hi-C Data Analysis and Compartment Identification
3. Results
3.1. Variant Allele Densities and Frequencies in FL and CLL
3.2. Somatic Mutations in CLL/MBL and FL Are Frequently Associated with a Deamination Pattern in AID Motifs
3.3. Trinucleotide Context of Somatic Mutations in FL and CLL/MBL
3.4. Inferring the Role of AID as an Underlying Mutagenic Mechanism in FL and CLL/MBL
3.5. FL and CLL Show Differential Distribution of Mutational Signatures across Tridimensional (3D) DNA Compartments
3.6. Analysis of Mutations in Genes Involved in DNA Repair
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Sepulveda-Yanez, J.H.; Alvarez-Saravia, D.; Fernandez-Goycoolea, J.; Aldridge, J.; van Bergen, C.A.M.; Posthuma, W.; Uribe-Paredes, R.; Veelken, H.; Navarrete, M.A. Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas. Int. J. Mol. Sci. 2021, 22, 13015. https://doi.org/10.3390/ijms222313015
Sepulveda-Yanez JH, Alvarez-Saravia D, Fernandez-Goycoolea J, Aldridge J, van Bergen CAM, Posthuma W, Uribe-Paredes R, Veelken H, Navarrete MA. Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas. International Journal of Molecular Sciences. 2021; 22(23):13015. https://doi.org/10.3390/ijms222313015
Chicago/Turabian StyleSepulveda-Yanez, Julieta H., Diego Alvarez-Saravia, Jose Fernandez-Goycoolea, Jacqueline Aldridge, Cornelis A. M. van Bergen, Ward Posthuma, Roberto Uribe-Paredes, Hendrik Veelken, and Marcelo A. Navarrete. 2021. "Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas" International Journal of Molecular Sciences 22, no. 23: 13015. https://doi.org/10.3390/ijms222313015