Genome-Wide DNA Alterations in X-Irradiated Human Gingiva Fibroblasts
Abstract
:1. Introduction
2. Results
2.1. Translocations
2.2. Distribution of SNVs and InDels in Genome Dataset
2.3. Intrachromosomal Distribution of SNVs and InDels
2.4. InDel-specific Signatures
3. Discussion
3.1. Dose-Response Correlation
3.2. Mutational Signatures on a Genomic Level
3.3. Intrachromosomal IR-Related Mutation Patterns
4. Materials and Methods
4.1. Cell Culture and IR Treatment
4.2. Next-Generation Sequencing Analysis
4.3. Bioinformatics Analysis
4.4. Data Filtering
4.5. Translocation Analysis
4.6. Variant Accumulation Analysis
4.7. SNV-based analyses
4.8. InDel-Based Analyses
4.9. Functional Annotation
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
IR | Ionizing radiation |
DSB | Double strand break |
NHEJ | Non-homologous end joining |
HR | Homologous recombination |
MMEJ | Microhomology-mediated end joining |
InDel | Insertion or deletion |
SNV | Single Nucleotide Variants |
HGF | Human Gingiva Fibroblasts |
NGS | Next generation sequencing |
Ti | Transition |
Tv | Transversion |
WGS | Whole genome sequencing |
TAD | Topological Associating Domain |
TCR | Transcription-coupled repair |
iPSCs | Induced pluripotent stem cells |
MMR | Mismatch repair |
CTCF | CCCTC-binding factor |
GATK | Genome Analysis Toolkit |
DP | Sequencing Depth, number of reads during variant calling step |
GQ | Genotype Quality based on Phred-Scaled confidence of assigned genotype |
RefSeq | Reference Sequence |
Appendix A
ID | Sample ID | Time | Dosage | Functional Effect | Putative Impact | GeneName | Transcript ID | Refseq mrna |
---|---|---|---|---|---|---|---|---|
chr19:20044988_C/G | 393 | 16 h | 0.5 Gy | stop_gained | HIGH | ZNF93 | ENST00000343769 | NM_031218 |
chr19:50040366_G/A | 448 | 7 Days | 2 Gy | stop_gained | HIGH | RCN3 | ENST00000597801 | NA |
chr19:52904936_A/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000360465 | NM_032423 |
chr19:52904936_A/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000436397 | NA |
chr19:52904936_A/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000391787 | NA |
chr19:52904936_A/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000494167 | NA |
chr19:52904936_A/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000493272 | NA |
chr19:52904936_A/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000531472 | NA |
chr19:52904937_G/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000360465 | NM_032423 |
chr19:52904937_G/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000436397 | NA |
chr19:52904937_G/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000391787 | NA |
chr19:52904937_G/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000494167 | NA |
chr19:52904937_G/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000493272 | NA |
chr19:52904937_G/T | 448 | 7 Days | 2 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000531472 | NA |
chr19:39229056_A/C | 449 | 7 Days | 10 Gy | splice_donor_variant&intron_variant | HIGH | CAPN12 | ENST00000328867 | NM_144691 |
chr19:39229056_A/C | 449 | 7 Days | 10 Gy | splice_donor_variant&intron_variant | HIGH | CAPN12 | ENST00000601953 | NA |
chr19:52904936_A/T | 449 | 7 Days | 10 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000360465 | NM_032423 |
chr19:52904936_A/T | 449 | 7 Days | 10 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000436397 | NA |
chr19:52904936_A/T | 449 | 7 Days | 10 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000391787 | NA |
chr19:52904936_A/T | 449 | 7 Days | 10 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000494167 | NA |
chr19:52904936_A/T | 449 | 7 Days | 10 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000493272 | NA |
chr19:52904936_A/T | 449 | 7 Days | 10 Gy | splice_acceptor_variant&intron_variant | HIGH | ZNF528 | ENST00000531472 | NA |
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Time | Radiation Dose | Functional Impacts | Inter-Chromosomal Translocations | |||
---|---|---|---|---|---|---|
Dataset 1 | High | Moderate | Low | Modifier | ||
0.5 Gy | 14 | 189 | 3785 | 33,384 | 22 | |
16 h | 2 Gy | 21 | 226 | 3800 | 35,714 | 24 |
10 Gy | 15 | 222 | 3984 | 35,514 | 19 | |
0.5 Gy | 18 | 216 | 3408 | 33,189 | 59 | |
7 Days | 2 Gy | 12 | 263 | 3717 | 35,336 | 90 |
10 Gy | 22 | 208 | 3980 | 36,754 | 74 | |
Dataset 2 | ||||||
0.5 Gy | 19 | 277 | 4849 | 50,437 | 14 | |
16 h | 2 Gy | 49 | 262 | 5119 | 52,567 | 10 |
10 Gy | 30 | 432 | 6107 | 60,561 | 16 | |
0.5 Gy | 62 | 1857 | 14,227 | 76,636 | 23 | |
7 Days | 2 Gy | 36 | 475 | 7416 | 69,550 | 26 |
10 Gy | 40 | 210 | 11,140 | 68,032 | 20 |
Time | Radiation Dose | SNVs Depth (DP) After (Before) Filter | InDels Depth (DP) After (Before) Filter | SNVs Counts After (Before) Filter | InDels Counts After (Before) Filter |
---|---|---|---|---|---|
Dataset 1 | |||||
16 h | 0.5 Gy | 1,029,599 (206,573,706) | 334,619 (25,449,747) | 34,261 (3,839,076) | 15,083 (715,406) |
2 Gy | 1,098,772 (221,379,800) | 372,440 (27,846,456) | 36,674 (3,859,535) | 17,982 (739,759) | |
10 Gy | 1,101,857 (222,284,695) | 379,065 (28,064,422) | 36,435 (3,854,999) | 17,098 (734,831) | |
7 Days | 0.5 Gy | 1,030,578 (217,184,675) | 352,673 (26,948,643) | 34,078 (3,846,812) | 15,698 (724,272) |
2 Gy | 1,092,867 (217,841,944) | 369,254 (27,518,060) | 36,256 (3,850,694) | 17,188 (734,633) | |
10 Gy | 1,142,613 (236,100,648) | 397,153 (29,973,246) | 36,836 (3,778,441) | 17,518 (730,883) | |
Dataset 2 | |||||
16 h | 0.5 Gy | 1,166,694 (130,621,022) | 242,653 (6,073,404) | 50,516 (3,848,840) | 16,987 (252,782) |
2 Gy | 1,137,296 (123,863,517) | 234,141 (5,764,483) | 52,666 (3,852,339) | 17,675 (254,521) | |
10 Gy | 1,474,964 (153,573,569) | 351,819 (7,637,043) | 60,688 (3,901,398) | 25,620 (269,267) | |
7 Days | 0.5 Gy | 2,268,357 (187,652,991) | 478,893 (9,473,714) | 77,818 (3,953,911) | 29,045 (274,854) |
2 Gy | 1,825,231 (17,5864,812) | 432,240 (8,902,319) | 69,691 (3,930,167) | 27,463 (272,142) | |
10 Gy | 387,902 (84,432,203) | 266,508 (1,973,176) | 27,251 (3,510,867) | 28,387 (91,240) |
Terms | Definition | Average Log Fold Change Form Filtered to Unfiltered |
---|---|---|
Del.mh.bimh.x (A) | Deletion in area of microhomology | −1.66 |
Del.none.len.x (B) | Deletion in undistinguished area | −1.69 |
Del.rep.len.x (C) | Deletion in repeat area | −1.72 |
Ins.mh.bimh.x (D) | Insertion in area of microhomology | −1.70 |
Ins.none.len.x (E) | Insertion in undistinguished area | −1.74 |
Ins.rep.len.x (F) | Insertion in repeat area | −1.74 |
SnpEff Sequence Ontology | Combined Terms |
---|---|
splice_region_variant&intron_variant; splice_region_variant; splice_region_variant&synonymous_variant; splice_region_variant&non_coding_exon_variant | splice_region |
splice_acceptor_variant&intron_variant; splice_donor_variant&intron_variant; splice_acceptor_variant&splice_donor_variant&intron_variant | splice_site |
missense_variant&splice_region_variant | missense_variant |
stop_retained_variant | synonymous_variant |
stop_gained&splice_region_variant | stop_gained |
5_prime_UTR_premature_start_codon_gain_variant | 5_prime_UTR_variant |
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Nath, N.; Hagenau, L.; Weiss, S.; Tzvetkova, A.; Jensen, L.R.; Kaderali, L.; Port, M.; Scherthan, H.; Kuss, A.W. Genome-Wide DNA Alterations in X-Irradiated Human Gingiva Fibroblasts. Int. J. Mol. Sci. 2020, 21, 5778. https://doi.org/10.3390/ijms21165778
Nath N, Hagenau L, Weiss S, Tzvetkova A, Jensen LR, Kaderali L, Port M, Scherthan H, Kuss AW. Genome-Wide DNA Alterations in X-Irradiated Human Gingiva Fibroblasts. International Journal of Molecular Sciences. 2020; 21(16):5778. https://doi.org/10.3390/ijms21165778
Chicago/Turabian StyleNath, Neetika, Lisa Hagenau, Stefan Weiss, Ana Tzvetkova, Lars R. Jensen, Lars Kaderali, Matthias Port, Harry Scherthan, and Andreas W. Kuss. 2020. "Genome-Wide DNA Alterations in X-Irradiated Human Gingiva Fibroblasts" International Journal of Molecular Sciences 21, no. 16: 5778. https://doi.org/10.3390/ijms21165778