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Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases POLE and POLD1 replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001003682 Cancer Genomics
EGAS00001003754 Other

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00004041192 cram 2.4 GB
EGAF00004041193 cram 2.3 GB
EGAF00004041194 cram 2.3 GB
EGAF00004041195 cram 2.3 GB
EGAF00004041196 cram 2.7 GB
EGAF00004041197 cram 2.4 GB
EGAF00004041198 cram 2.3 GB
EGAF00004041199 cram 2.4 GB
EGAF00004041200 cram 2.4 GB
EGAF00004041201 cram 2.4 GB
EGAF00004041202 cram 2.1 GB
EGAF00004041203 cram 2.3 GB
EGAF00004041204 cram 2.3 GB
EGAF00004041205 cram 2.4 GB
EGAF00004041206 cram 2.1 GB
EGAF00004041207 cram 2.2 GB
EGAF00004041208 cram 2.3 GB
EGAF00004041209 cram 2.0 GB
EGAF00004041210 cram 1.9 GB
EGAF00004041211 cram 2.2 GB
EGAF00004041212 cram 1.9 GB
EGAF00004041213 cram 2.2 GB
EGAF00004041477 cram 23.4 GB
EGAF00004041478 cram 23.3 GB
EGAF00004041479 cram 24.0 GB
EGAF00004041480 cram 24.2 GB
EGAF00004041481 cram 24.5 GB
EGAF00004041482 cram 25.5 GB
EGAF00004041483 cram 26.5 GB
EGAF00004041484 cram 25.0 GB
EGAF00004041485 cram 25.4 GB
EGAF00004041486 cram 24.0 GB
EGAF00004041487 cram 22.8 GB
EGAF00004041488 cram 24.8 GB
EGAF00004041489 cram 26.0 GB
EGAF00004041490 cram 24.0 GB
EGAF00004041491 cram 24.8 GB
EGAF00004041492 cram 24.7 GB
EGAF00004041493 cram 20.7 GB
EGAF00004041494 cram 21.6 GB
EGAF00004041495 cram 27.5 GB
EGAF00004041496 cram 22.9 GB
EGAF00004041497 cram 23.4 GB
EGAF00004041498 cram 25.3 GB
EGAF00004041499 cram 24.7 GB
EGAF00004041500 cram 20.2 GB
EGAF00004041501 cram 26.8 GB
EGAF00004041502 cram 28.4 GB
EGAF00004041503 cram 27.9 GB
EGAF00004041504 cram 25.2 GB
EGAF00004041505 cram 25.9 GB
EGAF00004041506 cram 25.3 GB
EGAF00004041507 cram 27.1 GB
EGAF00004041508 cram 26.2 GB
EGAF00004041509 cram 24.8 GB
EGAF00004041510 cram 23.1 GB
EGAF00004041511 cram 23.0 GB
EGAF00004041512 cram 25.6 GB
EGAF00004041513 cram 21.4 GB
EGAF00004041514 cram 23.9 GB
EGAF00004041515 cram 23.0 GB
EGAF00004041516 cram 27.0 GB
EGAF00004041517 cram 29.0 GB
EGAF00004041518 cram 25.4 GB
EGAF00004041519 cram 22.5 GB
EGAF00004041520 cram 20.9 GB
EGAF00004041521 cram 21.6 GB
EGAF00004041522 cram 22.6 GB
EGAF00004041523 cram 24.0 GB
EGAF00004041524 cram 21.6 GB
EGAF00004041525 cram 24.0 GB
EGAF00004041526 cram 24.1 GB
EGAF00004041527 cram 27.4 GB
EGAF00004041528 cram 23.8 GB
EGAF00004041529 cram 24.4 GB
EGAF00004041530 cram 24.4 GB
EGAF00004041531 cram 24.0 GB
EGAF00004041532 cram 27.4 GB
EGAF00004041533 cram 27.1 GB
EGAF00004041534 cram 24.6 GB
EGAF00004041535 cram 26.0 GB
EGAF00004041536 cram 23.4 GB
EGAF00004041537 cram 21.5 GB
EGAF00004041538 cram 20.7 GB
EGAF00004041539 cram 20.7 GB
EGAF00004041540 cram 19.0 GB
EGAF00004041541 cram 19.9 GB
EGAF00004041542 cram 22.2 GB
EGAF00004041543 cram 19.4 GB
EGAF00004041544 cram 25.4 GB
EGAF00004041545 cram 24.5 GB
EGAF00004041546 cram 20.1 GB
EGAF00004041547 cram 26.3 GB
EGAF00004041548 cram 27.1 GB
EGAF00004041549 cram 22.8 GB
EGAF00004041550 cram 23.8 GB
EGAF00004041551 cram 24.7 GB
EGAF00004041552 cram 23.3 GB
EGAF00004041553 cram 26.8 GB
EGAF00004041554 cram 22.8 GB
EGAF00004041555 cram 22.9 GB
EGAF00004041556 cram 22.9 GB
EGAF00004041557 cram 25.3 GB
EGAF00004041558 cram 25.5 GB
EGAF00004041559 cram 24.8 GB
EGAF00004041560 cram 23.2 GB
EGAF00004041561 cram 26.0 GB
EGAF00004041562 cram 24.3 GB
EGAF00004041563 cram 21.9 GB
EGAF00004041564 cram 26.0 GB
EGAF00004041565 cram 25.1 GB
EGAF00004041566 cram 29.6 GB
EGAF00004041567 cram 25.3 GB
EGAF00004041568 cram 26.4 GB
EGAF00004041569 cram 25.0 GB
EGAF00004041570 cram 20.5 GB
EGAF00004041571 cram 23.1 GB
EGAF00004041572 cram 23.6 GB
EGAF00004041573 cram 23.6 GB
EGAF00004041574 cram 29.8 GB
EGAF00004041575 cram 31.1 GB
EGAF00004041576 cram 29.3 GB
EGAF00004041577 cram 25.0 GB
EGAF00004041578 cram 25.6 GB
EGAF00004041579 cram 27.0 GB
EGAF00004041580 cram 27.5 GB
EGAF00004041581 cram 25.5 GB
EGAF00004041582 cram 26.0 GB
EGAF00004041583 cram 26.0 GB
EGAF00004041584 cram 24.7 GB
EGAF00004041585 cram 25.6 GB
EGAF00004041586 cram 26.1 GB
EGAF00004041587 cram 25.7 GB
EGAF00004041588 cram 25.7 GB
EGAF00004041589 cram 23.1 GB
EGAF00004041590 cram 25.3 GB
EGAF00004041591 cram 27.4 GB
EGAF00004041592 cram 30.0 GB
EGAF00004041593 cram 26.5 GB
EGAF00004041594 cram 25.7 GB
EGAF00004041595 cram 27.3 GB
EGAF00004041596 cram 26.1 GB
EGAF00004041597 cram 14.1 GB
EGAF00004041598 cram 15.3 GB
EGAF00004041599 cram 14.2 GB
EGAF00004041600 cram 14.9 GB
EGAF00004041601 cram 12.9 GB
EGAF00004041602 cram 12.8 GB
EGAF00004041603 cram 12.2 GB
EGAF00004041604 cram 12.1 GB
EGAF00004041605 cram 14.4 GB
EGAF00004041606 cram 11.4 GB
EGAF00004041607 cram 12.1 GB
EGAF00004041608 cram 9.6 GB
EGAF00004041609 cram 14.2 GB
EGAF00004041610 cram 15.4 GB
EGAF00004041611 cram 14.3 GB
EGAF00004041612 cram 15.0 GB
EGAF00004041613 cram 13.0 GB
EGAF00004041614 cram 12.8 GB
EGAF00004041615 cram 12.2 GB
EGAF00004041616 cram 12.2 GB
EGAF00004041617 cram 14.6 GB
EGAF00004041618 cram 11.5 GB
EGAF00004041619 cram 12.2 GB
EGAF00004041620 cram 9.6 GB
EGAF00004041621 cram 32.8 GB
EGAF00004041622 cram 27.3 GB
EGAF00004041623 cram 26.3 GB
EGAF00004041624 cram 24.0 GB
EGAF00004041625 cram 21.9 GB
EGAF00004041626 cram 24.8 GB
EGAF00004041627 cram 27.1 GB
EGAF00004041628 cram 23.9 GB
EGAF00004041629 cram 23.7 GB
EGAF00004041630 cram 22.4 GB
EGAF00004041631 cram 24.9 GB
EGAF00004041632 cram 27.2 GB
EGAF00004041633 cram 25.1 GB
EGAF00004041634 cram 25.4 GB
EGAF00004041635 cram 21.5 GB
EGAF00004041636 cram 10.0 GB
EGAF00004041637 cram 8.5 GB
EGAF00004041638 cram 7.3 GB
EGAF00004041639 cram 9.6 GB
EGAF00004041640 cram 8.2 GB
EGAF00004041641 cram 9.7 GB
EGAF00004041642 cram 7.6 GB
EGAF00004041643 cram 10.1 GB
EGAF00004041644 cram 7.4 GB
EGAF00004041645 cram 9.2 GB
EGAF00004041646 cram 8.5 GB
EGAF00004041647 cram 9.1 GB
EGAF00004041648 cram 8.9 GB
EGAF00004041649 cram 8.0 GB
EGAF00004041650 cram 7.6 GB
EGAF00004041651 cram 8.4 GB
EGAF00004041652 cram 7.0 GB
EGAF00004041653 cram 9.8 GB
EGAF00004041654 cram 10.0 GB
EGAF00004041655 cram 8.5 GB
EGAF00004041656 cram 7.1 GB
EGAF00004041657 cram 9.3 GB
EGAF00004041658 cram 8.2 GB
EGAF00004041659 cram 9.7 GB
EGAF00004041660 cram 7.8 GB
EGAF00004041661 cram 10.2 GB
EGAF00004041662 cram 7.3 GB
EGAF00004041663 cram 9.3 GB
EGAF00004041664 cram 8.6 GB
EGAF00004041665 cram 9.3 GB
EGAF00004041666 cram 8.8 GB
EGAF00004041667 cram 7.9 GB
EGAF00004041668 cram 7.4 GB
EGAF00004041669 cram 8.3 GB
EGAF00004041670 cram 6.9 GB
EGAF00004041671 cram 9.8 GB
EGAF00004041672 cram 10.1 GB
EGAF00004041673 cram 8.7 GB
EGAF00004041674 cram 7.4 GB
EGAF00004041675 cram 9.7 GB
EGAF00004041676 cram 8.3 GB
EGAF00004041677 cram 9.7 GB
EGAF00004041678 cram 7.7 GB
EGAF00004041679 cram 10.1 GB
EGAF00004041680 cram 7.5 GB
EGAF00004041681 cram 9.3 GB
EGAF00004041682 cram 8.6 GB
EGAF00004041683 cram 9.3 GB
EGAF00004041684 cram 9.1 GB
EGAF00004041685 cram 8.1 GB
EGAF00004041686 cram 7.8 GB
EGAF00004041687 cram 8.5 GB
EGAF00004041688 cram 7.2 GB
EGAF00004041689 cram 9.9 GB
EGAF00004041690 cram 29.2 GB
EGAF00004041691 cram 26.7 GB
EGAF00004041692 cram 26.5 GB
EGAF00004041693 cram 36.2 GB
EGAF00004041694 cram 30.8 GB
EGAF00004041695 cram 24.1 GB
EGAF00004041696 cram 9.1 GB
EGAF00004041697 cram 7.6 GB
EGAF00004041698 cram 8.2 GB
EGAF00004041699 cram 8.3 GB
EGAF00004041700 cram 9.2 GB
EGAF00004041701 cram 9.3 GB
EGAF00004041702 cram 7.8 GB
EGAF00004041703 cram 8.5 GB
EGAF00004041704 cram 8.5 GB
EGAF00004041705 cram 7.6 GB
EGAF00004041706 cram 10.5 GB
EGAF00004041707 cram 9.2 GB
EGAF00004041708 cram 6.9 GB
EGAF00004041709 cram 9.0 GB
EGAF00004041710 cram 6.9 GB
EGAF00004041711 cram 7.0 GB
EGAF00004041712 cram 8.0 GB
EGAF00004041713 cram 7.8 GB
EGAF00004041714 cram 9.2 GB
EGAF00004041715 cram 7.6 GB
EGAF00004041716 cram 8.2 GB
EGAF00004041717 cram 8.4 GB
EGAF00004041718 cram 9.2 GB
EGAF00004041719 cram 9.2 GB
EGAF00004041720 cram 7.8 GB
EGAF00004041721 cram 8.6 GB
EGAF00004041722 cram 8.5 GB
EGAF00004041723 cram 7.6 GB
EGAF00004041724 cram 10.5 GB
EGAF00004041725 cram 9.3 GB
EGAF00004041726 cram 7.0 GB
EGAF00004041727 cram 9.0 GB
EGAF00004041728 cram 7.0 GB
EGAF00004041729 cram 7.0 GB
EGAF00004041730 cram 8.0 GB
EGAF00004041731 cram 7.9 GB
EGAF00004041732 cram 8.8 GB
EGAF00004041733 cram 7.4 GB
EGAF00004041734 cram 8.0 GB
EGAF00004041735 cram 8.3 GB
EGAF00004041736 cram 9.1 GB
EGAF00004041737 cram 9.1 GB
EGAF00004041738 cram 7.7 GB
EGAF00004041739 cram 8.5 GB
EGAF00004041740 cram 8.6 GB
EGAF00004041741 cram 7.3 GB
EGAF00004041742 cram 10.1 GB
EGAF00004041743 cram 9.0 GB
EGAF00004041744 cram 6.5 GB
EGAF00004041745 cram 8.2 GB
EGAF00004041746 cram 6.4 GB
EGAF00004041747 cram 6.8 GB
EGAF00004041748 cram 7.4 GB
EGAF00004041749 cram 7.1 GB
EGAF00004041750 cram 22.2 GB
EGAF00004041751 cram 25.2 GB
EGAF00004041752 cram 22.1 GB
EGAF00004041753 cram 21.7 GB
EGAF00004041754 cram 19.5 GB
EGAF00004041755 cram 20.5 GB
301 Files (4.9 TB)