Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.
Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.
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DOI：
10.1038/ng.3821
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发表时间：
2017-05
期刊：
影响因子：
30.8
通讯作者：
Perry JRB
中科院分区：
文献类型：
--
作者：
Wright DJ;Day FR;Kerrison ND;Zink F;Cardona A;Sulem P;Thompson DJ;Sigurjonsdottir S;Gudbjartsson DF;Helgason A;Chapman JR;Jackson SP;Langenberg C;Wareham NJ;Scott RA;Thorsteindottir U;Ong KK;Stefansson K;Perry JRB
Y染色体在造血细胞中经常丢失，是男性中最常见的体细胞突变。然而，调控Y染色体嵌合丢失（mLOY）的机制及其临床意义尚不清楚。使用85,542名男性的基因型阵列强度数据和序列读数，我们确定了19个与mLOY相关的基因组区域（P<5x 10 -8）。累积起来，这些位点也预测了女性的X染色体丢失（N= 96，123，P= 4x 10 -6）。在全血中进行的额外的表观基因组范围的甲基化分析突出了与mLOY相关的36个差异甲基化位点。所鉴定的基因集中在细胞增殖和细胞周期调控方面，包括DNA合成（NPAT）、DNA损伤反应（ATM）、有丝分裂（PMF 1-CENPN-MAD 1 L1）和凋亡（TP 53）。我们强调mLOY和癌症易感性之间共享的遗传结构，除了推断吸烟对mLOY的因果关系。总的来说，我们的研究结果表明，基因型阵列强度数据能够在群体规模上测量细胞周期效率，识别与非整倍性，基因组不稳定性和癌症易感性有关的基因。
The Y-chromosome is frequently lost in hematopoietic cells, representing the most common somatic mutation in men. However, the mechanisms regulating mosaic loss of chromosome-Y (mLOY), and its clinical relevance, are unknown. Using genotype array intensity data and sequence reads in 85,542 men, we identify 19 genomic regions (P<5x10-8) associated with mLOY. Cumulatively, these loci also predicted X-chromosome loss in women (N=96,123, P=4x10-6). Additional epigenome-wide methylation analyses in whole blood highlighted 36 differentially methylated sites associated with mLOY. Identified genes converge on aspects of cell proliferation and cell-cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1-CENPN-MAD1L1) and apoptosis (TP53). We highlight shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype array intensity data enable a measure of cell-cycle efficiency at population scale, identifying genes implicated in aneuploidy, genome instability and cancer susceptibility.
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影响因子：
14.9
作者：
Christmann M;Kaina B
通讯作者：
Kaina B
DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
30.8
作者：
Chung, Charles C.;Kanetsky, Peter A.;Wang, Zhaoming;Hildebrandt, Michelle A. T.;Koster, Roelof;Skotheim, Rolf I.;Kratz, Christian P.;Turnbull, Clare;Cortessis, Victoria K.;Bakken, Anne C.;Bishop, D. Timothy;Cook, Michael B.;Erickson, R. Loren;Fossa, Sophie D.;Jacobs, Kevin B.;Korde, Larissa A.;Kraggerud, Sigrid M.;Lothe, Ragnhild A.;Loud, Jennifer T.;Rahman, Nazneen;Skinner, Eila C.;Thomas, Duncan C.;Wu, Xifeng;Yeager, Meredith;Schumacher, Fredrick R.;Greene, Mark H.;Schwartz, Stephen M.;McGlynn, Katherine A.;Chanock, Stephen J.;Nathanson, Katherine L.
通讯作者：
Nathanson, Katherine L.
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
9.8
作者：
Dumanski JP;Lambert JC;Rasi C;Giedraitis V;Davies H;Grenier-Boley B;Lindgren CM;Campion D;Dufouil C;European Alzheimer’s Disease Initiative Investigators;Pasquier F;Amouyel P;Lannfelt L;Ingelsson M;Kilander L;Lind L;Forsberg LA
通讯作者：
Forsberg LA