Large chromosome deletions, duplications, and gene conversion events accumulate with age in normal human colon crypts.
Large chromosome deletions, duplications, and gene conversion events accumulate with age in normal human colon crypts.
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DOI：
10.1111/acel.12053
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发表时间：
2013-04
期刊：
影响因子：
7.8
通讯作者：
Lieber MR
中科院分区：
文献类型：
--
作者：
Hsieh JC;Van Den Berg D;Kang H;Hsieh CL;Lieber MR
人们对随着年龄增长可能在正常人体细胞中积累的突变类型和数量知之甚少。这样的信息需要从单个细胞中获得足够的DNA，以通过广泛的扩增准确地进行可靠的分析，这因技术问题而复杂化。我们已经比较了结肠隐窝，其是puroneclonal克隆的并且每个包含约2000个细胞，以确定体内发生多少体细胞遗传变异（没有离体细胞培养）。使用高密度SNP微阵列，我们发现，染色体缺失，重复和基因转换显着更频繁的结肠从老年人。这些变化影响的长度范围从73 kb到46 Mb。虽然检测需要一个单一的突变干细胞的后代，以达到生态位优势超过邻近的干细胞，没有一个删除似乎可能赋予选择性优势。在干细胞进化过程中，突变可以通过正常人类隐窝中的中性漂移随机固定。随着年龄的增长，在个体隐窝中检测到染色体变化的事实表明，这种变化随着年龄的增长而积累，或者单个干细胞优势随着年龄的增长而增加，前者更有可能。随着年龄的增长，人类体细胞的这种渐进的全基因组差异对多细胞生物的衰老和疾病有影响。
Little is known about the types and numbers of mutations that may accumulate in normal human cells with age. Such information would require obtaining enough DNA from a single cell to accurately carry out reliable analysis with extensive amplification, and this is complicated by technical concerns. We have compared colon crypts, which are putatively clonal and contain ~2000 cells each, to determine how much somatic genetic variation occurs in vivo (without ex vivo cell culturing). Using high density SNP microarrays, we find that chromosome deletions, duplications and gene conversions were significantly more frequent in colons from the older individuals. These changes affected lengths ranging from 73kb to 46 Mb. Although detection requires progeny of a single mutant stem cell to reach niche dominance over neighboring stem cells, none of the deletions appear likely to confer a selective advantage. Mutations can become fixed randomly during stem cell evolution through neutral drift in normal human crypts. The fact that chromosomal changes are detected in individual crypts with increasing age suggests that either such changes accumulate with age or single stem cell dominance increases with age, and the former is more likely. This progressive genome-wide divergence of human somatic cells with age has implications for aging and disease in multicellular organisms.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Welch JS;Ley TJ;Link DC;Miller CA;Larson DE;Koboldt DC;Wartman LD;Lamprecht TL;Liu F;Xia J;Kandoth C;Fulton RS;McLellan MD;Dooling DJ;Wallis JW;Chen K;Harris CC;Schmidt HK;Kalicki-Veizer JM;Lu C;Zhang Q;Lin L;O'Laughlin MD;McMichael JF;Delehaunty KD;Fulton LA;Magrini VJ;McGrath SD;Demeter RT;Vickery TL;Hundal J;Cook LL;Swift GW;Reed JP;Alldredge PA;Wylie TN;Walker JR;Watson MA;Heath SE;Shannon WD;Varghese N;Nagarajan R;Payton JE;Baty JD;Kulkarni S;Klco JM;Tomasson MH;Westervelt P;Walter MJ;Graubert TA;DiPersio JF;Ding L;Mardis ER;Wilson RK
通讯作者：
Wilson RK
影响因子：
30.8
作者：
Laurie, Cathy C.;Laurie, Cecelia A.;Rice, Kenneth;Doheny, Kimberly F.;Zelnick, Leila R.;McHugh, Caitlin P.;Ling, Hua;Hetrick, Kurt N.;Pugh, Elizabeth W.;Amos, Chris;Wei, Qingyi;Wang, Li-E;Lee, Jeffrey E.;Barnes, Kathleen C.;Hansel, Nadia N.;Mathias, Rasika;Daley, Denise;Beaty, Terri H.;Scott, Alan F.;Ruczinski, Ingo;Scharpf, Rob B.;Bierut, Laura J.;Hartz, Sarah M.;Landi, Maria Teresa;Freedman, Neal D.;Goldin, Lynn R.;Ginsburg, David;Li, Jun;Desch, Karl C.;Strom, Sara S.;Blot, William J.;Signorello, Lisa B.;Ingles, Sue A.;Chanock, Stephen J.;Berndt, Sonja I.;Le Marchand, Loic;Henderson, Brian E.;Monroe, Kristine R.;Heit, John A.;de Andrade, Mariza;Armasu, Sebastian M.;Regnier, Cynthia;Lowe, William L.;Hayes, M. Geoffrey;Marazita, Mary L.;Feingold, Eleanor;Murray, Jeffrey C.;Melbye, Mads;Feenstra, Bjarke;Kang, Jae H.;Wiggs, Janey L.;Jarvik, Gail P.;McDavid, Andrew N.;Seshan, Venkatraman E.;Mirel, Daniel B.;Crenshaw, Andrew;Sharopova, Nataliya;Wise, Anastasia;Shen, Jess;Crosslin, David R.;Levine, David M.;Zheng, Xiuwen;Udren, Jenna I.;Bennett, Siiri;Nelson, Sarah C.;Gogarten, Stephanie M.;Conomos, Matthew P.;Heagerty, Patrick;Manolio, Teri;Pasquale, Louis R.;Haiman, Christopher A.;Caporaso, Neil;Weir, Bruce S.
通讯作者：
Weir, Bruce S.
DOI：
10.1073/pnas.97.15.8403
发表时间：
2000-07-18
影响因子：
11.1
作者：
Dollé, MET;Snyder, WK;Vijg, J
通讯作者：
Vijg, J
影响因子：
7.8
作者：
Bailey, KJ;Maslov, AY;Pruitt, SC
通讯作者：
Pruitt, SC