@article {9387,
	title = {Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.},
	journal = {Nature},
	volume = {616},
	year = {2023},
	month = {2023 Apr},
	pages = {755-763},
	abstract = {<p>Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but~this effect was not seen in~clones with~driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental~knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.</p>},
	keywords = {Alleles, Animals, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Mutation, Promoter Regions, Genetic},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-05806-1},
	author = {Weinstock, Joshua S and Gopakumar, Jayakrishnan and Burugula, Bala Bharathi and Uddin, Md Mesbah and Jahn, Nikolaus and Belk, Julia A and Bouzid, Hind and Daniel, Bence and Miao, Zhuang and Ly, Nghi and Mack, Taralynn M and Luna, Sofia E and Prothro, Katherine P and Mitchell, Shaneice R and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Sinner, Moritz F and von Falkenhausen, Aenne S and K{\"a}{\"a}b, Stefan and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Hou, Lifang and Lloyd-Jones, Donald M and Redline, Susan and Cade, Brian E and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and DeMeo, Dawn L and Vasan, Ramachandran S and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon L R and Peyser, Patricia A and He, Jiang and Rienstra, Michiel and van der Harst, Pim and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Cutler, Michael J and Knight, Stacey and Muhlestein, J Brent and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Smith, J Gustav and Melander, Olle and Nilsson, Peter M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and McGarvey, Stephen and Williams, L Keoki and Xiao, Shujie and Yang, Mao and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Marcus, Gregory M and Kane, John P and Pullinger, Clive R and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan M and Albert, Christine and Kooperberg, Charles and Zhou, Ying and Manson, JoAnn E and Desai, Pinkal and Johnson, Andrew D and Mathias, Rasika A and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Satpathy, Ansuman T and Natarajan, Pradeep and Kitzman, Jacob O and Whitsel, Eric A and Reiner, Alexander P and Bick, Alexander G and Jaiswal, Siddhartha}
}
@article {9419,
	title = {The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.},
	journal = {Sci Adv},
	volume = {9},
	year = {2023},
	month = {2023 Apr 28},
	pages = {eabm4945},
	abstract = {<p>Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.</p>},
	keywords = {Germ-Line Mutation, Hematopoiesis, Humans, Middle Aged, Mutation, Mutation, Missense, Phenotype},
	issn = {2375-2548},
	doi = {10.1126/sciadv.abm4945},
	author = {Weinstock, Joshua S and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Redline, Susan and Cade, Brian E and Gilliland, Frank D and Chen, Zhanghua and Gauderman, W James and Kumar, Rajesh and Grammer, Leslie and Schleimer, Robert P and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Weiss, Scott T and Lasky-Su, Jessica and DeMeo, Dawn L and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and Vasan, Ramachandran S and Johnson, Andrew D and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon and He, Jiang and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Manichaikul, Ani W and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and Gui, Hongsheng and Xiao, Shujie and Williams, L Keoki and Meyers, Deborah A and Li, Xingnan and Ortega, Victor and McGarvey, Stephen and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan and Albert, Christine and Kooperberg, Charles and Desai, Pinkal and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Mathias, Rasika and Natarajan, Pradeep and Jaiswal, Siddhartha and Reiner, Alexander P and Bick, Alexander G}
}
