@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 = {

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.

}, 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 {9538, title = {Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Nov}, pages = {1912-1919}, abstract = {

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

}, keywords = {Black People, Genome, Human, Genome-Wide Association Study, Hispanic or Latino, Humans, Mosaicism, Precision Medicine}, issn = {1546-1718}, doi = {10.1038/s41588-023-01553-1}, author = {Jakubek, Yasminka A and Zhou, Ying and Stilp, Adrienne and Bacon, Jason and Wong, Justin W and Ozcan, Zuhal and Arnett, Donna and Barnes, Kathleen and Bis, Joshua C and Boerwinkle, Eric and Brody, Jennifer A and Carson, April P and Chasman, Daniel I and Chen, Jiawen and Cho, Michael and Conomos, Matthew P and Cox, Nancy and Doyle, Margaret F and Fornage, Myriam and Guo, Xiuqing and Kardia, Sharon L R and Lewis, Joshua P and Loos, Ruth J F and Ma, Xiaolong and Machiela, Mitchell J and Mack, Taralynn M and Mathias, Rasika A and Mitchell, Braxton D and Mychaleckyj, Josyf C and North, Kari and Pankratz, Nathan and Peyser, Patricia A and Preuss, Michael H and Psaty, Bruce and Raffield, Laura M and Vasan, Ramachandran S and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Silverman, Edwin K and Smith, Jennifer A and Smith, Aaron P and Taub, Margaret and Taylor, Kent D and Yun, Jeong and Li, Yun and Desai, Pinkal and Bick, Alexander G and Reiner, Alexander P and Scheet, Paul and Auer, Paul L} } @article {9703, title = {Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate.}, journal = {Nat Aging}, year = {2024}, month = {2024 Jun 04}, abstract = {

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-M{\"u}llerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

}, issn = {2662-8465}, doi = {10.1038/s43587-024-00647-7}, author = {Mack, Taralynn M and Raddatz, Michael A and Pershad, Yash and Nachun, Daniel C and Taylor, Kent D and Guo, Xiuqing and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Kenny, Eimear E and Loos, Ruth J F 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 Cho, Michael H and DeMeo, Dawn L and Levy, Daniel and Johnson, Andrew D and Mathias, Rasika A and Yanek, Lisa R and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Raffield, Laura M and Carson, April P and Rotter, Jerome I and Rich, Stephen S and Manichaikul, Ani W and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Shoemaker, M Benjamin and Roden, Dan M and Kooperberg, Charles and Auer, Paul L and Desai, Pinkal and Blackwell, Thomas W and Smith, Albert V and Reiner, Alexander P and Jaiswal, Siddhartha and Weinstock, Joshua S and Bick, Alexander G} }