@article {9588, title = {Determinants of mosaic chromosomal alteration fitness.}, journal = {medRxiv}, year = {2023}, month = {2023 Oct 21}, abstract = {

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

}, doi = {10.1101/2023.10.20.23297280}, author = {Pershad, Yash and Mack, Taralynn and Poisner, Hannah and Jakubek, Yasminka A and Stilp, Adrienne M and Mitchell, Braxton D and Lewis, Joshua P and Boerwinkle, Eric and Loos, Ruth J and Chami, Nathalie and Wang, Zhe and Barnes, Kathleen and Pankratz, Nathan and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Bis, Joshua C and Shojaie, Ali and Silverman, Edwin K and Cho, Michael H and Yun, Jeong and DeMeo, Dawn and Levy, Daniel and Johnson, Andrew and Mathias, Rasika and Taub, Margaret and Arnett, Donna and North, Kari and Raffield, Laura M and Carson, April and Doyle, Margaret F and Rich, Stephen S and Rotter, Jerome I and Guo, Xiuqing and Cox, Nancy and Roden, Dan M and Franceschini, Nora and Desai, Pinkal and Reiner, Alex and Auer, Paul L and Scheet, Paul and Jaiswal, Siddhartha and Weinstock, Joshua S and Bick, Alexander G} } @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 {9749, title = {The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.}, journal = {medRxiv}, year = {2024}, month = {2024 Aug 26}, abstract = {

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg ( , , ), and one locus associated with a sex-associated mutation pathway ( . We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of and implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

}, doi = {10.1101/2024.08.22.24312319}, author = {Weinstock, Joshua S and Chaudhry, Sharjeel A and Ioannou, Maria and Viskadourou, Maria and Reventun, Paula and Jakubek, Yasminka A and Alexander Liggett, L and Laurie, Cecelia and Broome, Jai G and Khan, Alyna and Taylor, Kent D and Guo, Xiuqing and Peyser, Patricia A and Boerwinkle, Eric and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J and Psaty, Bruce M and Russell, Tracy P and Brody, Jennifer A and Yun, Jeong H and Cho, Michael H and Vasan, Ramachandran S and Kardia, Sharon L and Smith, Jennifer A and Raffield, Laura M and Bidulescu, Aurelian and O{\textquoteright}Brien, Emily and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Chen, Yii Der Ida and Gu, C Charles and Hsiung, Chao A and Kooperberg, Charles and Haring, Bernhard and Nassir, Rami and Mathias, Rasika and Reiner, Alex and Sankaran, Vijay and Lowenstein, Charles J and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Natarajan, Pradeep and Jaiswal, Siddhartha and Bick, Alexander and Post, Wendy S and Scheet, Paul and Auer, Paul and Karantanos, Theodoros and Battle, Alexis and Arvanitis, Marios} } @article {9866, title = {Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.}, journal = {Am J Hum Genet}, volume = {112}, year = {2025}, month = {2025 Feb 06}, pages = {276-290}, abstract = {

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.

}, keywords = {Alleles, Chromosome Deletion, Chromosomes, Human, Y, Genomics, Haplotypes, Humans, Male, Mosaicism, Phenotype, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2024.12.014}, author = {Jakubek, Yasminka A and Ma, Xiaolong and Stilp, Adrienne M and Yu, Fulong and Bacon, Jason and Wong, Justin W and Aguet, Francois and Ardlie, Kristin and Arnett, Donna K and Barnes, Kathleen and Bis, Joshua C and Blackwell, Tom and Becker, Lewis C and Boerwinkle, Eric and Bowler, Russell P and Budoff, Matthew J and Carson, April P and Chen, Jiawen and Cho, Michael H and Coresh, Josef and Cox, Nancy J and de Vries, Paul S and DeMeo, Dawn L and Fardo, David W and Fornage, Myriam and Guo, Xiuqing and Hall, Michael E and Heard-Costa, Nancy and Hidalgo, Bertha and Irvin, Marguerite Ryan and Johnson, Andrew D and Jorgenson, Eric and Kenny, Eimear E and Kessler, Michael D and Levy, Daniel and Li, Yun and Lima, Jo{\~a}o A C and Liu, Yongmei and Locke, Adam E and Loos, Ruth J F and Machiela, Mitchell J and Mathias, Rasika A and Mitchell, Braxton D and Murabito, Joanne M and Mychaleckyj, Josyf C and North, Kari E and Orchard, Peter and Parker, Stephen C J and Pershad, Yash and Peyser, Patricia A and Pratte, Katherine A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Shah, Sanjiv J and Smith, Jennifer A and Smith, Aaron P and Smith, Albert and Taub, Margaret A and Tiwari, Hemant K and Tracy, Russell and Tuftin, Bjoernar and Bick, Alexander G and Sankaran, Vijay G and Reiner, Alexander P and Scheet, Paul and Auer, Paul L} }