Genomic origin, fragmentomics, and transcriptional correlation of long cell-free DNA molecules in human plasma [RESEARCH]
Recent studies have revealed an unexplored population of long cell-free DNA (cfDNA) molecules in human plasma using long-read sequencing technologies. However, the biological properties of long cfDNA molecules (> 500 bp) remain largely unknown. To this end, we investigated the origins of long cfDNA molecules from different genomic elements. Analysis of plasma cfDNA using long-read sequencing revealed uneven distribution of long molecules from across the genome. Long cfDNA molecules showed overrepresentation in euchromatic regions of the genome, in sharp contrast to short DNA molecules. We observed a stronger relationshi...
Source: Genome Research - February 26, 2024 Category: Genetics & Stem Cells Authors: Che, H., Jiang, P., Choy, L. L. Y., Cheng, S. H., Peng, W., Chan, R. W. Y., Liu, J., Zhou, Q., Lam, J. W. K., Yu, S. C. Y., Lau, S. L., Leung, T. Y., Wong, J., Wong, V. W.-S., Wong, G. L. H., Chan, S. L., Chan, A. K. C., Lo, Y. M. D. Tags: RESEARCH Source Type: research
Pathogenic variants in CRX have distinct cis-regulatory effects on enhancers and silencers in photoreceptors [RESEARCH]
Dozens of variants in the gene for the homeodomain transcription factor (TF) cone-rod homeobox (CRX) are linked with human blinding diseases that vary in their severity and age of onset. How different variants in this single TF alter its function in ways that lead to a range of phenotypes is unclear. We characterized the effects of human disease-causing variants on CRX cis-regulatory function by deploying massively parallel reporter assays (MPRAs) in mouse retina explants carrying knock-ins of two variants, one in the DNA-binding domain (p.R90W) and the other in the transcriptional effector domain (p.E168d2). The degree of...
Source: Genome Research - February 14, 2024 Category: Genetics & Stem Cells Authors: Shepherdson, J. L., Friedman, R. Z., Zheng, Y., Sun, C., Oh, I. Y., Granas, D. M., Cohen, B. A., Chen, S., White, M. A. Tags: RESEARCH Source Type: research
Preferential formation of Z-RNA over intercalated motifs in long noncoding RNA [RESEARCH]
Secondary structure is a principal determinant of lncRNA function, predominantly regarding scaffold formation and interfaces with target molecules. Noncanonical secondary structures that form in nucleic acids have known roles in regulating gene expression and include G-quadruplexes (G4s), intercalated-motifs (iMs), and R-loops (RLs). In this paper, we utilized computational tools G4-iM Grinder and QmRLFS-finder to predict the formation of each of these structures throughout the lncRNA transcriptome in comparison to protein-coding transcripts. The importance of the predicted structures in lncRNA in biological contexts was a...
Source: Genome Research - February 14, 2024 Category: Genetics & Stem Cells Authors: Bhatt, U., Cucchiarini, A., Luo, Y., Evans, C. W., Mergny, J.-L., Iyer, K. S., Smith, N. M. Tags: RESEARCH Source Type: research
Differences in molecular sampling and data processing explain variation among single-cell and single-nucleus RNA-seq experiments [RESEARCH]
A mechanistic understanding of the biological and technical factors that impact transcript measurements is essential to designing and analyzing single-cell and single-nucleus RNA sequencing experiments. Nuclei contain the same pre-mRNA population as cells, but they contain a small subset of the mRNAs. Nonetheless, early studies argued that single-nucleus analysis yielded results comparable to cellular samples if pre-mRNA measurements were included. However, typical workflows do not distinguish between pre-mRNA and mRNA when estimating gene expression, and variation in their relative abundances across cell types has receive...
Source: Genome Research - February 14, 2024 Category: Genetics & Stem Cells Authors: Chamberlin, J. T., Lee, Y., Marth, G., Quinlan, A. R. Tags: RESEARCH Source Type: research
Pangenome genotyped structural variation improves molecular phenotype mapping in cattle [RESOURCES]
Expression and splicing quantitative trait loci (e/sQTL) are large contributors to phenotypic variability. Achieving sufficient statistical power for e/sQTL mapping requires large cohorts with both genotypes and molecular phenotypes, and so the genomic variation is often called from short-read alignments which are unable to comprehensively resolve structural variation. Here we build a pangenome from 16 HiFi haplotype-resolved assemblies to identify small and structural variation and genotype them with PanGenie in 307 short-read samples. We find high (>90%) concordance of PanGenie-genotyped and DeepVariant-called small v...
Source: Genome Research - February 14, 2024 Category: Genetics & Stem Cells Authors: Leonard, A. S., Mapel, X. M., Pausch, H. Tags: RESOURCES Source Type: research
Corrigendum: A mosquito small RNA genomics resource reveals dynamic evolution and host responses to viruses and transposons [CORRIGENDUM]
(Source: Genome Research)
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Ma, Q., Srivastav, S. P., Gamez, S., Dayama, G., Feitosa-Suntheimer, F., Patterson, E. I., Johnson, R. M., Matson, E. M., Gold, A. S., Brackney, D. E., Connor, J. H., Colpitts, T. M., Hughes, G. L., Rasgon, J. L., Nolan, T., Akbari, O. S., Lau, N. C. Tags: CORRIGENDUM Source Type: research
GenomeMUSter mouse genetic variation service enables multitrait, multipopulation data integration and analysis [RESOURCES]
Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait–variant associatio...
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Ball, R. L., Bogue, M. A., Liang, H., Srivastava, A., Ashbrook, D. G., Lamoureux, A., Gerring, M. W., Hatoum, A. S., Kim, M. J., He, H., Emerson, J., Berger, A. K., Walton, D. O., Sheppard, K., El Kassaby, B., Castellanos, F., Kunde-Ramamoorthy, G., Lu, L Tags: RESOURCES Source Type: research
High-throughput and genome-scale targeted mutagenesis using CRISPR in a nonmodel multicellular organism, Bombyx mori [METHODS]
This study also shows the effectiveness, practicality, and convenience of large-scale mutant libraries in other nonmodel organisms. (Source: Genome Research)
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Ma, S., Zhang, T., Wang, R., Wang, P., Liu, Y., Chang, J., Wang, A., Lan, X., Sun, L., Sun, H., Shi, R., Lu, W., Liu, D., Zhang, N., Hu, W., Wang, X., Xing, W., Jia, L., Xia, Q. Tags: METHODS Source Type: research
Data integration and inference of gene regulation using single-cell temporal multimodal data with scTIE [METHODS]
Single-cell technologies offer unprecedented opportunities to dissect gene regulatory mechanisms in context-specific ways. Although there are computational methods for extracting gene regulatory relationships from scRNA-seq and scATAC-seq data, the data integration problem, essential for accurate cell type identification, has been mostly treated as a standalone challenge. Here we present scTIE, a unified method that integrates temporal multimodal data and infers regulatory relationships predictive of cellular state changes. scTIE uses an autoencoder to embed cells from all time points into a common space by using iterative...
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Lin, Y., Wu, T.-Y., Chen, X., Wan, S., Chao, B., Xin, J., Yang, J. Y. H., Wong, W. H., Wang, Y. X. R. Tags: METHODS Source Type: research
Power-law behavior of transcriptional bursting regulated by enhancer-promoter communication [METHODS]
Revealing how transcriptional bursting kinetics are genomically encoded is challenging because genome structures are stochastic at the organization level and are suggestively linked to gene transcription. To address this challenge, we develop a generic theoretical framework that integrates chromatin dynamics, enhancer–promoter (E-P) communication, and gene-state switching to study transcriptional bursting. The theory predicts that power law can be a general rule to quantitatively describe bursting modulations by E-P spatial communication. Specifically, burst frequency and burst size are up-regulated by E-P communicat...
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Wang, Z., Zhang, Z., Luo, S., Zhou, T., Zhang, J. Tags: METHODS Source Type: research
A Bayesian framework to study tumor subclone-specific expression by combining bulk DNA and single-cell RNA sequencing data [METHODS]
Genetic and gene expression heterogeneity is an essential hallmark of many tumors, allowing the cancer to evolve and to develop resistance to treatment. Currently, the most commonly used data types for studying such heterogeneity are bulk tumor/normal whole-genome or whole-exome sequencing (WGS, WES); and single-cell RNA sequencing (scRNA-seq), respectively. However, tools are currently lacking to link genomic tumor subclonality with transcriptomic heterogeneity by integrating genomic and single-cell transcriptomic data collected from the same tumor. To address this gap, we developed scBayes, a Bayesian probabilistic frame...
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Qiao, Y., Huang, X., Moos, P. J., Ahmann, J. M., Pomicter, A. D., Deininger, M. W., Byrd, J. C., Woyach, J. A., Stephens, D. M., Marth, G. T. Tags: METHODS Source Type: research
A statistical learning method for simultaneous copy number estimation and subclone clustering with single-cell sequencing data [METHODS]
In this study, we developed a subclone clustering method based on a fused lasso model, referred to as FLCNA, which can simultaneously detect CNAs in single-cell DNA sequencing (scDNA-seq) data. Spike-in simulations were conducted to evaluate the clustering and CNA detection performance of FLCNA, benchmarking it against existing copy number estimation methods (SCOPE, HMMcopy) in combination with commonly used clustering methods. Application of FLCNA to a scDNA-seq data set of breast cancer revealed different genomic variation patterns in neoadjuvant chemotherapy-treated samples and pretreated samples. We show that FLCNA is ...
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Qin, F., Cai, G., Amos, C. I., Xiao, F. Tags: METHODS Source Type: research
Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos [METHODS]
Meiotic recombination is crucial for human genetic diversity and chromosome segregation accuracy. Understanding its variation across individuals and the processes by which it goes awry are long-standing goals in human genetics. Current approaches for inferring recombination landscapes rely either on population genetic patterns of linkage disequilibrium (LD)—capturing a time-averaged view—or on direct detection of crossovers in gametes or multigeneration pedigrees, which limits data set scale and availability. Here, we introduce an approach for inferring sex-specific recombination landscapes using data from prei...
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Ariad, D., Madjunkova, S., Madjunkov, M., Chen, S., Abramov, R., Librach, C., McCoy, R. C. Tags: METHODS Source Type: research
Characterization of the distribution and dynamics of chromatin states in the C. elegans germline reveals substantial H3K4me3 remodeling during oogenesis [RESEARCH]
Chromatin organization in the C. elegans germline is tightly regulated and critical for germ cell differentiation. Although certain germline epigenetic regulatory mechanisms have been identified, how they influence chromatin structure and ultimately gene expression remains unclear, in part because most genomic studies have focused on data collected from intact worms comprising both somatic and germline tissues. We therefore analyzed histone modification and chromatin accessibility data from isolated germ nuclei representing undifferentiated proliferating and meiosis I populations to define chromatin states. We correlated t...
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Mazzetto, M., Gonzalez, L. E., Sanchez, N., Reinke, V. Tags: RESEARCH Source Type: research
Oxidative stress accelerates intestinal tumorigenesis by enhancing 8-oxoguanine-mediated mutagenesis in MUTYH-deficient mice [RESEARCH]
Oxidative stress–induced DNA damage and its repair systems are related to cancer etiology; however, the molecular basis triggering tumorigenesis is not well understood. Here, we aimed to explore the causal relationship between oxidative stress, somatic mutations in pre-tumor-initiated normal tissues, and tumor incidence in the small intestines of MUTYH-proficient and MUTYH-deficient mice. MUTYH is a base excision repair enzyme associated with human colorectal cancer. Mice were administered different concentrations of potassium bromate (KBrO3; an oxidizing agent)–containing water for 4 wk for mutagenesis studies...
Source: Genome Research - February 7, 2024 Category: Genetics & Stem Cells Authors: Ohno, M., Takano, N., Hidaka, K., Sasaki, F., Yamauchi, K., Aoki, Y., Nohmi, T., Nakabeppu, Y., Nakatsu, Y., Tsuzuki, T. Tags: RESEARCH Source Type: research
