Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain ...dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. We tested the effects of common deletion polymorphisms on TAD structure by linear regression analysis of nearby quantitative chromatin interactions (contacts) within 240 kb of the deletion, and we specifically tested the hypothesis that deletions at TAD boundaries (TBs) could result in large-scale alterations in chromatin conformation.
Large (> 10 kb) deletions had significant effects on long-range chromatin interactions. Deletions were associated with increased contacts that span the deleted region and this effect was driven by large deletions that were not located within a TAD boundary (nonTB). Some deletions at TBs, including a 80 kb deletion of the genes CFHR1 and CFHR3, had detectable effects on chromatin contacts. However for TB deletions overall, we did not detect a pattern of effects that was consistent in magnitude or direction. Large inversions in the population had a distinguishable signature characterized by a rearrangement of contacts that span its breakpoints.
Our study demonstrates that common SVs in the population impact long-range chromatin structure, and deletions and inversions have distinct signatures. However, the effects that we observe are subtle and variable between loci. Genome-wide analysis of chromatin conformation in large cohorts will be needed to quantify the influence of common SVs on chromatin structure.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The rhesus macaque (
Macaca mulatta
) is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp), ...increasing the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discover novel lineage-specific genes and expand gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequence data from 853 captive rhesus macaques identifies polymorphism in 85.7 million single-nucleotide and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing non-invasive NHP models of human disease.
A compendium of rhesus macaque genome variation
Complex structural variants (CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants. However, detecting the ...compounded mutational signals of CSVs is challenging through a commonly used model-match strategy. As a result, there has been limited progress for CSV discovery compared with simple structural variants. Here, we systematically analyzed the multi-breakpoint connection feature of CSVs, and proposed Mako, utilizing a bottom-up guided model-free strategy, to detect CSVs from paired-end short-read sequencing. Specifically, we implemented a graph-based pattern growth approach, where the graph depicts potential breakpoint connections, and pattern growth enables CSV detection without pre-defined models. Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms. Notably, validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70%, where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp, respectively. Moreover, the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types, including two novel types of adjacent segment swap and tandem dispersed duplication. Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs. Mako is publicly available at https://github.com/xjtu-omics/Mako.
A study was performed to investigate the sensitivity of river phosphorus loading to changes in precipitation, temperature, and flow rate. This research performs sensitivity analyses using elasticity ...principles similar to those employed by economists (i.e., price elasticity of demand) to uncover climate-nutrient-loading relationships. Here, the concept of elasticity is implemented in a water quality context to identify the sensitivity of total phosphorus (dissolved and particulate) loading in an urban stream to several climate variables using multivariate approaches. Previous analyses have used single parameter elasticity methods to represent the general relationship between nutrient loading and a variable of interest, but these methods cannot reflect the complicated nonlinear relationships inherent among nutrients, precipitation, temperature, and streamflow. Instead, the multivariate analysis presented in this study relies on the combined interactions among precipitation, temperature, and streamflow to successfully distinguish their individual impacts on nutrient loading. This study presents field data results and develops models that can be used to estimate phosphorus loads while determining the sensitivity of total phosphorus loading to changes in climate variables. It was found that total phosphorus loading at Alewife Brook depends significantly on season, rainfall, combined sewer overflow incidents, and flow rate. These results were significant for the development of a nutrient loading model that predicted a 3.6% to 7.4% increase in total phosphorus loading at Alewife Brook if small increases in precipitation, temperature, flow rate, and combined sewer overflow incidents occur. These results could be useful for developing models to better predict water quality responses to climate variability.
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