Construction of a genome-scale structural map at single-nucleotide resolution

Greenbaum, Jason A.; Pang, Bo; Tullius, Tom

doi:10.1101/gr.6073107

Cited by 65 publications

(84 citation statements)

References 43 publications

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“…They were, however, significantly enriched in Lamin B1 associated domains (LADs), in gene-poor Giemsa positive, strongly A/Trich heterochromatin, in solvent-accessible sites (BU ORChID), and at methylated cytosines ( Fig. 4; Supplemental Table S9; Balasubramanian et al 1998;Greenbaum et al 2007;Guelen et al 2008;Meissner et al 2008). In contrast, they were significantly depleted in regions with histone methylation/acetylation associated with active gene transcription, especially in regions with high H3K36me3 levels, associated with transcriptional activation and elongation (Ram et al 2011) and at conserved loci (GERP) (Supplemental Fig.…”

Section: Spectrum Of Functional Elements Of Somatic Mutations Is Simimentioning

confidence: 99%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

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The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

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Section: Spectrum Of Functional Elements Of Somatic Mutations Is Simimentioning

confidence: 99%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

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“…For the purpose of the work presented here, a key feature of the hydroxyl radical cleavage experiment is that different DNA sequences can produce similar cleavage patterns (Price and Tullius 1993;Greenbaum et al 2007). Since the same local DNA structure can be adopted by different sequences of nucleotides, it is possible that a region of the genome that functions by virtue of its structure may not be conserved in nucleotide sequence.…”

Section: Resultsmentioning

confidence: 99%

“…We have determined the hydroxyl radical cleavage patterns of a substantial collection of DNA sequences, constructed a database of these patterns, and then used this database to develop an algorithm to predict the cleavage pattern of any DNA sequence (Greenbaum et al 2007;see Methods). We used this algorithm to predict the cleavage pattern of the 30 Mb of DNA within the ENCODE regions.…”

Section: Resultsmentioning

confidence: 99%

Detection of DNA structural motifs in functional genomic elements

Greenbaum¹,

Parker²,

Tullius³

2007

Genome Res.

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The completion of the human genome project has fueled the search for regulatory elements by a variety of different approaches. Many successful analyses have focused on examining primary DNA sequence and/or chromatin structure. However, it has been difficult to detect common sequence motifs within the feature of chromatin structure most closely associated with regulatory elements, DNase I hypersensitive sites (DHSs). Considering just the nucleotide sequence and/or the chromatin structure of regulatory elements may neglect a critical feature of what is recognized by the regulatory machinery-DNA structure. We introduce a new computational method to detect common DNA structural motifs in a large collection of DHSs that are found in the ENCODE regions of the human genome. We show that DHSs have common DNA structural motifs that show no apparent sequence consensus. One such structural motif is much more highly enriched in experimentally identified DHSs that are in CpG islands and near transcription start sites (TSSs), compared to DHSs not in CpG islands and farther from TSSs, suggesting that DNA structural motifs may participate in the formation of functional regulatory elements. We propose that studies of the conservation of DNA structure, independent of sequence conservation, will provide new information about the link between the nucleotide sequence of a DNA molecule and its experimentally demonstrated function. These approaches have been highly productive, and we now have a growing catalog of annotated functional elements in the human genome. However, the physical nature of functional sites in genomic DNA remains an important open question. The regulatory machinery that assembles on genomic DNA does so by recognizing in some way the presence of a functional element in the genomic DNA. While nucleotide sequence might be expected to be the key determinant of a functional element, local DNA structure is, in fact, what the regulatory machinery "senses" when scanning the genome for functional elements.Regions of the genome that are hypersensitive to digestion by deoxyribonuclease I (called DNase I hypersensitive sites, DHSs) have been shown to be associated with a wide variety of functional genomic elements, including promoters, enhancers, origins of replication, and centromeres (Gross and Garrard 1988;Felsenfeld 1992;Felsenfeld and Groudine 2003). Highthroughput methods recently have been developed to locate DHSs throughout large stretches of a genome (Crawford et al. 2004(Crawford et al. , 2006aDorschner et al. 2004;Sabo et al. 2004aSabo et al. ,b, 2006, including the entire set of ENCODE regions (The ENCODE Project Consortium 2004) that encompass 1% of the human genome.Although DHSs occur nonrandomly in the genome, it has been difficult to detect specific DNA sequence motifs that are held in common by DHSs (Noble et al. 2005). Here we ask whether, instead of a common nucleotide sequence, a particular local structure of genomic DNA is associated with genomic loci that are hypersensitive to DNase I. To address this qu...

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“…The question that is often raised is whether these short lengths of DNA may in fact not be relevant (and, in the case of crystals, be otherwise distorted (Dickerson et al, 1994)) relative to sequences embedded in a genomic context. Studies by Tullius' group using hydroxyl-radical foot printing (Greenbaum et al, 2007), have shown significant sequence dependent variation in the solvent accessibility and, thus, the helical structure of protein-free genomic DNA. These structural variations at the genomic level are highly correlated with variations in helical parameters measured in DNA crystal structures (unpublished results) derived from a selfconsistent data set (Hays et al, 2005).…”

Section: B-dnamentioning

confidence: 99%