Genome Biology - Latest Articles

Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance

David Martino — 2013-05-22T00:00:00Z

Background: The extent to which development- and age-associated epigenetic changes are influenced by genetic, environmental and stochastic factors remains to be discovered. Twins provide an ideal model with which to investigate these influences but previous cross-sectional twin studies provide contradictory evidence of within-pair epigenetic drift over time. Longitudinal twin studies can potentially address this discrepancy. Results: In a pilot, genome-scale study of DNA from buccal epithelium, a relatively homogeneous tissue, we show that one third of the CpGs assayed show dynamic methylation between birth and 18 months. Although all classes of annotated genomic regions assessed show an increase in DNA methylation over time, probes located in intragenic regions, enhancers and low-density CpG promoters are significantly over-represented, while CpG islands and high-CpG density promoters are depleted among the most dynamic probes. Comparison of co-twins demonstrated that within-pair drift in DNA methylation in our cohort is specific to a subset of pairs, who show more differences at 18 months. The rest of the pairs show either minimal change in methylation discordance, or more similar, converging methylation profiles at 18 months. As with age-associated regions, sites that change in their level of within-pair discordance between birth and 18 months are enriched in genes involved in development, but the average magnitude of change is smaller than for longitudinal change. Conclusions: Our findings suggest that DNA methylation in buccal epithelium is influenced by nonshared stochastic and environmental factors which could reflect a degree of epigenetic plasticity within an otherwise constrained developmental program.

Genome of the long-living sacred lotus (Nelumbo nucifera Gaertn.)

Ray Ming — 2013-05-10T00:00:00Z

Background: Sacred lotus is a basal eudicot with agricultural, medicinal, cultural and religious importance. It was domesticated in Asia about 7,000 years ago, and cultivated for its rhizomes and seeds as a food crop. It is particularly noted for its 1,300-year seed longevity and exceptional water repellency, known as the lotus effect. The latter property is due to the nanoscopic closely-packed protuberances on its self-cleaning leaf surface, which have been adapted for the manufacture of a self-cleaning industrial paint, Lotusan.ResearchThe genome of the China Antique variety of the sacred lotus was sequenced with Illumina and 454 technologies, at respective depths of 101x and 5.2x. The final assembly has a contig N50 of 38.8 kbp and a scaffold N50 of 3.4 Mbp, and covers 86.5% of the estimated 929 Mbp total genome size. The genome notably lacks the paleo-triplication observed in other eudicots, but reveals a lineage-specific duplication. The genome has evidence of slow evolution, with a 30% slower nucleotide mutation rate than observed in grape. Comparisons of the available sequenced genomes suggest a minimum gene set for vascular plants of 4,223 genes. Strikingly, the sacred lotus has sixteen COG2132 multi-copper oxidase family proteins with root specific expression; these are involved in root meristem phosphate starvation, reflecting adaptation to limited nutrient availability in an aquatic environment. Conclusions: The slow nucleotide substitution rate makes the sacred lotus a better resource than the current standard, grape, for reconstructing the pan-eudicot genome, and should therefore accelerate comparative analysis between eudicots and monocots.

After the gold rush

Neil Hall — 2013-05-07T00:00:00Z

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How to evaluate a graduate studentship, or choosing the right doctoral advisor

Duncan Odom — 2013-04-29T00:00:00Z

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CRISPR-Cas systems target a diverse collection of invasive mobile genetic elements in human microbiomes

Quan Zhang — 2013-04-29T00:00:00Z

Background: Bacteria and archaea develop immunity against invading genomes by incorporating pieces of the invaders' sequences, called spacers, into a CRISPR locus between repeats, forming arrays of repeat-spacer units. When spacers are expressed, they direct Cas proteins to silence complementary invading DNA. In order to characterize the invaders of human microbiomes, we use spacers from CRISPR arrays that we had previously assembled from shotgun metagenomic datasets, and identify contigs that contain these spacers' targets. Results: We discover 95,000 contigs that are putative invasive mobile genetic elements (MGEs), some targeted by hundreds of CRISPR spacers. We find that oral sites in healthy human populations have a much greater variety of MGEs than stool samples. MGEs carry genes encoding diverse functions: only 7% of the MGEs are similar to known phages or plasmids, although a much greater proportion contain phage- or plasmid-related genes. A small number of contigs share similarity with known integrative and conjugative elements, providing the first examples of CRISPR defenses against this class of element. We provide detailed analyses of a few large MGEs of various types, and a relative abundance analysis of MGEs and putative hosts, exploring the dynamic activities of MGEs in human microbiomes. A joint analysis of MGEs and CRISPRs shows that protospacer-adjacent motifs drive their interaction network; however, some CRISPR-Cas systems target MGEs lacking motifs. Conclusions: We identify a large collection of invasive MGEs in human microbiomes, an important resource for further study of the interaction between the CRISPR-Cas immune system and invaders.

EMu: probabilistic inference of mutational processes and their localization in the cancer genome

Andrej Fischer — 2013-04-29T00:00:00Z

The spectrum of mutations discovered in cancer genomes can be explained by the activity of a few elementary mutational processes. We present a novel probabilistic method, EMu, to infer the mutational signatures of these processes from a collection of sequenced tumors. EMu naturally incorporates the tumor-specific opportunity for different mutation types according to sequence composition. Applying EMu to breast cancer data, we derive detailed maps of the activity of each process, both genome-wide and within specific local regions of the genome. Our work provides new opportunities to study the mutational processes underlying cancer development. EMu is available at http://www.sanger.ac.uk/resources/software/emu/.

jMOSAiCS: joint analysis of multiple ChIP-seq datasets

Xin Zeng — 2013-04-29T00:00:00Z

A novel probabilistic method for jointly analyzing multiple ChIP-seq datasets offers an improvement over chromHMM

Phosphoproteomics data classify hematological cancer cell lines according to tumor type and sensitivity to kinase inhibitors

Pedro Casado — 2013-04-29T00:00:00Z

Background: Tumor classification based on their predicted responses to kinase inhibitors is a major goal for advancing targeted personalized therapies. Here, we used a phosphoproteomic approach to investigate biological heterogeneity across hematological cancer cell lines including acute myeloid leukemia, lymphoma and multiple myeloma. Results: Mass spectrometry was used to quantify 2,000 phosphorylation sites across three acute myeloid leukemia, three lymphoma and three multiple myeloma cell lines in six biological replicates. The intensities of the phosphorylation sites grouped these cancer cell lines according to their tumor type. In addition, a phosphoproteomic analysis of seven acute myeloid leukemia cell lines revealed a battery of phosphorylation sites whose combined intensities correlated with the growth-inhibitory responses to three kinase inhibitors with remarkable correlation coefficients and fold changes (>100 between the most resistant and sensitive cells). Modeling based on regression analysis indicated that a subset of phosphorylation sites could be used to predict response to the tested drugs. Quantitative analysis of phosphorylation motifs indicated that resistant and sensitive cells differed in their patterns of kinase activities, but, interestingly, phosphorylations correlating with responses were not on members of the pathway being targeted; instead, these mainly were on parallel kinase pathways. Conclusion: This study reveals that the information on kinase activation encoded in phosphoproteomics data correlates remarkably well with the phenotypic responses of cancer cells to compounds that target kinase signaling and could be useful for the identification of novel markers of resistance or sensitivity to drugs that target the signaling network.

Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis

Srikanth Nagalla — 2013-04-29T00:00:00Z

Background: Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified. Results: To investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically-annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting: B-cells and/or plasma cells;, T-cells and natural killer cells,;and monocytes and dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high-tertile immune metagene expression equated with reduced risk of metastasis while tumors with low-tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes. Conclusions: These findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.

Sixty years of genome biology

W Doolittle — 2013-04-25T00:00:00Z

Sixty years after Watson and Crick published the double helix model of DNA's structure, thirteen members of Genome Biology's Editorial Board select key advances in the field of genome biology subsequent to that discovery.