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PUBLIC RELEASE DATE:
27-Aug-2014

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Contact: Dan Krotz
dakrotz@lbl.gov
510-486-4019
DOE/Lawrence Berkeley National Laboratory
@BerkeleyLab

Encyclopedia of how genomes function gets much bigger

Berkeley Lab scientists contribute to NIH-funded analyses of human, worm, fly genomes

A big step in understanding the mysteries of the human genome was unveiled today in the form of three analyses that provide the most detailed comparison yet of how the genomes of the fruit fly, roundworm, and human function.

The research, appearing August 28 in in the journal Nature, compares how the information encoded in the three species' genomes is "read out," and how their DNA and proteins are organized into chromosomes.

The results add billions of entries to a publicly available archive of functional genomic data. Scientists can use this resource to discover common features that apply to all organisms. These fundamental principles will likely offer insights into how the information in the human genome regulates development, and how it is responsible for diseases.

The analyses were conducted by two consortia of scientists that include researchers from the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab). Both efforts were funded by the National Institutes of Health's National Human Genome Research Institute.

One of the consortiums, the "model organism Encyclopedia of DNA Elements" (modENCODE) project, catalogued the functional genomic elements in the fruit fly and roundworm. Susan Celniker and Gary Karpen of Berkeley Lab's Life Sciences Division led two fruit fly research groups in this consortium. Ben Brown, also with the Life Sciences Division, participated in another consortium, ENCODE, to identify the functional elements in the human genome.

The consortia are addressing one of the big questions in biology today: now that the human genome and many other genomes have been sequenced, how does the information encoded in an organism's genome make an organism what it is? To find out, scientists have for the past several years studied the genomes of model organisms such as the fruit fly and roundworm, which are smaller than our genome, yet have many genes and biological pathways in common with humans. This research has led to a better understanding of human gene function, development, and disease.

Comparing transcriptomes

In all organisms, the information encoded in genomes is transcribed into RNA molecules that are either translated into proteins, or utilized to perform functions in the cell. The collection of RNA molecules expressed in a cell is known as its transcriptome, which can be thought of as the "read out" of the genome.

In the research announced today, dozens of scientists from several institutions looked for similarities and differences in the transcriptomes of human, roundworm, and fruit fly. They used deep sequencing technology and bioinformatics to generate large amounts of matched RNA-sequencing data for the three species. This involved 575 experiments that produced more than 67 billion sequence reads.

A team led by Celniker, with help from Brown and scientists from several other labs, conducted the fruit fly portion of this research. They mapped the organism's transcriptome at 30 time points of its development. They also explored how environmental perturbations such as heavy metals, herbicides, caffeine, alcohol and temperature affect the fly's transcriptome. The result is the finest time-resolution analysis of the fly genome's "read out" to date—and a mountain of new data.

"We went from two billion reads in research we published in 2011, to 20 billion reads today," says Celniker. "As a result, we found that the transcriptome is much more extensive and complex than previously thought. It has more long non-coding RNAs and more promoters."

When the scientists compared transcriptome data from all three species, they discovered 16 gene-expression modules corresponding to processes such as transcription and cell division that are conserved in the three animals. They also found a similar pattern of gene expression at an early stage of embryonic development in all three organisms.

This work is described in a Nature article entitled "Comparative Analysis of the Transcriptome across Distant Species."

Comparing chromatin

Another group, also consisting of dozens of scientists from several institutions, analyzed chromatin, which is the combination of DNA and proteins that organize an organism's genome into chromosomes. Chromatin influences nearly every aspect of genome function.

Karpen led the fruit fly portion of this work, with Harvard Medical School's Peter Park contributing on the bioinformatics side, and scientists from several other labs also participating. The team mapped the distribution of chromatin proteins in the fruit fly genome. They also learned how chemical modifications to chromatin proteins impact genome functions.

Their results were compared with results from human and roundworm chromatin research. In all, the group generated 800 new chromatin datasets from different cell lines and developmental stages of the three species, bringing the total number of datasets to more than 1400. These datasets are presented in a Nature article entitled "Comparative Analysis of Metazoan Chromatin Organization."

Here again, the scientists found many conserved chromatin features among the three organisms. They also found significant differences, such as in the composition and locations of repressive chromatin.

But perhaps the biggest scientific dividend is the data itself.

"We found many insights that need follow-up," says Karpen. "And we've also greatly increased the amount of data that others can access. These datasets and analyses will provide a rich resource for comparative and species-specific investigations of how genomes, including the human genome, function."

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Lawrence Berkeley National Laboratory addresses the world's most urgent scientific challenges by advancing sustainable energy, protecting human health, creating new materials, and revealing the origin and fate of the universe. Founded in 1931, Berkeley Lab's scientific expertise has been recognized with 13 Nobel prizes. The University of California manages Berkeley Lab for the U.S. Department of Energy's Office of Science. For more, visit http://www.lbl.gov.

Berkeley Lab is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.



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