Saturday, June 2, 2012
DNA EVIDENCE
Friday, March 2, 2012
Neuron Cell Stickiness May Hold Key to Evolution of the Human Brain
BERKELEY, CA — The stickiness of human neurons may have been a key factor in why the human brain evolved beyond the brains of our primate relatives. In a study comparing the genomes of humans, chimpanzees, mice and other vertebrates, researchers at the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) and Joint Genome Institute (JGI) found a strikingly high degree of genetic differences in DNA sequences that appear to regulate genes involved in nerve cell adhesion molecules. Cell adhesion controls many aspects of brain development including growth and structure, and enables neurons to connect with other neurons and supportive proteins. Differences in the molecular connections of human neurons compared to the neurons of chimps, mice and other animals, could help explain why the human brain is capable of far more complex cognitive functions.
In a paper published in the Nov 3, 2006 issue of the journal Science, a team of researchers led by Edward Rubin, MD, director of both JGI and Berkeley Lab’s Genomics Division, report on a comparative genomics study of conserved noncoding sequences (CNSs) - sequences of DNA shared by many different organisms that do not code for proteins but play an important role in regulating gene expression. In their Science paper, the researchers identified 992 CNSs whose sequences were specifically modified in humans and enriched near genes involved in neuronal cell adhesion. This is the first genome-wide unbiased study to detect clear evidence of human-specific evolution in brain-related sequences. After further comparisons, the researchers concluded these CNSs “may have contributed to the uniquely human features of brain development and function.”
The paper is entitled Accelerated evolution of conserved noncoding sequences in the human genome. Co-authoring the paper with Rubin were Shyam Prabhakar and James Noonan of Berkeley Lab, and Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Germany.
“One of the big questions in genetics is what are the DNA sequences in the human genome responsible for the capabilities that distinguish us from the rest of the animal kingdom,” said Rubin. “We have long suspected that it would be a combination of DNA sequences coding for genes and DNA sequences that control when genes are switched on or off. In this study by comparing the entire genome of many organisms to that of humans we were able to identify a series of human-specific sequence changes that have a high likelihood of turning genes on and off.”
Homo sapiens share more than 98 percent of their genome with their chimpanzee cousins, but the final products of those genomes are quite dissimilar. Nowhere are these differences more pronounced than in the brain, where the human model is far larger and more complex than those of all other primates. Previous unbiased whole-genome studies that focused on genes have failed to find a broad pattern of human-specific evolution in brain genes. This led the Berkeley Lab researchers to suspect that the genetic basis of human-specific brain evolution might be found in the sequences that regulate genes, rather than the genes themselves.
Rubin is a leading authority on CNSs who has advanced the principle that if evolution has conserved a specific non-coding DNA sequence over many millions of years, the sequence is likely to function as a switch turning genes on or off. In this latest study, he and his Science co-authors investigated whether CNSs also bear the signature of accelerated evolution.
Explained Prabhakar, who devised the statistical methods and performed most of the computational analysis for this study, “We started with a set of 110,549 CNSs previously identified by whole-genome multiple sequence comparisons and known to have evolved over at least the last 100 million years. We measured the average rate of evolution in the human lineage in these sequences and then identified
992 elements with a significant excess of human-specific nucleotide substitutions relative to the baseline. This is about 79-percent more than we would expect to see by chance at our assigned probability threshold.”
When Prabhakar and Noonan ran an analysis to determine whether the accelerated CNSs disproportionately occurred near genes with particular functions, they discovered that neuronal cell adhesion was the only biological process displaying a significant excess of accelerated CNSs. To determine whether this pattern of accelerated CNSs was repeated in other animals, the researchers performed similar analyses on the chimpanzee and mouse genomes. They examined 1,050 accelerated chimpanzee CNSs and 4,707 accelerated mouse CNSs.
Said Noonan, “While the accelerated chimpanzee CNSs were also significantly enriched near neuronal cell adhesion genes, there was no overlap between them and human DNA sequences, which suggests that the accelerated evolution of adhesion cell function occurred independently in humans and chimpanzees. We failed to detect any CNS enrichment near cell adhesion genes in mice.”
The actual differences in the distribution of neuronal adhesion proteins in human versus chimpanzee brains are currently not known, but the Berkeley Lab-JGI researchers are now conducting experiments to determine the functional consequences of the accelerated CNSs they've identified.
Said Prabhakar, “On the computational side, we’re trying to identify other kinds of sequence changes that may have played a role in human evolution, such as nucleotide insertions, deletions or duplications, and chromosomal rearrangements.”
Added Rubin, “In hindsight the results of our study make sense since our cognitive abilities are clearly one of the most distinct of all human attributes and we would expect these abilities to result from human-specific aspects of neuronal development. Our results also suggest that analysis of the differences in human and chimpanzee neuronal cell adhesion gene expression is a good place to begin exploring the molecular basis of how humans became so cognitively advanced in the 5 to 6 million years since we shared a common ancestor with chimps.”
This research was supported by grants from the U.S. Department of Energy, the National Heart, Lung and Blood Institute and the National Institute of General Medical Sciences.
In a paper published in the Nov 3, 2006 issue of the journal Science, a team of researchers led by Edward Rubin, MD, director of both JGI and Berkeley Lab’s Genomics Division, report on a comparative genomics study of conserved noncoding sequences (CNSs) - sequences of DNA shared by many different organisms that do not code for proteins but play an important role in regulating gene expression. In their Science paper, the researchers identified 992 CNSs whose sequences were specifically modified in humans and enriched near genes involved in neuronal cell adhesion. This is the first genome-wide unbiased study to detect clear evidence of human-specific evolution in brain-related sequences. After further comparisons, the researchers concluded these CNSs “may have contributed to the uniquely human features of brain development and function.”
The paper is entitled Accelerated evolution of conserved noncoding sequences in the human genome. Co-authoring the paper with Rubin were Shyam Prabhakar and James Noonan of Berkeley Lab, and Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Germany.
“One of the big questions in genetics is what are the DNA sequences in the human genome responsible for the capabilities that distinguish us from the rest of the animal kingdom,” said Rubin. “We have long suspected that it would be a combination of DNA sequences coding for genes and DNA sequences that control when genes are switched on or off. In this study by comparing the entire genome of many organisms to that of humans we were able to identify a series of human-specific sequence changes that have a high likelihood of turning genes on and off.”
Homo sapiens share more than 98 percent of their genome with their chimpanzee cousins, but the final products of those genomes are quite dissimilar. Nowhere are these differences more pronounced than in the brain, where the human model is far larger and more complex than those of all other primates. Previous unbiased whole-genome studies that focused on genes have failed to find a broad pattern of human-specific evolution in brain genes. This led the Berkeley Lab researchers to suspect that the genetic basis of human-specific brain evolution might be found in the sequences that regulate genes, rather than the genes themselves.
Rubin is a leading authority on CNSs who has advanced the principle that if evolution has conserved a specific non-coding DNA sequence over many millions of years, the sequence is likely to function as a switch turning genes on or off. In this latest study, he and his Science co-authors investigated whether CNSs also bear the signature of accelerated evolution.
Explained Prabhakar, who devised the statistical methods and performed most of the computational analysis for this study, “We started with a set of 110,549 CNSs previously identified by whole-genome multiple sequence comparisons and known to have evolved over at least the last 100 million years. We measured the average rate of evolution in the human lineage in these sequences and then identified
992 elements with a significant excess of human-specific nucleotide substitutions relative to the baseline. This is about 79-percent more than we would expect to see by chance at our assigned probability threshold.”
When Prabhakar and Noonan ran an analysis to determine whether the accelerated CNSs disproportionately occurred near genes with particular functions, they discovered that neuronal cell adhesion was the only biological process displaying a significant excess of accelerated CNSs. To determine whether this pattern of accelerated CNSs was repeated in other animals, the researchers performed similar analyses on the chimpanzee and mouse genomes. They examined 1,050 accelerated chimpanzee CNSs and 4,707 accelerated mouse CNSs.
Said Noonan, “While the accelerated chimpanzee CNSs were also significantly enriched near neuronal cell adhesion genes, there was no overlap between them and human DNA sequences, which suggests that the accelerated evolution of adhesion cell function occurred independently in humans and chimpanzees. We failed to detect any CNS enrichment near cell adhesion genes in mice.”
The actual differences in the distribution of neuronal adhesion proteins in human versus chimpanzee brains are currently not known, but the Berkeley Lab-JGI researchers are now conducting experiments to determine the functional consequences of the accelerated CNSs they've identified.
Said Prabhakar, “On the computational side, we’re trying to identify other kinds of sequence changes that may have played a role in human evolution, such as nucleotide insertions, deletions or duplications, and chromosomal rearrangements.”
Added Rubin, “In hindsight the results of our study make sense since our cognitive abilities are clearly one of the most distinct of all human attributes and we would expect these abilities to result from human-specific aspects of neuronal development. Our results also suggest that analysis of the differences in human and chimpanzee neuronal cell adhesion gene expression is a good place to begin exploring the molecular basis of how humans became so cognitively advanced in the 5 to 6 million years since we shared a common ancestor with chimps.”
This research was supported by grants from the U.S. Department of Energy, the National Heart, Lung and Blood Institute and the National Institute of General Medical Sciences.
Joint Genome Institute to sequence key African frog genome
WALNUT CREEK, CA -- In their continuing search for new clues to how human genes function and how vertebrates develop and evolve, researchers at the U.S. Department of Energy's Joint Genome Institute (JGI) are gearing up to map the DNA of a diminutive, fast-growing African frog named Xenopus tropicalis.
Frogs have long been a favorite subject for biologists because their growth from eggs to tadpoles to mature organisms sheds light on the processes that guide the development of cells and organs. X. tropicalis was chosen for sequencing because its genetic structure is similar to humans but smaller and easier to decode than that of other frog species.
"Frogs and other amphibians occupy a key evolutionary position between mammals and fish, the organisms whose genomes have been or are currently being sequenced," said Paul Richardson, the JGI project manager. "The publicly available Xenopus genome sequence will be a scientifically valuable resource for the research community."
"Until now, experiments with frogs have shown us how vertebrates develop from an egg to an organism," said Richard Harland, a developmental biologist at the University of California, Berkeley, and an early advocate of the project. "But we're looking forward to new possibilities from the genome sequence.
"Using a compare-and-contrast approach with the human sequence, and the experiments that are possible in frogs, we'll definitely make real progress in decoding the human genome," Harland said.
Added Robert Grainger, a leading Xenopus researcher from the University of Virginia: "Studies on frogs have long been instrumental in understanding such fundamental processes as cell division and how cells in the embryo communicate with one another. Because these are the processes that go awry when birth defects occur or cancer strikes, we must seek a better understanding of them. This genome project will provide a major step in that direction."
The JGI, one of the largest public genome sequencing centers in the world, is operated jointly by three DOE national laboratories managed by the University of California: Lawrence Berkeley and Lawrence Livermore in California, and Los Alamos in New Mexico. In addition to the Xenopus project, the JGI has genomics programs focused on microbes, fungi, fish, and plants.
The Institute brings together the research capabilities of the national labs and helps to convene multi-national teams that undertake large-scale genomic projects. This collaborative approach was used recently to sequence the genome of the pufferfish Fugu rubripes . Researchers reported last month that by comparing the Fugu sequence with the results of the Human Genome Project, they were able to predict the presence of nearly 1,000 previously unidentified human genes.
For the Xenopus project, the JGI convened an advisory board to organize and disseminate information about the sequencing effort. Members include researchers from the National Institutes of Health (NIH), UC Berkeley, UC Irvine, the University of Virginia, the Institute for Systems Biology in Seattle, Children's Hospital in Cincinnati, and the University of Calgary in Canada, as well as from the United Kingdom and Japan. Steven L. Klein, chair of a Xenopus working group at NIH's National Institute of Child Health and Human Development, noted that his agency will provide additional resources to NIH-sponsored labs to add data for this collaborative genome project.
JGI is a leader in sequencing organisms of crucial interest to researchers around the world. For the Human Genome Project, JGI sequenced human chromosomes 5, 16, and 19, which together constitute 11 percent of the human genome. JGI sequenced mouse DNA related to human chromosome 19 to illuminate the molecular evolutionary history of the two species. JGI has also sequenced the environmentally important white rot fungus (Phanerochaete chrysosporium) and nearly 50 important microorganisms.
With its main headquarters and Production Genomics Facility in Walnut Creek, JGI employs about 240 people and has programs in genomic sequencing, computation, functional genomics, genomic diversity, and new technology development. Funding is provided predominantly by the Department of Energy's Office of Science, Office of Biological and Environmental Research. Other agencies that have contributed to funding JGI include DOE's National Nuclear Security Administration, NIH, the National Science Foundation, and the U.S. Department of Agriculture.
Frogs have long been a favorite subject for biologists because their growth from eggs to tadpoles to mature organisms sheds light on the processes that guide the development of cells and organs. X. tropicalis was chosen for sequencing because its genetic structure is similar to humans but smaller and easier to decode than that of other frog species.
"Frogs and other amphibians occupy a key evolutionary position between mammals and fish, the organisms whose genomes have been or are currently being sequenced," said Paul Richardson, the JGI project manager. "The publicly available Xenopus genome sequence will be a scientifically valuable resource for the research community."
"Until now, experiments with frogs have shown us how vertebrates develop from an egg to an organism," said Richard Harland, a developmental biologist at the University of California, Berkeley, and an early advocate of the project. "But we're looking forward to new possibilities from the genome sequence.
"Using a compare-and-contrast approach with the human sequence, and the experiments that are possible in frogs, we'll definitely make real progress in decoding the human genome," Harland said.
Added Robert Grainger, a leading Xenopus researcher from the University of Virginia: "Studies on frogs have long been instrumental in understanding such fundamental processes as cell division and how cells in the embryo communicate with one another. Because these are the processes that go awry when birth defects occur or cancer strikes, we must seek a better understanding of them. This genome project will provide a major step in that direction."
The JGI, one of the largest public genome sequencing centers in the world, is operated jointly by three DOE national laboratories managed by the University of California: Lawrence Berkeley and Lawrence Livermore in California, and Los Alamos in New Mexico. In addition to the Xenopus project, the JGI has genomics programs focused on microbes, fungi, fish, and plants.
The Institute brings together the research capabilities of the national labs and helps to convene multi-national teams that undertake large-scale genomic projects. This collaborative approach was used recently to sequence the genome of the pufferfish Fugu rubripes . Researchers reported last month that by comparing the Fugu sequence with the results of the Human Genome Project, they were able to predict the presence of nearly 1,000 previously unidentified human genes.
For the Xenopus project, the JGI convened an advisory board to organize and disseminate information about the sequencing effort. Members include researchers from the National Institutes of Health (NIH), UC Berkeley, UC Irvine, the University of Virginia, the Institute for Systems Biology in Seattle, Children's Hospital in Cincinnati, and the University of Calgary in Canada, as well as from the United Kingdom and Japan. Steven L. Klein, chair of a Xenopus working group at NIH's National Institute of Child Health and Human Development, noted that his agency will provide additional resources to NIH-sponsored labs to add data for this collaborative genome project.
JGI is a leader in sequencing organisms of crucial interest to researchers around the world. For the Human Genome Project, JGI sequenced human chromosomes 5, 16, and 19, which together constitute 11 percent of the human genome. JGI sequenced mouse DNA related to human chromosome 19 to illuminate the molecular evolutionary history of the two species. JGI has also sequenced the environmentally important white rot fungus (Phanerochaete chrysosporium) and nearly 50 important microorganisms.
With its main headquarters and Production Genomics Facility in Walnut Creek, JGI employs about 240 people and has programs in genomic sequencing, computation, functional genomics, genomic diversity, and new technology development. Funding is provided predominantly by the Department of Energy's Office of Science, Office of Biological and Environmental Research. Other agencies that have contributed to funding JGI include DOE's National Nuclear Security Administration, NIH, the National Science Foundation, and the U.S. Department of Agriculture.
A FIRST LINE OF DEFENSE AGAINST DISEASE ORGANISMS
WALNUT CREEK, CA -- The Department of Energy's Joint Genome Institute (JGI), whose Production Genomics Facility in Walnut Creek is one of the fastest and most powerful in the U.S., has been enlisted to help safeguard public safety by determining the whole genome sequences of a variety of infectious bacteria -- a first step toward developing tests that can be used to rapidly identify their presence in the environment.
While the anthrax strains used in recent bioterrorist attacks could be identified, there are no field tests for dozens of other potentially dangerous microbes. To develop new tests and improve existing ones, knowing the whole genomic sequence of each organism and its close relatives can be vitally important.
JGI is ideally suited to this effort because of its capacity and depth of experience in sequencing microorganisms. In a little over three years JGI has sequenced scores of microbes; last year it sequenced 15 bacteria in a single month and today is capable of sequencing an average microbe's genome twice over in a single day.
Starting May 7, 2002, JGI's Production Genomics Facility (PGF) will determine draft genome sequences of several bacteria already under study at Lawrence Livermore and Los Alamos National Laboratories. JGI was founded in 1997 by these two laboratories and Lawrence Berkeley National Laboratory; all three laboratories are managed for the Department of Energy by the University of California.
The first pathogens to be sequenced under the current program are members of the Bacillus, Brucella, Clostridium, Francisella, Shigella, and Yersinia groups. In many of these groups, several strains or related species will be sequenced, for example, two strains of Bacillus anthracis (anthrax) and one of the similar species Bacillus thuringiensis.
Depending on how quickly the organisms become available, JGI plans to sequence the whole genomes of many more potentially hazardous bacteria and a number of their less harmful relatives.
Sequencing at JGI will not involve actual pathogens. Whole organisms will be received and handled at laboratories equipped with appropriate containment facilities, like those in place at Livermore and Los Alamos, where the DNA of each pathogen will be reduced to fragments to be sent in a disassembled state to JGI's Production Genomics Facility.
The genome of a typical bacterium is a circular piece of DNA containing approximately two to five million "base pairs" -- pairs of the chemical bases, integral to the DNA molecule, that form the letters of the genetic code. Genomes from millions of individual bacteria are fragmented to create a library of random pieces each about two to three thousand base pairs long. Each fragment represents only about 0.0005 percent of the complete genome.
Because intact genomes are not involved, the Centers for Disease Control and Prevention have registered the PGF to receive this fragmentary DNA with no change in standard procedures. The PGF will work with multiple copies of each fragment. Automated equipment determines the exact sequence of bases on each strand. The data is then assembled by a computer program to reconstruct the order of the bases in the whole genome.
The completed sequence exists only as a string of letters in a computer's output. No physical genomes will be handled at JGI, and the standard laboratory strain of E. coli in which individual DNA fragments are reproduced will be disposed of after sterilization, according to the standard operating procedures of the PGF. Draft sequences will be shared with Los Alamos and Lawrence Livermore laboratories for finishing and annotation.
JGI has been a leader in sequencing organisms of crucial interest to researchers around the world. For the Human Genome Project, JGI sequenced human chromosomes 5, 16, and 19, which together constitute some 11 percent of the human genome. JGI sequenced mouse DNA related to human chromosome 19 to illuminate the molecular evolutionary history of the two species. Working with an international consortium of universities and industry, JGI participated in the sequencing of the gene-rich puffer fish (Fugu rubripes). The 165 million base-pair genome of the sea squirt (Ciona intestinalis) was sequenced jointly by JGI, Japan's National Institute of Genetics, and Kyoto University. JGI has also sequenced the environmentally important white rot fungus (Phanerochaete chrysosporium) and over 50 important microorganisms.
The Joint Genome Institute is one of the largest publicly funded human genome sequencing institutions in the world. With its main headquarters and Production Genomics Facility in Walnut Creek, JGI employs about 240 people and has programs in genomic sequencing, computation, functional genomics, genomic diversity, and new technology development. Funding is provided predominantly by the Department of Energy's Office of Science; other agencies that have contributed to funding JGI include DOE's National Nuclear Security Administration, the National Institutes of Health, the National Science Foundation, and the U.S. Department of Agriculture.
While the anthrax strains used in recent bioterrorist attacks could be identified, there are no field tests for dozens of other potentially dangerous microbes. To develop new tests and improve existing ones, knowing the whole genomic sequence of each organism and its close relatives can be vitally important.
JGI is ideally suited to this effort because of its capacity and depth of experience in sequencing microorganisms. In a little over three years JGI has sequenced scores of microbes; last year it sequenced 15 bacteria in a single month and today is capable of sequencing an average microbe's genome twice over in a single day.
Starting May 7, 2002, JGI's Production Genomics Facility (PGF) will determine draft genome sequences of several bacteria already under study at Lawrence Livermore and Los Alamos National Laboratories. JGI was founded in 1997 by these two laboratories and Lawrence Berkeley National Laboratory; all three laboratories are managed for the Department of Energy by the University of California.
The first pathogens to be sequenced under the current program are members of the Bacillus, Brucella, Clostridium, Francisella, Shigella, and Yersinia groups. In many of these groups, several strains or related species will be sequenced, for example, two strains of Bacillus anthracis (anthrax) and one of the similar species Bacillus thuringiensis.
Depending on how quickly the organisms become available, JGI plans to sequence the whole genomes of many more potentially hazardous bacteria and a number of their less harmful relatives.
Sequencing at JGI will not involve actual pathogens. Whole organisms will be received and handled at laboratories equipped with appropriate containment facilities, like those in place at Livermore and Los Alamos, where the DNA of each pathogen will be reduced to fragments to be sent in a disassembled state to JGI's Production Genomics Facility.
The genome of a typical bacterium is a circular piece of DNA containing approximately two to five million "base pairs" -- pairs of the chemical bases, integral to the DNA molecule, that form the letters of the genetic code. Genomes from millions of individual bacteria are fragmented to create a library of random pieces each about two to three thousand base pairs long. Each fragment represents only about 0.0005 percent of the complete genome.
Because intact genomes are not involved, the Centers for Disease Control and Prevention have registered the PGF to receive this fragmentary DNA with no change in standard procedures. The PGF will work with multiple copies of each fragment. Automated equipment determines the exact sequence of bases on each strand. The data is then assembled by a computer program to reconstruct the order of the bases in the whole genome.
The completed sequence exists only as a string of letters in a computer's output. No physical genomes will be handled at JGI, and the standard laboratory strain of E. coli in which individual DNA fragments are reproduced will be disposed of after sterilization, according to the standard operating procedures of the PGF. Draft sequences will be shared with Los Alamos and Lawrence Livermore laboratories for finishing and annotation.
JGI has been a leader in sequencing organisms of crucial interest to researchers around the world. For the Human Genome Project, JGI sequenced human chromosomes 5, 16, and 19, which together constitute some 11 percent of the human genome. JGI sequenced mouse DNA related to human chromosome 19 to illuminate the molecular evolutionary history of the two species. Working with an international consortium of universities and industry, JGI participated in the sequencing of the gene-rich puffer fish (Fugu rubripes). The 165 million base-pair genome of the sea squirt (Ciona intestinalis) was sequenced jointly by JGI, Japan's National Institute of Genetics, and Kyoto University. JGI has also sequenced the environmentally important white rot fungus (Phanerochaete chrysosporium) and over 50 important microorganisms.
The Joint Genome Institute is one of the largest publicly funded human genome sequencing institutions in the world. With its main headquarters and Production Genomics Facility in Walnut Creek, JGI employs about 240 people and has programs in genomic sequencing, computation, functional genomics, genomic diversity, and new technology development. Funding is provided predominantly by the Department of Energy's Office of Science; other agencies that have contributed to funding JGI include DOE's National Nuclear Security Administration, the National Institutes of Health, the National Science Foundation, and the U.S. Department of Agriculture.
Subscribe to:
Posts (Atom)