Contrary to predictions, males of high genetic quality are not very successful when it comes to fertilizing eggs.

SOURCE

Contrary to predictions, males of high genetic quality are not very successful when it comes to fertilizing eggs. A new study on seed beetles by Swedish and Danish scientists Göran Arnqvist and Trine Bilde shows that when a female mates with several males, the males of low genetic quality are the most successful in fertilizing eggs. The study is published in this week's issue of Science.

In almost all animals, females mate with several different males, despite the fact that a single mating is often sufficient to fertilize her eggs. Multiple mating also carries costs to females, such as the risk of catching sexually transmitted diseases.
One commonly held belief is that this behaviour may allow females to choose the sperm of the male with highest genetic quality to fertilize her eggs. Professor Göran Arnqvist from the Department of Ecology and Evolution, Uppsala University and associate professor Trine Bilde from the Department of Biological Sciences, University of Aarhus, have tested this possibility directly for the first time and shown that it is not true.
Their study on seed beetles shows that, contrary to predictions, males of low genetic quality are more successful in fertilizing eggs. Males who gained the highest share of paternity were actually males with low genetic quality. These males also fathered offspring that did less well.
"The results support the suggestion that genes that are good for males may often be bad for their mates. Therefore, in beetles at least, multiple mating does not award females with genetic benefits," says Göran Arnqvist.
Source: Uppsala University (news : web)

Geography And History Shape Genetic Differences In Humans

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ScienceDaily (June 5, 2009) — New research indicates that natural selection may shape the human genome much more slowly than previously thought. Other factors -- the movements of humans within and among continents, the expansions and contractions of populations, and the vagaries of genetic chance – have heavily influenced the distribution of genetic variations in populations around the world.

The study, conducted by a team from the Howard Hughes Medical Institute, the University of Chicago, the University of California and Stanford University, is published June 5 in the open-access journal PLoS Genetics.
In recent years, geneticists have identified a handful of genes that have helped human populations adapt to new environments within just a few thousand years—a strikingly short timescale in evolutionary terms. However, the team found that for most genes, it can take at least 50,000-100,000 years for natural selection to spread favorable traits through a human population. According to their analysis, gene variants tend to be distributed throughout the world in patterns that reflect ancient population movements and other aspects of population history.
"We don't think that selection has been strong enough to completely fine-tune the adaptation of individual human populations to their local environments," says co-author Jonathan Pritchard. "In addition to selection, demographic history -- how populations have moved around -- has exerted a strong effect on the distribution of variants."
To determine whether the frequency of a particular variant resulted from natural selection, Pritchard and his colleagues compared the distribution of variants in parts of the genome that affect the structure and regulation of proteins to the distribution of variants in parts of the genome that do not affect proteins. Since these neutral parts of the genome are less likely to be affected by natural selection, they reasoned that studying variants in these regions should reflect the demographic history of populations.
The researchers found that many previously identified genetic signals of selection may have been created by historical and demographic factors rather than by selection. When the team compared closely related populations they found few large genetic differences. If the individual populations' environments were exerting strong selective pressure, such differences should have been apparent.
Selection may still be occurring in many regions of the genome, says Pritchard. But if so, it is exerting a moderate effect on many genes that together influence a biological characteristic. "We don't know enough yet about the genetics of most human traits to be able to pick out all of the relevant variation," says Pritchard. "As functional studies go forward, people will start figuring out the phenotypes that are associated with selective signals," says lead author Graham Coop. "That will be very important, because then we can figure out what selection pressures underlie these episodes of natural selection."
But even with further research, much will remain unknown about the processes that have resulted in human traits. In particular, Pritchard and Coop urge great caution in trying to link selection with complex characteristics like intelligence. "We're in the infancy of trying to understand what signals of selection are telling us," says Coop, "so it's a very long jump to attribute cultural features and group characteristics to selection."
Journal reference:
Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, et al. The Role of Geography in Human Adaptation. PLoS Genetics, 2009; 5 (6): e1000500 DOI: 10.1371/journal.pgen.1000500
Adapted from materials provided by Public Library of Science, via EurekAlert!, a service of AAAS.

Chemists see first building blocks to life on Earth

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British scientists said on Wednesday that they had figured out key steps in the process by which life on Earth may have emerged from a seething soup of simple chemicals.

Genetic information in living organisms today is held in deoxyribonucleic acid (DNA), the famous "double helix" molecule of sugar, phosphate and a base.
But DNA is too sophisticated to have popped up in an instant, and one avenue of thought says its single-stranded cousin, ribonucleic acid, or RNA, came first.
RNA plays a key role in making proteins and, in viruses, is used to store genetic code.
It is chemically similar to DNA but is simpler and tougher in structure, and thus looks like a good candidate for Earth's first information-coding nucleic acid.
But for all its allure, the "RNA first" theory has run into practical problems.
Its three ingredients -- the base, ribose sugar and phosphate -- must have formed separately and then combined to form the molecule, according to conventional thinking.
Critics, though, say that RNA, while somewhat simpler than DNA, is still a complex molecule and could not have been assembled spontaneously.
These doubters have been comforted by the failure to find any feasible chain of chemical events to explain how the three components all came together.
But a paper published in the British journal Nature by University of Manchester chemists puts forward a different explanation.
The team, led by Professor John Sutherland, venture that an RNA-like synthesis took place through a series of chemical reactions and an important intermediate substance.
Their lab model uses starting materials and environmental conditions that are believed to have been around in early Earth and are also used in the standard "RNA first" scenario.
Their theory starts with a simple sugar called glycolaldehyde, which reacts with cyanmide (a compound of cyanide and ammonia) and phosphate to produce an intermediate compound called 2-aminooxazole.
Gentle warming from the Sun and cooling at night help purify the 2-aminooxazole, turning it into a plentiful precursor which contributes the sugar and base portions of the new ribonucleotide molecule.
The presence of phosphate and ultraviolet light from the Sun complete the synthesis.
In a commentary also published by Nature, US molecular biologist Jack Szostak hailed the research as an elegant explanation as to why the sugar and base would not have to form separately before forming the new molecule.
"It will stand for years as one of the great advances in prebiotic chemistry," the term for the study of the chemical processes that led to life on Earth, he enthused.
Opinions vary as to when the first organisms appeared on Earth.
One estimate, based on fossilised mats of bacteria found in Australia, is that this happened around 3.8 billion years ago, around 700 million years after the planet was formed.
(c) 2009 AFP

Biotechnology: Engineered Moss Can Produce Human Proteins

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ScienceDaily (May 11, 2009) — ETH Zurich researchers have shown that mosses and humans share unexpected common characteristics. These evolutionary relics could be useful in the production of therapeutic proteins.

At first glance, mosses and human beings have little in common. The moss Physcomitrella patens is small, pale green, immobile, and uses sunlight as its energy source. Humans are large, mobile, and need to obtain energy by eating vegetable or animal foods.
Transferring mammalian genes into moss
This made the result of the experiments carried out by researchers in the group led by Martin Fussenegger, Professor of Chemical and Bioengineering at ETH Zurich, all the more astonishing. In collaboration with researchers at the University of Freiburg im Breisgau, the PhD student Marc Gitzinger carried out tests to see what happens when unmodified human or mammalian genes are inserted into the moss genome. They transferred the foreign, unmodified genes into the moss and discovered that the moss was easily able to manufacture the proteins encoded therein.
This cannot be taken for granted, since the same process does not work when a mammalian gene is implanted into what are known as “higher” flowering plants. The reason is that sections of the start and finish sequences of the genes of animals, plants, fungi and bacteria are considerably different. They are responsible for ensuring that a gene in the organism is recognized as such, and the proteins encoded by it are produced in the correct amount and are released from the cell. The more remote the relationship between living organisms, the greater the difference between these sequences. This is why biotechnologists must normally adapt them to a foreign organism before transplanting a gene into it. The researchers were astonished to find that this was not necessary in the case of the moss.
Moss as a generalist
The explanation given for this by Ralf Reski, Professor of Plant Biotechnology at the University of Freiburg im Breisgau, is that the moss has remained a generalist. It underwent the last major modification about 450 million years ago when it changed from living in water to a life on land, adapting to the new living conditions and then remaining unaltered for millions of years, both in its appearance and at a genetic level.
The process used by the moss to produce its proteins is less sophisticated than in “higher” organisms. In contrast to the moss, these latter organisms underwent major further developments and specializations over the course of 450 million years. On the other hand, the moss clearly retained – for millions of years – the ability to read foreign genes such as those from mammals and thus also from humans, and to translate them into proteins, probably without ever having made any use of this capability during these 450 million years.
A cost-effective alternative to mammalian cells
Today, the moss Physcomitrella patens and its ability to manufacture mammalian proteins could help to satisfy the large worldwide demand for therapeutic proteins. One well-known example is insulin, which enables diabetics to control their blood sugar level.
Nowadays, therapeutic proteins are mainly manufactured in mammalian cells, which are very expensive to culture. They need to be maintained at body temperature with a continuous supply of nutrients and oxygen, and the production process is costly. At present, global production capacity cannot match the demand. Because of the difficulties involved in handling them, production is possible only in industrialized countries.
In contrast, the moss Physcomitrella patens is comparatively undemanding. It needs water, a couple of nutrient salts and some light to allow it to flourish and produce proteins. This makes it convenient and simple to handle in a bioreactor, and, in the future, it might enable even less developed nations to satisfy their requirement for therapeutic proteins. However, further research will be needed before the moss can be used to produce therapeutic proteins on an industrial scale.
Journal reference:
Gitzinger et al. Functional cross-kingdom conservation of mammalian and moss (Physcomitrella patens) transcription, translation and secretion machineries. Plant Biotechnology Journal, 2009; 7 (1): 73 DOI: 10.1111/j.1467-7652.2008.00376.x
Adapted from materials provided by ETH Zurich.

Deep in the Red: Using Infrared to Watch What Goes On in a Living Body

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An infrared version of the Nobel Prize-winning green fluorescent protein could make the technique even more powerful.

Fluorescent proteins, which are compounds that can absorb and then emit light, have become a powerful instrument in the cell biologist's toolkit—so powerful, in fact, that the discovery and development of green fluorescent proteins from jellyfish earned the 2008 Nobel Prize in Chemistry. (Here's a Q&A with one of the winners, Columbia University's Martin Chalfie, about his work.) These proteins have limitations, however: They need to be excited with the blue to orange part of the visible spectrum, at wavelengths of 495 to 570 nanometers. These wavelengths of light are too short to penetrate tissue very well, and so green fluorescent proteins are mainly used in test tube studies to watch cell division or to label certain cell types.
But one of the 2008 Nobelists, Roger Y. Tsien of the University of California, San Diego, and his U.C.S.D. colleagues report in today's issue of Science that they have developed a new fluorescent protein that could enable scientists to tag and visualize cellular activity as it happens inside a live animal. The protein, after absorbing light from the far-red part of the spectrum, shines in the near-infrared, at wavelengths of around 700 nanometers.
These longer wavelengths can penetrate mammalian tissue and even pass through bone. "Say you label a tumor with a green fluorescent protein, and if this labeled tumor is buried inside the animal, then you barely can get green fluorescence out," says lead researcher Xiaokun Shu. "But if you label this deeply buried tumor by infrared fluorescent proteins, you will get a stronger signal because infrared penetrates tissue more efficiently."
Tsien's group derived the infrared fluorescent protein from a hardy bacterium called Deinococcus radiodurans, famous for its ability to survive extreme environments. Bacteria do not actually use this class of proteins, called bacteriophytochromes, to emit light. "They use these bacteriophytochromes to control gene expression,” Shu says—the proteins convert absorbed light into energy to signal certain genes to turn on or off.
The initial challenge for researchers was to re-engineer the protein so that absorbed light would be re-emitted instead of being used as a source of power. They accomplished the feat by deleting the part of the protein that converts the absorbed light into chemical energy; as a result, this truncated and mutant form gave up its absorbed energy as an infrared glow. The scientists incorporated the engineered bacterial protein into mammalian cells—specifically, into the liver of a live mouse, which lit up with infrared light.
The finding paves the way for in vivo visualization of a wide range of biochemical processes and internal organs in animals. (Its use in humans is unlikely, as it would require gene therapy and the ethically dubious transplantation of bacterial genes into humans.)
“This is so important," comments David James, a cell biologist from Australia's Garvan Institute in Sydney, "because a lot of knowledge at the moment is confined to individual cells grown on a glass coverslip," leaving open the question of whether that knowledge "is transferable to an animal." The infrared version could also solve the problem of naturally occuring fluorescence from other biological molecules, which tend to glow at wavelengths similar to conventional fluorescent protein markers and thereby create a lot of “background noise," James says.

But even greater potential lies in harnessing the bacteriophytochrome's original function, namely, powering gene expression. It should be feasible, Tsien thinks, to put back in the signal-controlling properties of the phytochrome. Then it could be possible with animals to “switch on genes and control biochemistry" with light, he says.
For example, you want to explore the effects on mouse behavior of switching on a particular gene that controls some aspect of brain function, but, thankfully for the mouse, you do not want to open up its skull or stick a needle in its brain. "If the infrared fluorescent protein can be made to turn back into an infrared phytochrome, you could have the switch all ready and just waiting for enough infrared light," Tsien speculates. Because infrared light can penetrate the skull, it can reach the phytochrome and remotely switch the gene on, resulting in observable changes in the mouse's behavior.
It's the next evolutionary step for fluorescent proteins, remarks Tsien, who believes that phytochromes represent a class of proteins with enormous potential. If he's correct, then in the coming years, expect more scientists to see the (infrared) light.

By Bianca Nogrady

DNA Sequencing Becomes Much Quicker

Source:

http://www.sciencedaily.com/releases/2007/10/071015093528.htm

Science Daily — A new technique that combines gene chip technology with the latest generation of gene sequencing machines to allow fast and accurate sequencing of selected parts of the genome has been developed by researchers from the Human Genome Sequencing Center at Baylor College of Medicine in Houston and NimbleGen Systems, Inc., a Wisconsin-based company recently purchased by Roche Applied Science.
"This new technology will replace polymerase chain reaction (PCR) for many purposes," said Dr. Richard Gibbs, director of the HGSC and senior author of the report. "If the aim is to sequence a whole genome for everybody, this is a huge step in that direction."
The report, which appears in Nature Methods, describes the use of microarrays to enrich or increase the volume of specific genomic sequences. High throughput DNA sequencing machines made by 454 Life Sciences then determine the exact genetic code of the material.
For example, if scientists were looking for a mutation in a particular cancer-causing gene (such as BRCA1 that is associated with breast and ovarian cancer), they could make a microarray that is complementary to the part of the genome in which one is interested. This takes advantage of the fact that the adenine (A) bases always attach to the thymine (T) and the cytosine (C) always attaches to the guanine (G) in reactions.
"You take the DNA and you hybridize it (allow the DNA to stick to its complement) on the chip," said Dr. George Weinstock, co-director of the HGSC. "Then you wash away everything that doesn't stick. This can enrich the portion of the genome to be studied by factors of three hundred or more."
The new process is simpler, more accurate and efficient than the multiplex PCR that was previously used to sequence portions of the genome. In one experiment, more than 6,400 exons (the part of the genetic code that carries the instructions for making proteins), were analyzed. Using the old technology this would have taken at least six months.
"We hope to be able to use this to sequence all the exons in the genome," Gibbs said.
Resequencing of genes or other genomic regions of interest is a key step in detecting mutations associated with various complex human diseases, such as cancer, asthma and heart disease. The predominant method for selection of specific genomic regions for resequencing has primarily relied on PCR (polymerase chain reaction) to enrich for specific DNA fragments.
However, PCR is limited in the length of sequence it can amplify, is difficult to scale or multiplex for the enrichment of thousands of fragments, and has limited performance in the repetitive regions typical of complex genomes, such as human. The sequence capture microarray technology bridges the gap between next-generation DNA sequencing technology and current sample preparation methods by providing an adaptable, massively parallel method for selective enrichment of genomic regions of interest. Roche NimbleGen's sequence capture technology enables high-performance targeting of thousands of specific genes or loci using a single microarray hybridization-based enrichment process.
The Nature Methods paper published by Baylor demonstrates that the sequence capture process is simpler, more accurate, more efficient and more cost-effective than the multiplex PCR that was previously used to prepare genomic samples for sequencing. In one experiment, more than 6,700 exons (the part of the genetic code that together form genes), were enriched and analyzed, as well as contiguous genomic regions of up to 5 million bases.
The study, entitled "Direct Selection of Human Genomic Loci by Microarray Hybridization," appears online (14 October 2007 ahead of print) in the journal Nature Methods.
The authors are Albert TJ, Molla MN, Muzny DM, Nazareth L, Wheeler D, Song X, Richmond TA, Middle CM, Rodesch MJ, Packard CJ, Weinstock GM, and Gibbs RA. (DOI:10.1038/NMETH1111)
Others who took part in this study include David Wheeler, Donna Muzny and Xingzhi Song of BCM and Thomas J. Albert, Michael N. Molla, Lynne Nazareth, Todd. A. Richmond, Chris M. Middle, Matthew J. Rodesch and Charles J. Packard of NimbleGen.
Funding for this work came from the U.S. National Human Genome Research Institute and the National Cancer Institute.
Note: This story has been adapted from material provided by Baylor College Of Medicine.

Fausto Intilla
www.oloscience.com

Beyond A 'Speed Limit' On Mutations, Species Risk Extinction

Source:

http://www.sciencedaily.com/releases/2007/10/071001172753.htm

Science Daily — Harvard University scientists have identified a virtual "speed limit" on the rate of molecular evolution in organisms, and the magic number appears to be 6 mutations per genome per generation -- a level beyond which species run the strong risk of extinction as their genomes lose stability.
By modeling the stability of proteins required for an organism's survival, Eugene Shakhnovich and his colleagues have discovered this essential thermodynamic limit on a species's rate of evolution. Their discovery, published recently in the Proceedings of the National Academy of Sciences, draws a crucial connection between the physical properties of genetic material and the survival fitness of an entire organism.
"While mathematical genetics research has brought about some remarkable discoveries over the years, these approaches always failed to connect the dots between the reproductive fitness of organisms and the molecular properties of the proteins encoded by their genomes," says Shakhnovich, professor of chemistry and chemical biology in Harvard's Faculty of Arts and Sciences. "We've made an important step toward finally bridging the gap between macroscopic and microscopic biology."
According to Shakhnovich, crucial aspects of an organism's evolutionary fitness can be directly inferred by inspecting its DNA sequences and analyzing how the proteins encoded by those sequences fold. DNA sequences encode the order of amino acids in a protein, and amino acids act as the protein's basic building blocks by arranging themselves into a structure that allows the protein to perform its biological function.
The research was inspired in part by the longstanding recognition that knocking out essential genes, making them inactive, produces a lethal phenotype, or a physiologically unviable organism.
"From there, we made the simple assumption that in order for an organism to be viable, all of its essential genes -- those that support basic cell operations -- have to encode at least minimally stable proteins," says Shakhnovich. "What occurs over the long process of evolution is that random mutations can either encode slightly more or less stable proteins."
If enough mutations push an essential protein towards an unstable, non-functional structure, the organism will die. Shakhnovich's group found that for most organisms, including viruses and bacteria, an organism's rate of genome mutation must stay below 6 mutations per genome per generation to prevent the accumulation of too many potentially lethal changes in genetic material.
The existence of a mutation limit for viruses helps explain how the immune system can perform its function. Because viral replication and survival can only occur at a limited rate, the body has a window of time to develop antibodies against infectious agents. Furthermore, if the mutation rate is high, the size of the genome in question must be small to stay within the bounds of the speed limit -- thus organisms that tend to mutate quickly are those with concise genomes, such as viruses and bacteria.
The Shakhnovich speed limit also offers an explanation for observed differences in genome sizes between organisms with genome error correction -- such as bacteria, mammals, birds, and reptiles -- and those without, such as RNA viruses: In more complex organisms, cells have evolved correction systems to detect and fix errors in DNA replication. These systems drastically reduce the number of mutations per replication, increasing the mutational stability of the genome and allowing more intricate and delicate biological systems to develop without the risk of interruptive mutations.
"It's an interesting corollary because it suggests that there is a fundamental tradeoff between evolutionary security and adaptive flexibility: Larger, more complex organisms have to have error correction to protect organismic viability, but this means the rate of evolution slows down significantly," Shakhnovich says. "As organisms become more complex, they have more to lose and can't be as radically experimental with their genomes as some viruses and bacteria."
Co-authors on the paper are Konstantin B. Zeldovich of the Department of Chemistry and Chemical Biology and Peiqiu Chen of the departments of Physics and of Chemical and Chemical Biology in Harvard's Faculty of Arts and Sciences. Their work is funded by the National Institutes of Health.
Note: This story has been adapted from material provided by Harvard University.

Fausto Intilla
www.oloscience.com

Indian Bug Is The Ancestor Of Crohn's Disease Pathogen

Source:

http://www.sciencedaily.com/releases/2007/10/071002213435.htm

Science Daily — An Indian team of researchers led by Seyed E. Hasnain of the Institute of Life Sciences (ILS), University of Hyderabad, India has found that a seemingly unknown mycobacterial organism Mycobacterium indicus pranii (MIP) could be the earliest ancestor of the 'generalist' branch of mycobacterial pathogens.
The 'generalist' bacteria infect anything from cockroaches to human and are capable of surviving in soil and water as against human adapted 'specialists' such as tubercle and leprosy bacilli. TB, a disease that killed about 1.7 million humans last year alone, is caused by a member of the Mycobacterial family of pathogens.
The finding further suggests that the prominent 'generalist' pathogen M. avium which seriously haunts AIDS patients, together with its close associate M. avium paratuberculosis (MAP), the agent of Crohn's disease in humans and Johne's disease in cattle descended from the MIP. It was also found that the MIP and the MAP bacilli initially inhabited water bodies and infected marine organisms predated by fishes finally arriving on soil through bird-droppings.
The MIP bacilli, also called as Mycobacterium w (Mw) were first isolated in India by G. P. Talwar at the All India Institute of Medical Sciences, New Delhi, in eighties and it is currently used, after an extensive and perhaps the largest clinical trial in the world, as an immunotherapeutic against leprosy in India.
The success with MIP based leprosy vaccine has led to human clinical evaluations of MIP in interventions against HIV-AIDS, psoriasis and bladder cancer in India. MIP, commercially available as 'Immuvac', is currently the focus of advanced multi-centric phase III clinical trials for its antituberculosis efficacy.
The comparative genomics study based on complete sequence of the MIP organism published in PLoS One reports observations based on the first ever whole genome sequencing project from India, carried out jointly by the ILS, the Centre for DNA fingerprinting and Diagnostics also at Hyderabad and the University of Delhi.
The study provides an important evolutionary basis for the acquisition and optimization of virulence in mycobacteria and determinants of boundaries therein. Similarly these efforts constitute a step forward in understanding the role of non-pathogenic and saprophytic mycobacteria in immunomodulation and in triggering innate immune responses. The study advocates exploitation of genetic similarity between MIP and MAP as a plausible advantage for therapeutic intervention against Crohn's and Johne's diseases.
Citation: Ahmed N, Saini V, Raghuvanshi S, Khurana JP, Tyagi AK, et al (2007) Molecular Analysis of a Leprosy Immunotherapeutic Bacillus Provides Insights into Mycobacterium Evolution. PLoS ONE 2(10): e968. doi:10.1371/journal.pone.0000968
Note: This story has been adapted from material provided by Public Library of Science.

Fausto Intilla
www.oloscience.com

Individual Differences Caused By Shuffled Chunks Of DNA In The Human Genome

Source:

http://www.sciencedaily.com/releases/2007/09/070927154931.htm

Science Daily — A study by Yale researchers offers a new view of what causes the greatest genetic variability among individuals -- suggesting that it is due less to single point mutations than to the presence of structural changes that cause extended segments of the human genome to be missing, rearranged, or present in extra copies.

"The focus for identifying genetic differences has traditionally been on point mutations or SNPs -- changes in single bases in individual genes," said Michael Snyder, the Cullman Professor of Molecular, Cellular & Developmental Biology and senior author of the study, which was published in Science Express. "Our study shows that a considerably greater amount of variation between individuals is due to rearrangement of big chunks of DNA."
Although the original human genome sequencing effort was comprehensive, it left regions that were poorly analyzed. Recently, investigators found that even in healthy individuals, many regions in the genome show structural variation. This study was designed to fill in the gaps in the genome sequence and to create a technology to rapidly identify structural variations between genomes at very high resolution over extended regions.
"We were surprised to find that structural variation is much more prevalent than we thought and that most of the variants have an ancient origin. Many of the alterations we found occurred before early human populations migrated out of Africa," said first author Jan Korbel, a postdoctoral fellow in the Department of Molecular Biophysics & Biochemistry at Yale.
To look at structural variants that were shared or different, DNA from two females -- one of African descent and one of European descent -- was analyzed using a novel DNA-based methodology called Paired-End Mapping (PEM). Researchers broke up the genome DNA into manageable-sized pieces about 3000 bases long; tagged and rescued the paired ends of the fragments; and then analyzed their sequence with a high-throughput, rapid-sequencing method developed by 454 Life Sciences.
"454 Sequencing can generate hundreds of thousands of long read pairs that are unique within the human genome to quickly and accurately determine genomic variations," explained Michael Egholm, a co-author of the study and vice president of research and development at 454 Life Sciences.
"Previous work, based on point mutations estimated that there is a 0.1 percent difference between individuals, while this work points to a level of variation between two- and five-times higher," said Snyder.
"We also found 'hot spots' -- particular regions where there is a lot of variation," said Korbel. "While these regions may be still actively undergoing evolution, they are often regions associated with genetic disorder and disease."
"These results will have an impact on how people study genetic effects in disease," said Alex Eckehart Urban, a graduate student in Snyder's group, and one of the principal authors on the study. "It was previously assumed that 'landmarks,' like the SNPs mentioned earlier, were fairly evenly spread out in the genomes of different people. Now, when we are hunting for a disease gene, we have to take into account that structural variations can distort the map and differ between individual patients."
"While it may sound like a contradiction," says Snyder, "this study supports results we have previously reported about gene regulation as the primary cause of variation. Structural variation of large of spans of the genome will likely alter the regulation of individual genes within those sequences."
According to the authors, even in healthy people, there are variants in which part of a gene is deleted or sequences from two genes are fused together without destroying the cellular activity with which they are associated. They say these findings show that the "parts list" of the human genome may be more variable, and possibly more flexible, than previously thought.
Other authors from Yale in addition to primary authors Alex E Urban and Jan Korbel, who is also affiliated with the European Molecular Biology Laboratory in Heidelberg, Germany, are Fabian Grubert, Philip Kim, Dean Palejev, Nicholas Carriero, Andrea Tanzer, Eugenia Saunders, Sherman Weissman, and Mark Gerstein. The research was funded the National Institutes of Health, a Marie Curie Fellowship, the Alexander von Humboldt Foundation, The Wellcome Trust, Roche Applied Science and the Yale High Performance Computation Center.
Citation: Science: Science Express (on line) September 28, 2007.
Note: This story has been adapted from material provided by Yale University.

Fausto Intilla

www.oloscience.com

New Method Can Reveal Ancestry Of All Genes Across Many Different Genomes

Source:

http://www.sciencedaily.com/releases/2007/09/070911155206.htm

Science Daily — The wheels of evolution turn on genetic innovation -- new genes with new functions appear, allowing organisms to grow and adapt in new ways. But deciphering the history of how and when various genes appeared, for any organism, has been a difficult and largely intractable task.

Now a team led by scientists at the Broad Institute of MIT and Harvard has broken new ground by developing a method, described in the September 6 advance online edition of Nature, that can reveal the ancestry of all genes across many different genomes. First applied to 17 species of fungi, the approach has unearthed some surprising clues about why new genes pop up in the first place and the biological nips and tucks that bolster their survival.
"Having the ability to trace the history of genes on a genomic scale opens the doors to a vast array of interesting and largely unexplored scientific questions," said senior author Aviv Regev, an assistant professor of biology at MIT and a core member of the Broad Institute. Although the principles laid out in the study pertain to fungi, they could have relevance to a variety of other species as well.
It has been recognized for decades that new genes first arise as carbon copies of existing genes. It is thought that this replication allows one of the gene copies to persist normally, while giving the other the freedom to acquire novel biological functions. Though the importance of this so-called gene duplication process is well appreciated -- it is the grist for the mill of evolutionary change -- the actual mechanics have remained murky, in part because scientists have lacked the tools to study it systematically.
Driven by the recent explosion of whole genome sequence data, the authors of the new study were able to assemble a natural history of more than 100,000 genes belonging to a group of fungi known as the Ascomycota. From this, the researchers gained a detailed view of gene duplication across the genomes of 17 different species of fungi, including the laboratory model Saccharomyces cerevisiae, commonly known as baker's yeast.
The basis for the work comes from a new method termed "SYNERGY", which first author Ilan Wapinski and his coworkers developed to help them reconstruct the ancestry of each fungal gene. By tracing a gene's lineage through various species, the method helps determine in which species the gene first arose, and if -- and in what species -- it became duplicated or even lost altogether. SYNERGY draws its strength from the use of multiple types of data, including the evolutionary or "phylogenetic" tree that depicts how species are related to each other, and the DNA sequences and relative positions of genes along the genome.
Perhaps most importantly, the method does not tackle the problem of gene origins in one fell swoop, as has typically been done, but rather breaks it into discrete, more manageable bits. Instead of treating all species at once, SYNERGY first focuses on a pair of the most recently evolved species -- those at the outer branches of the tree -- and works, two-by-two, toward the more ancestral species that comprise the roots.
From this analysis, Regev and her colleagues were able to identify a set of core principles that govern gene duplication in fungi. The findings begin to paint a picture of how new genes are groomed over hundreds of millions of years of evolution.
The study was supported by grants from the Burroughs Wellcome Fund and the National Institute of General Medical Sciences.
Note: This story has been adapted from a news release issued by Massachusetts Institute Of Technology.

Fausto intilla

www.oloscience.com

Color Night Vision In The Aye-Aye, A Most Unusual Primate

Source:

http://www.sciencedaily.com/releases/2007/09/070904114535.htm

Science Daily — A quest to gain a more complete picture of color vision evolution has led Biodesign Institute researcher Brian Verrelli to an up-close, genetic encounter with one of the world's most rare and bizarre-looking primates.
Verrelli and his ASU team have performed the first sweeping study of color vision in the aye-aye (pronounced "eye-eye"), a bushy-tailed, Madagascar native primate with a unique combination of physical features including extremely large eyes and ears, and elongated fingers for reaching hard to access insects and other foods. Verrelli, lead author George Perry, and collaborator Robert Martin's results, published in the journal Molecular Biology and Evolution, have led to some surprising conclusions on how this nocturnal primate may have retained color vision function.
Verrelli's group focuses on color vision to better understand genetic variation between human and other primate populations and the truly big evolutionary questions as to what makes us human. "At least within humans and some other primates, we know that there are three different genes responsible for color vision," said Verrelli. The genes, called opsins, come in three forms that shape our color vision palette, one for blue, another for green, and a third for red.
"What makes that very interesting is that the green and red are found on the X chromosome [sex chromosome], and it is the manipulation of those two genes alone which is related to color blindness for eight to ten percent of the male population," explains Verrelli. In a 2004 study in the American Journal of Human Genetics by Verrelli and collaborator Sarah Tishkoff of the University of Maryland, they suggested that natural genetic selection has provided women with a frequent ability to better discriminate between colors than men.
"These three genes may explain all the variation that we might see across human populations in color vision," said Verrelli. "But how did our range of color vision variation come to be in the first place?"
To help trace back the evolution of color vision, Verrelli's collaborator Perry turned to the endangered aye-aye, a primate representative of lemurs. These primates split from other groups including humans, apes, and monkeys more than sixty million years ago, and are thought to be in some ways representative of the early primates that lived at that time. "We chose the aye-aye specifically because it has a very interesting behavior in that it is fully nocturnal, and so, it raises an obvious and straightforward question: If you are an animal that lives at night, do you need color vision?"
In a simple case of 'use it or lose it,' the prevailing theory suggested that nocturnal primates cannot use color vision to see, and so the genes that they have for color vision accumulated mutations and degraded over evolutionary time.
From a practical standpoint, studying color vision in the aye-aye proved to be a daunting endeavor. Since the aye-aye is an endangered species, obtaining DNA samples in the wild was not possible. The group turned to a few rare international research institutions and colleagues that have aye-ayes to obtain DNA samples for their study.
In all total, they obtained samples from eight aye-ayes for their study. It took a year and a half to analyze the samples, since Perry and Verrelli had to invent the methodology to perform the first wide-range genetic analysis on the aye-aye. "From a conservation, population and functional viewpoint, it was the first study of its kind," said Verrelli.
The results his team found were so startling that they had to recheck them twice. "When examining these genes in the aye-aye, we realized that they are not degrading," said Verrelli. "In fact, for the green opsin gene, we did not find a single mutation in it. The opsin genes look to be absolutely fully functional, which is completely counter to how we had believed color vision evolved in nocturnal mammals."
The authors plan to collaborate with others to perform behavioral studies to see if aye-ayes can respond to colors and further molecular studies to identify the exact color absorption by the opsin proteins to see how this may differ from other primates that are not nocturnal.
The study has not only proved important to understanding color vision evolution, but also has shown the value of examining the dazzling diversity of life, especially in endangered species.
"We not only need to focus on organisms that are related to us and are common, but also organisms that are uncommon and endangered, for there may be behaviors and physical features that, once they are lost, we may never understand."
The study was completed in collaboration with the Biodesign Institute's Center for Evolutionary Functional Genomics, ASU's School of Life Sciences and School of Human Evolution and Social Change, and the Department of Anthropology at the Field Museum of Chicago.
Note: This story has been adapted from a news release issued by Arizona State University.

Fausto Intilla
www.oloscience.com

Parasitic Battles Can Involve Gene Transfer That Aids Evolution

Source:

http://www.sciencedaily.com/releases/2007/09/070905134534.htm

Science Daily — Scientists at MIT's Department of Civil and Environmental Engineering and the Technion Israel Institute of Technology have for the first time recorded the entire genomic expression of both a host bacterium and an infecting virus over the eight-hour course of infection.

The results of this research likely will encourage scientists in several fields to rethink their approach to the study of host-virus systems, which are believed to play a key evolutionary role by facilitating the transfer of genes between species.
Professors Debbie Lindell of the Technion and Sallie Chisholm of MIT and co-authors report in the Sept. 6 issue of Nature that their study of a system involving the marine bacteria, Prochlorococcus, leads them to speculate that viral infection may play a role in shaping the genetic repertoire of families of bacteria, even though individual infected bacteria die.
This could indicate that the meeting between a marine bacterial host and its virus may not be just a battle between two individuals, but an evolutionarily significant exchange that helps both species become more fit for life in the ocean environment.
"The current status of host-virus relations has been influenced by a rich history of interactions," said Lindell. "While we can't definitively pin down the sequence of past co-evolutionary events, our findings suggest a novel means through which the exchange of beneficial genes between host and virus have been triggered."
And, because the pattern of genomic expression in this host-virus system differed significantly from that in the more commonly studied system of intestinal bacteria such as E. coli and a virus called T7, the research will likely lead to increased appreciation for the need to study diverse types of marine bacteria, rather than relying on a single system as a broad model.
"We hope this work will encourage scientists to explore a wide range of host-pathogen systems and thus lead to a significant broadening of our understanding of the diversity of the host-pathogen interactions existing in nature," said Chisholm, one of the discoverers of Prochlo-rococcus in 1985. "More importantly, these studies will help us understand the role these interactions play in shaping microbial ecosystems."
Researchers have only in the past few decades begun discovering and studying ecologically relevant ocean bacteria, such as Prochlorococcus, which play a very important role in our lives. These single-celled photosynthetic bacteria use light energy to produce oxygen and organic carbon --supplying a significant portion of the oxygen we breathe--and forming the basis for the ocean food chain.
In previously studied host-virus systems, a virus hijacks the bacterial host cell and shuts down genome expression immediately, preventing the bacterium from conducting its own metabolic processes. The attacking virus redirects expression to its own genome and activates the genes beneficial for its activity, which is to replicate itself quickly at the cost of the host.
But uncharacteristically, in the system of Prochlorococcus and virus P-SSP7, an unprecedented 41 of the bacteria's 1,717 genes were upregulated. That is, the researchers detected increased quantities of the messenger RNA encoded by these genes in the cell during the infection process. The upregulation of so many host genes during infection is a phenomenon unseen before in the world of bacteriology.
Moreover, many of the host genes upregulated during infection are among those that are found in genomic islands in the host, variable regions that appear to be hot-spots for genetic exchange between bacterial hosts and viruses. In this case, some of the genes that have been transferred back and forth encode for proteins that affect the bacteria's ability to adapt to changes in environmental factors, such as nutrient deprivation and light stress. The scientists hypothesize that modifications made to the bacterial genes when they were in the virus led to new versions of the proteins that may provide the bacteria with an increased ability to withstand environmental changes. It is also possible that multiple copies of a gene provide some benefit.
Another unusual occurrence is that the viral genome contains genes transferred from bacterial hosts that encode energy-producing proteins, including photosynthesis genes that cyanobacteria need for metabolism and DNA replication. Although these genes are positioned far apart in the viral genome, they are transcribed at the same time during infection rather than in the usual left-to-right order. This leads the researchers to surmise that the virus is trying to keep its host alive longer so that the host continues to provide the energy needed for the virus's own DNA replication.
Lindell and Chisholm believe the most plausible scenario to explain the gene upregulation and gene trading is that the bacterium activates certain genes in response to infection as a means of self-protection. The virus has "learned" to use those genes to its own advantage and so incorporates them into its own genome. Later, when infecting another bacterium, the virus upregulates those genes itself to facilitate its own reproduction within the host bacterium. When a bacterium survives an infection, those viral modified genes are incorporated back into the bacterial DNA in genome islands, making that bacterium and its descendants more likely to survive in the harsh ocean environment.
"These viral parasites cooperate with their hosts during infection, providing proteins that probably function within host metabolic pathways, to squeeze every bit of energy out them before killing them off," said Lindell. "Yet on evolutionary scales, such host-pathogen interactions are influencing the evolution of gene content in both host and virus, which in turn is likely impacting their ability to colonize new niches."
Next steps in the research are to see if the host-like genes in the virus really do confer a fitness advantage to the virus and then to the host bacterium when transferred back.
Funding for this research came from the Department of Energy's GTL Program, the Gordon and Betty Moore Foundation, and the National Science Foundation.
Lindell performed the research as a postdoctoral associate in Chisholm's lab before joining the Technion faculty in the Department of Biology in October 2006. It builds on previous work in Chisholm's lab at MIT, including research by Lindell and co-author Matthew Sullivan, who in 2004 noted the presence of host genes in the viruses and their transfer back to the host, and by Maureen Coleman, who in 2006 found genomic islands in the host that had most likely come from viruses.
Other authors are MIT graduate students Gregory Kettler and Coleman; MIT postdoctoral associate Sullivan; Jacob Jaffe of the Broad Institute; Matthias Futschik and Ilka Axmann of Humboldt University; Trent Rector, Robert Steen and George Church of Harvard Medical School; and Wolfgang Hess of the University of Freiburg.
Note: This story has been adapted from a news release issued by Massachusetts Institute of Technology.

Fausto Intilla

www.oloscience.com

Human-Animal Hybrid Embryos Approved For Research In Britain

Source:

http://www.sciencedaily.com/releases/2007/09/070906104037.htm

Science Daily — The following is the statement by the Human Fertilisation and Embryo Authority, the body which oversees human embryo research in Britain. The group will allow the creation of part-human, part-animal hybrid embryos for research purposes. British regulations already require that human embryos for research purposes are destroyed within 14 days of their creation.

Statement:
"The decision on how the HFEA should approach the licensing of human - animal hybrids and chimera research has presented a particular challenge as this research is so novel in legal, scientific and ethical terms.
"In order to ensure that the Authority was able to make an appropriate and reasoned decision, we needed to ensure we had a comprehensive and robust evidence base as a foundation for that decision.
"Once we had established that such research would legally fall within the HFEA's remit to license, we were then able to start to assess whether such research would, in principle, be necessary and desirable in both scientific and ethical terms.
"As such the HFEA, working with support from the Government's Sciencewise programme, put together a detailed and comprehensive consultation gathering evidence from scientists and the wider public about the issues raised by this research. This has been far more than just opinion polling and has involved a series of detailed deliberative sessions where the full range of issues raised by such research were discussed. This enabled participants to make their own informed judgements, asking questions and challenging their own views.
"Having looked at all the evidence the Authority has decided that there is no fundamental reason to prevent cytoplasmic hybrid research. However, public opinion is very finely divided with people generally opposed to this research unless it is tightly regulated and it is likely to lead to scientific or medical advancements.
"This is not a total green light for cytoplasmic hybrid research, but recognition that this area of research can, with caution and careful scrutiny, be permitted. Individual research teams should be able to undertake research projects involving the creation of cytoplasmic hybrid embryos if they can demonstrate, to the satisfaction of an HFEA licence committee, that their planned research project is both necessary and desirable. They must also meet the overall standards required by the HFEA for any embryo research.
"Having looked at the principles behind this kind of research, an HFEA licence committee will now look at the details of the two specific research applications that were submitted earlier this year. We would hope to have a decision on both applications in November.
"In general, people who do not fundamentally oppose embryo research are prepared to accept that human animal research may have some value. But there is a clear demand from people to know more about what researchers are doing and their plans for future work, highlighting a need for better communication about science and research from both the scientific community and ourselves as regulator. In the coming months we will be looking to see how this can be delivered.
"In terms of other kinds of hybrid and chimera research, it became very clear that not only did the scientific community not wish to perform such research at present but that the prospect was so distant that they could not envisage what form this research would possibly take in the future.
"The Authority felt it would be completely wrong to make a decision on broader hybrid and chimera research without an adequate evidence base. However, the HFEA will continue to monitor the potential for this wider research and any emerging evidence through its 'horizon scanning' programme."
Note: This story has been adapted from a news release issued by Human Fertilisation and Embryo Authority.

Fausto Intilla
www.oloscience.com

New Species May Form WIth A Little Help From Immune System

Source:

http://www.sciencedaily.com/releases/2007/09/070905103023.htm

Science Daily — Plant geneticists and animal breeders alike know the problem: single individuals or entire broods will not thrive, some die early, or remain, even if they survive, the runts of the litter and thus not useful for continued breeding programs. What is annoying for the breeder, fascinates geneticists and molecular biologists. The unfit offspring are an example that genetic material cannot always be combined at will.

Apparently there are reproductive barriers that not only prevent the exchange of genes between well established species, but also between varieties of one and the same species. How these barriers arise is of central importance if one wants to understand the origin of biodiversity. A research team led by Detlef Weigel from the Max Planck Institute of Developmental Biology in Germany and Jeff Dangl from the University of North Carolina has now shown that a mis-regulated immune system can establish reproductive barriers and might be a first step toward speciation. The international collaboration studied a genetic incompatibility known as hybrid necrosis, using thale cress, Arabidopsis thaliana.
The new work, reported in PLoS Biology, was based on the observation that unfit hybrids from different plant species are very similar. Their growth is retarded, the leaves become yellow and necrotic, the tissue collapses and they often do not survive to make flowers; the syndrome is generally known as hybrid necrosis. "We suspected that hybrid necrosis is always caused by the same biochemical mechanism," explains Weigel, director at the Max Planck Institute.
To test this hypothesis, the scientists took 280 genetically different strains of Arabidopsis from all over the world, which they crossed in 861 different combinations. Most of the hybrid plants were strong and grew normally, but 20 - or two percent - of the crosses produced only small necrotic and unhealthy plants. Genomics-based experiments showed that these hybrids all had a comparable profile of gene activity:
A common group of some 1000 genes were either more strongly or more weakly active in the hybrids than in their healthy parents. Moreover, this pattern was very similar to what is seen with a strong immune response mounted against pathogens during a normal infection. The plant immune response typically involves the sacrifice of a few cells at and around the infection site. But in the wimpy hybrids, healthy tissue also suffered - without pathogen infection. The hybrid plants apparently mistook their own cells for dangerous germs.
Although the genes that determined the abnormal autoimmunity were different in most crosses, the researchers discovered that often only two genes were required to cause the necrotic hybrid response. One of the fatal genes came from the father, the other from the mother. In one case that the researchers studied in more detail, they found that the gene that causes necrosis in hybrids, but not in the parents, is normally used to sense the presence of a pathogen.
The scientists emphasize, however, that the hybrids are not the victims of malfunctioning genes: in contrast to many hereditary diseases, the necrosis is not due to each parent carrying a defective copy of the same gene. Rather, there is a destructive interaction between two different genes, each of which evolved differently in the two parents. The genes on their own are harmless or even beneficial, since the parents are healthy. Only the combination of the altered gene variants creates problems. These types of genetic malfunction are often known as Dobzhanshy-Muller incompatibilities, after the two giants of early modern genetics who first studied these necrotic hybrids in fruit flies.
The results of the German-American team challenge the classical definition of a species, according to which individuals of one species can mate at will and produce fertile offspring. Apparently there are barriers to the free interchange of genes even within a species; after all, one out of 50 crosses in this study was not successful. "The formation of new species thus needs to be understood as a gradual process, where barriers within a species continually increase, until two groups cannot be crossed at all anymore" says Weigel.
While this view is widely accepted today, it is mostly unclear, why such genetic barriers arise in the first place. Which advantage has the plant, when sometimes all seeds from a cross die? The current study offers a possible explanation. The plant genome changes under pressure from pathogens.
"Plant and pathogen are locked in a race," says Dangl, professor and expert in the genetics of plant pathology at the University of North Carolina. The pathogens tirelessly develop new strategies to attack the plant and evade its immune system. The plant, in turn, tries to be prepared against as many new microbe "weapons" as possible. Armed to the teeth, it can happen that a harmless protein variant from a more distant relative is all of a sudden classified as dangerous and attacked.
The scientists are optimistic that their insights can be applied to other species. Common traits indicate that hybrid necrosis in crops such as wheat is caused by the same mechanisms as in tale cress. Dangl therefore believes that Arabidopsis can serve as a useful model for the understanding of hybrid necrosis in general. "Such a model would be very useful for breeding, since such genetic incompatibilities prevents some of the crosses breeders would like to make," according to Dangl.
The finding that only a few genes are responsible for each case of hybrid necrosis is particularly encouraging. It seems that only a few genetic changes are required to circumvent crossing barriers und to achieve a desired new combination of genetic traits. The flip side of the coin is that only minimal modifications in the genome can be sufficient to suppress the free exchange of genes between relatives, and that perhaps not much is needed to form a new species.
Authors of the study were Detlef Weigel, Kirsten Bomblies, Janne Lempe, Norman Warthmann and Christa Lanz from the Max Planck Institute for Developmental Biology, Tübingen, Germany; and Petra Epple und Jeffery L. Dangl from the University of North Carolina in Chapel Hill, North Carolina, USA.
Reference: Detlef Weigel, Kirsten Bomblies, Janne Lempe, Norman Warthmann, Christa Lanz and Petra Epple und Jeffery L. Dangl "Autoimmune response as a mechanism for a Dobzhansky-Muller-type incompatibility syndrome in plants" PLoS Biology 5, e236 (4. September 2007)
Note: This story has been adapted from a news release issued by Max-Planck-Gesellschaft.

Fausto Intilla

www.oloscience.com

First Diploid Human Genome Sequence Shows We're Surprisingly Different

Source:

http://www.sciencedaily.com/releases/2007/09/070904072204.htm

Science Daily — Researchers at the J. Craig Venter Institute (JCVI), along with collaborators at The Hospital for Sick Children (Sick Kids) in Toronto and the University of California, San Diego (UCSD), have published a genome sequence of an individual, J. Craig Venter, Ph.D., that covers both of his chromosome pairs (or diploid genome), one set being inherited from each of his parents.

Two other versions of the human genome currently exist—one published in 2001 by Dr. Venter and colleagues at Celera Genomics, and another at the same time by a consortium of government and foundation-funded researchers. These genomes were not of any single individual, but rather were a mosaic of DNA sequences from various donors. In the case of Celera it was a consensus assembly from five individuals, while the publicly-funded version was based on patching together sequences from over 100 anonymous human sources. Both versions greatly underestimated human genetic diversity.
This new genome (called “HuRef”) represents the first time a true diploid genome from one individual—Dr. Venter, has been published. The research is available in the open access public journal, PLoS Biology.
Researchers at the JCVI have been sequencing and analyzing this version of Dr. Venter’s genome since 2003. Building on reanalyzed data from Dr. Venter’s genome that constituted 60% of the previously published Celera genome, the team had the goal of constructing a definitive reference human genome based on one individual. Using whole genome shotgun sequencing and highly accurate DNA sequencing using Sanger-based chemistry, the team produced additional data which constitutes the final 32 million sequence reads.
From the combined data of more than 20 billion base pairs of DNA, the team was able to assemble the majority of Dr. Venter's genome. Since this genome assembly uniquely catalogues the contributions of each of the parental chromosomes, for the first time the amount of variation existing between the two could be determined. Surprisingly, a higher than expected amount of genetic variation was found to exist between the two human chromosomes.
“Each time we peer deeper into the human genome we uncover more valuable insight into our intricate biology,” said Dr. Venter. “With this publication we have shown that human to human variation is five to seven-fold greater than earlier estimates proving that we are in fact more unique at the individual genetic level than we thought.” He added, “It is clear however that we are still at the earliest stages of discovery about ourselves and only with additional sequencing of more individual genomes will we garner a full understanding of how our genes influence our lives.”
Within the human genome there are several different kinds of DNA variants. The most studied type is single nucleotide polymorphisms or SNPs, which are thought to be the essential variants implicated in human traits and disease susceptibility. A total of 4.1 million variants covering 12.3 million base pairs of DNA were uncovered in this analysis of Dr. Venter’s genome. Of the 4.1 million variations between chromosome sets, 3.2 million were SNPs. This is a typical number expected to be found in any other human genome, but there were at least 1.2 million variants that had not been described before. Surprisingly, nearly one million were different kinds of variants including: insertion/deletions (“indels”), copy number variants, block substitutions and segmental duplications.
While the SNP events outnumbered the non-SNP variants, the latter class involved a larger portion (74%) of the variable component of Dr. Venter's genome. This data suggests that human-to-human variation is much greater than the 0.1% difference found in earlier genome sequencing projects. The new estimate based on this data is that genomes between individuals have at least 0.5% total genetic variation (or are 99.5% similar) The researchers suggest that much more research needs to be done on these non-SNP variants to better understand their role in individual genomics.
According to Samuel Levy, Ph.D., lead author and senior scientist at JCVI, “The ability to use unbiased, high throughput, sequencing methods coupled with advance computational analytic methods, enables us to characterize more comprehensively the wide variety of individual genetic variation. This offers us an unprecedented opportunity to study the prevalence and impact of these DNA variants on traits and diseases in human populations.”
Another important feature that is made possible by having an individual, diploid genome is the ability to generate more informed haplotype assemblies. Haplotypes are groups of linked variations along the chromosomes. Other studies have generated many common haplotypes, however these are based on averages of large populations rather than individuals. Individual haplotypes enable scientists to study rare or 'private' variants that might explain and help predict traits and diseases in that particular person—allowing an individualized approach in genomic applications.
In the HuRef analysis, the team used the heterozygous portion of the 4.1 million variant set and new algorithms to build haplotype assemblies. These haplotype assemblies were typically an order of magnitude larger than what can be achieved by genotyping a single individual, with over half the genome contained in segments greater than 200,000 base pairs in length. The JCVI researchers expect this number to improve significantly as additional sequence coverage is added to HuRef using a variety of new sequencing technologies.
"In the future it will be possible to know the parental origin of DNA that is contributing, either alone or in combination, to various traits or disease," said co-author Stephen Scherer, Ph.D., senior scientist in Genetics and Genomic Biology at SickKids and professor of Molecular and Medical Genetics at the University of Toronto. "This study discovered that in an individual genome upwards of 44% of genes were variable in sequence, a number that geneticists have wondered about for 50 years. With this type of knowledge now in hand, the stage is set for an era of personalized medicine where genome sequence information becomes a critical reference to assist with health-related decisions", concluded Scherer.
Background
The publication of Dr. Venter’s genome represents the first publication of an individual’s genome and the first human genome publication since the first sequence and analysis of the human genome published in Science in 2001 by Dr. Venter and colleagues at Celera Genomics. The publicly funded genome project also published their version of the human genome at the same time in the journal Nature. At Celera there were five individuals whose genomes were used for that consensus human genome assembly. One of those individuals was Dr. Venter whose DNA constituted the majority of the DNA for that genome. The publicly funded genome project used DNA from a variety of individuals and is a composite version.
The new HuRef version of the human genome is the sequence and assembly of one individual in which the person’s two sets of chromosomes (one inherited from the mother and one set from the father) are represented. It is this kind of genome sequencing and analysis that will usher in the true era of individualized medicine.
Dr. Venter and the team at JCVI have long been proponents of finding new and improved methods for sequencing genomes since it is only through cost-effective and accurate sequencing methods that millions of human genomes can be sequenced. In September 2003, the JCVI announced a $500,000 prize for advances leading to the sequencing of one genome for $1,000 or less. The JCVI prize was eventually joined with the $10 million Archon X Prize for Genomics.
For the HuRef project, the team at JCVI used a more traditional method of sequencing—whole genome shotgun assembly which is built upon Sanger dideoxy sequencing. Then, Applied Biosystems 3730xl high-throughput DNA sequencing machines were employed since these methods still produce the longest and most accurate lengths of DNA. This project was designed to produce an accurate and more complete version of a single individual’s genome rather than producing a fast and potentially less expensive version. From the HuRef genome however the researchers believe that newer methods for sequencing can be used to enable more people to have their genome’s sequenced and analyzed. It is clear that the HuRef version is likely the last time that these more traditional methods of sequencing will be employed.
Funding for the research on the new HuRef diploid genome was from the J. Craig Venter Institute.
Note: This story has been adapted from a news release issued by J. Craig Venter Institute.

Fausto Intilla

www.oloscience.com

A Genetic Trigger For The Cambrian Explosion Unraveled?

Source:

http://www.sciencedaily.com/releases/2007/08/070831180409.htm

Science Daily — A team of scientists led by young Croatian evolutionary geneticist Tomislav Domazet-Lošo from Ruder Boškovic Institute (RBI) in Zagreb, Croatia, developed a novel methodological approach in evolutionary studies. Using the method they named 'genomic phylostratigraphy', its authors shed new and unexpected light on some of the long standing macroevolutionary issues, which have been puzzling evolutionary biologists since Darwin.

The only direct method of research in evolutionary history involves analyzing the fossil remains of once living organisms, excavated in various localities throughout of the world. However, that approach often cannot provide the full evolutionary pathway of some species, as it requires uncovering of many fossils from various stages of its evolutionary history. As the fossil record is imperfect, the evolution research fundamentally hinges on luck factor in discovering the adequate paleontological sites.
However, the RBI team proposed a novel and interesting approach to bypass this obstacle. Namely, they suggested that the genome of every extant species carries the ‘snapshots’ of evolutionary epochs that species went trough. What's even more important, they also developed the method which enables evolution researchers to readily convert those individual 'snapshots’ into the full-length 'evolutionary movie' of a species.
Applying their new methodology on the fruit fly genomic data they tackled some of the most intriguing evolutionary puzzles - some of which distressed even Darwin himself. First, they demonstrated that parts of the living organism exposed to the environment – so called ‘ectoderm’ - are more prone to evolutionary changes. Further, they explained the evolutionary origin of the ‘germ layers’, the primary tissue forms that form during the first days after the conception of a new animal, and from which subsequently all other tissues are developed. Finally, they discovered the potential genetic trigger for the 'Cambrian explosion', a major global evolutionary event on the planet, when some 540 million years ago almost all animal forms known today suddenly 'appeared'.
The first public lecture on these findings will be given by dr. Domazet-Lošo on September 4th at 5. ISABS Conference in Forensic Genetics and Molecular Anthropology, held in Split, Croatia. The groundbreaking paper fully presenting the theory of genomic phylostratigraphy will appear in the November issue of 'Trends in genetics', the most established monthly journal in Genetics.
Reference: Domazet-Lošo, T. et al. (2007) 'A phylostratigraphy approach to uncover the genomic history of major adaptations in metazoan lineages'. Trends in Genetics (to appear in the November 2007 issue of the journal)
Note: This story has been adapted from a news release issued by Rudjer Boskovic Institute.

Fausto Intilla

www.oloscience.com