Category Archives: Genome

T

he feat made headlines around the world: Scientists Say Human Genome is Complete, the New York Times announced in 2003. The Human Genome, the journals Science and Nature said in identical ta-dah cover lines unveiling the historic achievement.

There was one little problem.

As a matter of truth in advertising, the finished sequence isnt finished, said Eric Lander, who led the lab at the Whitehead Institute that deciphered more of the genome for the government-funded Human Genome Project than any other. I always say finished is a term of art.

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Its very fair to say the human genome was never fully sequenced, Craig Venter, another genomics luminary, told STAT.

The human genome has not been completely sequenced and neither has any other mammalian genome as far as Im aware, said Harvard Medical School bioengineer George Church, who made key earlyadvances in sequencing technology.

Geneticist Craig Venter helped sequence the human genome. Now he wants yours

What insiders know, however, is not well-understood by the rest of us, who take for granted that each A, T, C, and G that makes up the DNA of all 23 pairs of human chromosomes has been completely worked out.When scientists finished the first draft of the human genome, in 2001, and again when they had the final version in 2003, no one lied, exactly. FAQsfrom the National Institutes of Health refer to the sequences essential completion, and to the question, Is the human genome completely sequenced? they answer, Yes, with the caveat that its as complete as it can be given available technology.

Perhaps nobody paid much attention because the missing sequences didnt seem to matter. But now it appears they may play a role in conditions such as cancer and autism.

A lot of people in the 1980s and 1990s [when the Human Genome Project was getting started] thought of these regions as nonfunctional, said Karen Miga, a molecular biologist at the University of California, Santa Cruz. But thats no longer the case. Some of them, called satellite regions, misbehave in some forms of cancer, she said, so something is going on in these regions thats important.

Miga regards them as the explorer Livingstone did Africa terra incognita whose inaccessibility seems like a personal affront. Sequencing the unsequenced, she said, is the last frontier for human genetics and genomics.

Church, too, has been making that point, mentioning it at both the May meeting of an effort to synthesize genomes, and at last weekends meeting of the International Society for Stem Cell Research. Most of the unsequenced regions, he said, have some connection to agingand aneuploidy (an abnormal number of chromosomes such as what occurs in Down syndrome).Church estimates 4 percent to 9 percent of the human genome hasnt been sequenced. Miga thinks its 8 percent.

The reason for these gapsis that DNA sequencing machines dont read genomes like humans read books, from the first word to the last. Instead, they first randomly chop up copies of the 23 pairs of chromosomes, which total some 3 billion letters, so the machines arent overwhelmed. The resulting chunks contain from 1,000 letters (during the Human Genome Project) to a few hundred (in todays more advanced sequencing machines). The chunks overlap. Computersmatch up the overlaps, assembling the chunks into the correct sequence.

Thats between difficult and impossible to do if the chunks contain lots of repetitive segments, such as TTAATATTAATATTAATA, or TTAATA three times. The problem is, when you have the same exact words, its hard to assemble, said Lander, just as if jigsaw puzzle pieces show the same exact blue sky.

In 2004, the genome project reportedthat there were 341 gaps in the sequence. Most of the gaps 250 are in the main part of each chromosome, where genes make the proteins that life runs on. These gaps are tiny. Only afew gaps 33 at last count lie in or near each chromosomes centromere (where the two parts of a chromosome connect) and telomeres (the caps at the end of chromosomes), but these 33 are 10 times as long in totalas the 250 gaps.

That makes the centromeres in particular the genomes uncharted Zambezi. Evan Eichler of the University of Washingtonsaid every chromosome has such sequence-defying repetitive elements think of them as DNA stutters including an infamous one thats 171 letters long and repeated end-to-end for thousands of letters.

At the beginning of the Human Genome Project, said Lander, now director of the Broad Institute of MIT and Harvard, it became very clear these highly repetitive sequences would not be tractable with existing technology. It wasnt a cause of a great deal of agonizing at the time, since he and other project leaders expected the next generation of scientists to find a solution.

That hasnt really happened, partly because there hasnt been much motivation to map these regions.Im between agnostic and a little skeptical that these bits will be important for disease, but maybe Im saying that because we cant read them, Lander said.

As new sequencing technology has begun allowing scientists topeek into unsequenced territory, however, theyhave seen that these tough-to-sequence regions frequently have important genes, said Michael Hunkapiller, chairman and CEO of Pacific Biosciences, which makes DNA sequencers. (In 1998, Hunkapiller recruited Venter to his new company, Celera Genomics, to race the government-backed genome project; the race ended in a de facto tie.)

PacBios reason for being is to increase the length of DNA segments that can be read and assemble them, Hunkapiller said. Longer reads have an effect like enlarging jigsaw puzzle pieces; even though the pieces still contain a lot of repeated blue sky, the greater size makes it more likely theyll also contain something sufficiently novel to make assembling them easier. PacBios maximum DNA read is now about 60,000 letters,Hunkapiller said, andaverages 15,000.

With such long reads, Lander said, you could get through a lot of these nasty [unsequenced] regions.

Genome writers gather in New York to pitch bomb-sniffing plants and more. Wheres the funding?

Thats looking more and more like a worthy undertaking, and not only because the unsequenced regions might contain actual protein-making genes. There is evidence that the non-gene parts especially the DNA stutters clearly have disease implications, Hunkapiller said. Three-quarters of the [genome] differences between one person and another are in [such] variants rather than the single-letterspelling differences in As, Ts, Cs, and Gs which get all the attention.In a 2007 paper, Venter (now the chairman of Human Longevity Inc.) and his team showed that there are more person-to-person differences like this, called structural variants, than there are single-letter changes.

Yet about 90 percent of the structural variants, the vast majority of which werent sequenced by either the genome project or a later effort called the 1000 Genomes Project, have been missed, Eichler and his colleagues reported last year.

One reason the stutters are unusually influential is that this repetitive DNA can move around, make copies of itself, flip its orientation, and do other acrobaticsthat can have quite dramatic functional effects, Hunkapiller said. For one thing, repetitive elements around the centromeres, called satellites, might cause a dividing cell to become cancerous, Miga said, because they can destabilizethe entire genome.

When researchers at Stanford University tried to find the genetic cause of a young mans mysterious disease, which caused non-cancerous tumors to grow throughout his body, they found nothing using the standard whole-genome sequencing, Hunkapiller said. But the long reads made possible by the PacBio machines looked for structural variants and found the problem right away, he said.

The stutters might even be what makes us human. Some of these complex duplications appear to be important for the evolution of higher neuroadaptive function aka brain development, Eichler said. A gene called ARHGAP11B, which was created by one such duplication, causes the cortex to develop the myriad folds that support complex thought; SRGAP2C, also a duplication, triggers brain development.

These are new genes that evolved specifically in our lineage over the last few million years, said Eichler. The same duplications can also produce DNA rearrangements associated with neurodevelopmental disorders such as autism and intellectual disability.

Finish the sequence! hasnt become a rallying cry, but maybe it should be, Venter said: Id be the last one to give you a quote saying that we dont need to bother with these [unsequenced] regions.

Sharon Begley can be reached at sharon.begley@statnews.com Follow Sharon on Twitter @sxbegle

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Psst, the human genome was never completely sequenced. Some scientists say it should be - STAT

Researchers report in Nature Communications (Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma) that a genetic sequencing study has revealed that some patients with osteosarcoma could be helped by an existing drug.

The team, from the Wellcome Trust Sanger Institute, University College London Cancer Institute, and the Royal National Orthopedic Hospital NHS Trust, that 10% of patients with a genetic mutation in particular growth-factor-signaling genes may benefit from IGF1R inhibitors.

The results, the scientists say,suggest a re-trial of IGF1R inhibitors for the subset of patients with osteosarcoma who are likely to respond based on their genetic profile.

The current treatment for osteosarcoma is chemotherapy followed by surgery, where the bone tumors are removed. There has not been a new treatment for osteosarcoma in almost 40 years.

In the study, investigators analyzed the genome of 112 childhood and adult tumorsdouble the number of tumors studied previously. In 10% of cases, the team discovered cancer-causing mutations in insulin-like growth factor (IGF) signaling genes.IGF signaling plays a major role in bone growth and development during puberty. Researchers believe that IGF signaling is also implicated in the uncontrolled bone growth that is characteristic of osteosarcoma.

IGF signaling genes are the target of IGF1R inhibitors. Past clinical trials of IGF1R inhibitors as a treatment for osteosarcoma yielded mixed results, although occasionally patients responded to therapy. IGF1R inhibitors have not been further tested in osteosarcoma, as it had been unclear which patients would benefit from the treatment.

"Osteosarcoma is difficult to treat, notes Sam Behjati, Ph.D., first author from the Wellcome Trust Sanger Institute and University of Cambridge. Despite extensive research over the past 40 years, no new treatment options have been found. In this study, we reveal a clear biological target for osteosarcoma that can be reached with existing drugs."

In the study, scientists looked for mutations in the tumors to understand the mechanism of osteosarcoma development. The genetic information revealed a specific process for rearranging the chromosomes that results in several cancer-driving mutations at once.

In a whole-genome study of osteosarcoma, structural variants were identified as a major source of driver mutation. Some of these variants occurred in the context of chromothripsis, the shattering of chromosomes resulting in copy number oscillations, wrote the researchers. Using whole-exome sequencing combined with copy number arrays, Kovac et al. described genomic alterations in osteosarcoma indicative of compromised homology-directed DNA repair.

"We have unpicked the mechanism behind osteosarcoma for the first time, adds Adrienne Flanagan, Ph.D., senior author from the Royal National Orthopedic Hospital NHS Trust and University College London Cancer Institute. We discovered a new processchromothripsis amplificationin which the chromosome is shattered, multiplied, and rejigged to generate multiple cancer-driving mutations at the same time. We believe this is why we see very similar osteosarcoma tumors in children and adults, which are not the result of aging."

"Currently, there are no new osteosarcoma treatments on the horizon, says Peter Campbell, M.D., Ph.D., lead author from the Wellcome Trust Sanger Institute. Genomic sequencing has provided the evidence needed to revisit clinical trials of IGF1R inhibitors for the subset of patients that responded in the past. The mutations of patients' tumors may enable clinicians to predict who will, and will not respond to these drugs, resulting in more efficient clinical trials.

Read more:
Whole-Genome Study Shows IGF1R Inhibitors May Help Some Osteosarcoma Patients - Genetic Engineering & Biotechnology News

Since the Human Genome Project concluded in 2003, genome sequencing has become cheaper and more accessible. But currenttechnology has its limitations. Now, for the first time, Stanford University researchers have used long-read, whole genome sequencing to diagnose a patient.

Sequencing a genome involves determiningthe order of nucleotide base pairs, or letters, in that individuals DNA. This is done by snippingDNA into pieces that a sequencer can read, and then using a computer to put these fragments in order.

Current short-read technology chops DNA up into words that are about 100 letters long.Long-read sequencing makes wordsthat can be thousands of letters long, said Euan Ashley, the studys senior author and a professor of cardiovascular medicine, genetics and biomedical data science at Stanford, in a statement.

This allows us to illuminate dark corners of the genome like never before, Ashley said. Cutting up DNA into smaller pieces means there are more breaks between individual segments. Some parts of the genome can be missedabout 5%of it, the researchers wrote. Any mutationsdeletions or insertionsthat exceed a certain length are undetectable with short-read sequencing.

The Stanford team used long-read sequencing to make a diagnosis for Ricky Ramon, a patient whose symptoms pointed to Carney complex, a rare genetic condition caused by mutations in the PRKAR1A gene. But short-read sequencing found no disease-causing gene variants in Ramons genome.

Carney complex is characterized by an increased risk for several types of tumors, including benign tumors in the heart. Ramon has undergone multiple surgeries to remove these tumors, called myxomas, from his heart. He is being considered for a heart transplant, but the transplant team needed a solid diagnosis to move forward.

Using long-read technology from Menlo Park, CA-based Pacific Biosciences, the Stanford team discovered a deletion of more than 2,000 base pairs in Ramons genome, confirming a diagnosis of Carney complex.

While short-read sequencing now costs less than $1,000 per genome, Ashley estimates the cost of the long-read sequencing used in this study to be between $5,000 to $6,000.

If we can get the cost of long-read sequencing down to where its accessible for everyone, I think it will be very useful, he said.

See more here:
Long-read sequencing 'illuminates' previously inaccessible parts of ... - FierceBiotech

Researchers from the University of Tuebingen and the Max Planck Institute for the Science of Human History in Jena, both in Germany, have decoded the genome of ancient Egyptians for the first time, with unexpected results.

Modern Egyptians, by comparison, share much more DNA with sub-Saharan populations.

The findings have turned years of theory on its head, causing Egyptologists to re-evaluate the region's history while unlocking new tools for scientists working in the field.

Extracting genome data is a new frontier for Egyptologists, however.

Scientists took 166 bone samples from 151 mummies, dating from approximately 1400 B.C. to A.D. 400, extracting DNA from 90 individuals and mapping the full genome in three cases.

Previous DNA analysis of mummies has been treated with a necessary dose of skepticism, explains professor Johannes Krause of the Max Planck Institute.

"When you touch a bone, you probably leave more DNA on the bone than is inside (it)," he argued. "Contamination is a big issue. ... Only in the last five or six years has it become possible to actually study DNA from ancient humans, because we can now show whether DNA is ancient or not by (its) chemical properties."

Heat and high humidity in tombs, paired with some of the chemicals involved in mummification, all contribute to DNA degradation, the paper adds, but it describes its findings as "the first reliable data set obtained from ancient Egyptians."

Analyzing samples spanning over a millennium, researchers looked for genetic differences compared with Egyptians today. They found that the sample set showed a strong connection with a cluster of ancient non-African populations based east of the Mediterranean Sea.

Krause describes the far-reaching data set gained from looking at mitochondrial genomes: "This is not just the DNA of one person. It's the DNA of the parents, grandparents, grandparents' parents, grand-grand-grandparents' parents and so forth.

"So if we don't find sub-Saharan African ancestry in those people, that is pretty representative, at least for Middle Egypt."

Krause hypothesizes that ancient Northern Egypt would be much the same, if not more, linked to the Near East. Ancient Southern Egypt might be a different matter, however, where populations lived closer to Nubia, home of the "Black Pharaohs" in what is now Sudan.

"The genetics of the Abusir el-Meleq community did not undergo any major shifts during the 1,300-year timespan we studied," said Wolfgang Haak, group leader at the Max Planck Institute.

This period covered the rule of Alexander the Great (332-323 B.C.), the Ptolemaic dynasty (323-30 B.C.) and part of Roman rule (30 B.C.-A.D. 641). Strict social structures and legal incentives to marry along ethnic lines within these communities may have played a part in the Egyptians' genetic stasis, the paper speculates.

"A lot of people has assumed foreign invaders ... brought a lot of genetic ancestry into the region," Krause said. "People expected that through time, Egypt would become more European, but we see the exact opposite."

Modern Egyptians were found to "inherit 8% more ancestry from African ancestors" than the mummies studied. The paper cites increased mobility along the Nile, increased long-distance commerce and the era of the trans-Saharan slave trade as potential reasons why.

The team's findings do come with one obvious caveat: "All our genetic data (was) obtained from a single site in Middle Egypt and may not be representative for all of ancient Egypt," the paper concedes.

While the study might be limited in scope, the team believes it has made some technical breakthroughs.

"I expect there will be a ton of ancient Egyptian mummy genomes (mapped) in the next couple of years," Krause said, adding that "multiple groups" are following his team's lead.

"There's always more research we can do. This is not the end. It's just the beginning."

Read more:
DNA discovery reveals genetic history of ancient Egyptians - CNN

In the mixed-up world of gene silencing, its not exactly clear why some genomic regions are hard to access. These regions, it has been suggested, may simply be too tightly packed to permit the passage of regulatory proteins needed for functions such as DNA repair. Tightly packed DNA, however, doesnt always behave as expected. For example, heterochromatin has been known to exclude small proteins while admitting large ones.

Such anomalous behavior naturally attracts the attention of scientists. Eager to resolve the problems accompanying the compaction explanation for the silencing of heterochromatin, scientists based at Lawrence Berkeley National Laboratory decided to consider an alternative mechanism. It turns out to be the same one that accounts for the separation of oil and water.

A Berkeley Lab team led by Gary Karpen, a senior scientist specializing in biological systems and engineering, uncovered evidence that heterochromatin organizes large parts of the genome into specific regions of the nucleus using liquid-liquid phase separation, a mechanism well-known in physics but whose importance for biology has only recently been revealed.

Details appeared June 21, 2017 in the journal Nature, in an article entitled, Phase separation drives heterochromatin domain formation. The article suggests that phase separation, a phenomenon already known to have biological relevance in giving rise to diverse non-membrane-bound nuclear, cytoplasmic, and extracellular compartments, also mediates the formation of heterochromatin domains.

We show that Drosophila HP1a protein undergoes liquidliquid demixing in vitro, and nucleates into foci that display liquid properties during the first stages of heterochromatin domain formation in early Drosophila embryos, wrote the articles authors. Furthermore, in both Drosophila and mammalian cells, heterochromatin domains exhibit dynamics that are characteristic of liquid-phase separation, including sensitivity to the disruption of weak hydrophobic interactions, and reduced diffusion, increased coordinated movement, and inert probe exclusion at the domain boundary.

Essentially, the researchers observed two non-mixing liquids in the cell nucleus: one that contained expressed genes, and one that contained silenced heterochromatin. They found that heterochromatic droplets fused together just like two drops of oil surrounded by water.

In lab experiments, researchers purified heterochromatin protein 1a (HP1a), a main component of heterochromatin, and saw that this single component was able to recreate what they saw in the nucleus by forming liquid droplets.

Chromatin organization by phase separation, noted Amy Strom, study lead author and a graduate student in Karpen's lab, means that proteins are targeted to one liquid or the other based not on size, but on other physical traits, like charge, flexibility, and interaction partners."

The authors of the Nature article concluded that the heterochromatic domains form via phase separation mature into structures that include liquid and stable compartments. They also proposed that emergent biophysical properties associated with phase-separated systems are critical to understanding the unusual behaviors of heterochromatin, and how chromatin domains in general regulate essential nuclear functions.

"The importance of DNA sequences in health and disease has been clear for decades, but we only recently have come to realize that the organization of sections of DNA into different physical domains or compartments inside the nucleus is critical to promote distinct genome functions," commented Dr. Karpen.

The Berkeley Lab study, which used fruit fly and mouse cells, will be published alongside a companion paper in Nature led by UC San Francisco researchers, who showed that the human version of the HP1a protein has the same liquid droplet properties, suggesting that similar principles hold for human heterochromatin.

Interestingly, this type of liquid-liquid phase separation is very sensitive to changes in temperature, protein concentration, and pH levels.

"It's an elegant way for the cell to be able to manipulate gene expression of many sequences at once," commented Strom.

Other cellular structures, including some involved in disease, are also organized by phase separation.

"Problems with phase separation have been linked to diseases such as dementia and certain neurodegenerative disorders," remarked Dr. Karpen.

He noted that as we age, biological molecules lose their liquid state and become more solid, accumulating damage along the way. Dr. Karpen pointed to diseases like Alzheimer's and Huntington's, in which proteins misfold and aggregate, becoming less liquid and more solid over time.

"If we can better understand what causes aggregation, and how to keep things more liquid, we might have a chance to combat these types of disease," Strom suggested.

The work is a big step forward for understanding how DNA functions, but could also help researchers improve their ability to manipulate genes.

"Gene therapy, or any treatment that relies on tight regulation of gene expression, could be improved by precisely targeting molecules to the right place in the nucleus," explained Karpen. "It is very difficult to target genes located in heterochromatin, but this understanding of the properties linked to phase separation and liquid behaviors could help change that and open up a third of the genome that we couldn't get to before."

This includes targeting gene-editing technologies like CRISPR, which has recently opened up new doors for precise genome manipulation and gene therapy.

Go here to read the rest:
Shaking Up Genome Regulation by Considering Oil/Water-Like ... - Genetic Engineering & Biotechnology News

BBC News

The power of a billion: India's genomics revolution - BBC News BBC News Could an effort to gather genetic data from its population of one billion people help India take the lead in advanced healthcare? and more »

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The power of a billion: India's genomics revolution - BBC News - BBC News

June 21, 2017 Liquid-like fusion of heterochromatin protein 1a droplets in the embryo of a fruit fly. Credit: Amy Strom/Berkeley Lab

The same mechanisms that quickly separate mixtures of oil and water are at play when controlling the organization in an unusual part of our DNA called heterochromatin, according to a new study by researchers at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab).

Researchers studying genome and cell biology provide evidence that heterochromatin organizes large parts of the genome into specific regions of the nucleus using liquid-liquid phase separation, a mechanism well known in physics but whose importance for biology has only recently been revealed.

They present their findings June 21 in the journal Nature, addressing a long-standing question about how DNA functions are organized in space and time, including how genes are regulated to be silenced or expressed.

"The importance of DNA sequences in health and disease has been clear for decades, but we only recently have come to realize that the organization of sections of DNA into different physical domains or compartments inside the nucleus is critical to promote distinct genome functions," said study corresponding author, Gary Karpen, senior scientist at Berkeley Lab's Biological Systems and Engineering Division.

The long stretches of DNA in heterochromatin contain sequences that, for the most part, need to be silenced for cells to work properly. Scientists once thought that compaction of the DNA was the primary mechanism for controlling which enzymes and molecules gain access to the sequences. It was reasoned that the more tightly wound the strands, the harder it would be to get to the genetic material inside.

That mechanism has been questioned in recent years by the discovery that some large protein complexes could get inside the heterochromatin domain, while smaller proteins can remain shut out.

In this new study of early Drosophila embryos, the researchers observed two non-mixing liquids in the cell nucleus: one that contained expressed genes, and one that contained silenced heterochromatin. They found that heterochromatic droplets fused together just like two drops of oil surrounded by water.

In lab experiments, researchers purified heterochromatin protein 1a (HP1a), a main component of heterochromatin, and saw that this single component was able to recreate what they saw in the nucleus by forming liquid droplets.

"We are excited about these findings because they explain a mystery that's existed in the field for a decade," said study lead author Amy Strom, a graduate student in Karpen's lab. "That is, if compaction controls access to silenced sequences, how are other large proteins still able to get in? Chromatin organization by phase separation means that proteins are targeted to one liquid or the other based not on size, but on other physical traits, like charge, flexibility, and interaction partners."

The Berkeley Lab study, which used fruit fly and mouse cells, will be published alongside a companion paper in Nature led by UC San Francisco researchers, who showed that the human version of the HP1a protein has the same liquid droplet properties, suggesting that similar principles hold for human heterochromatin.

Interestingly, this type of liquid-liquid phase separation is very sensitive to changes in temperature, protein concentration, and pH levels.

"It's an elegant way for the cell to be able to manipulate gene expression of many sequences at once," said Strom.

Other cellular structures, including some involved in disease, are also organized by phase separation.

"Problems with phase separation have been linked to diseases such as dementia and certain neurodegenerative disorders," said Karpen.

He noted that as we age, biological molecules lose their liquid state and become more solid, accumulating damage along the way. Karpen pointed to diseases like Alzheimer's and Huntington's, in which proteins misfold and aggregate, becoming less liquid and more solid over time.

"If we can better understand what causes aggregation, and how to keep things more liquid, we might have a chance to combat these types of disease," Strom added.

The work is a big step forward for understanding how DNA functions, but could also help researchers improve their ability to manipulate genes.

"Gene therapy, or any treatment that relies on tight regulation of gene expression, could be improved by precisely targeting molecules to the right place in the nucleus," says Karpen. "It is very difficult to target genes located in heterochromatin, but this understanding of the properties linked to phase separation and liquid behaviors could help change that and open up a third of the genome that we couldn't get to before."

This includes targeting gene-editing technologies like CRISPR, which has recently opened up new doors for precise genome manipulation and gene therapy.

Explore further: Discovery of a novel chromosome segregation mechanism during cell division

More information: Amy R. Strom et al, Phase separation drives heterochromatin domain formation, Nature (2017). DOI: 10.1038/nature22989

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Researchers find new mechanism for genome regulation - Phys.org - Phys.Org

Biomedical researchers tend to envision genes for traits from height to Alzheimers disease as being clustered in a limited number of pathways.

Two assumptions have guided this perspective: that specific traits or diseases are influenced by a few dozen genes andthat this limited menu of genes tends to be governed bymolecular pathways known to be associated with the disease.

For example, researchers might look for genes promoting diabetes in molecular pathways associated with sugar metabolism. Similarly, a hunt for genes that increase the risk for Alzheimers would focus on pathways active in the brain.

But while those assumptions make intuitive sense, Jonathan Pritchard, PhD, professor of genetics and of biology, said he has found that data dont always agree.

Recently, Pritchard and colleagues (shown above) published apaper in Cellsuggesting that the bulk of the inheritance of complex traits comes not from those few dozen core genes but from thousands of gene variants scattered across the genome. Graduate student Evan Boyle and postdoctoral scholar Yang Li, PhD, share lead authorship.

As Ireported in anews release:

The gene activity of cells is so broadly networked that virtually any gene can influence disease, the researchers found. As a result, most of the heritability of diseases is due not to a handful of core genes, but to tiny contributions from vast numbers of peripheral genes that function outside disease pathways.

Any given trait, it seems, is not controlled by a small set of genes. Instead, nearly every gene in the genome influences everything about us. The effects may be tiny, but they add up.

Its an interesting perspective, one that is sure to spur a host of inquiries.

Previously:New technique offers glimpse at human evolution in action,Genetics: A look back at the first 100 years,Computing our evolution Photo by Steve Fisch

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Genes that affect diseases and other traits may be scattered across genome - Scope (blog)

The towering 234-year-old 'Napoleon' oak on the campus of the University of Lausanne in Switzerland has weathered storms both meteorological and political. The tree was young when Napoleons troops passed through town in 1800, and has grown into a majestic city landmark. But through it all, its genome has remained largelyand surprisinglyunchanged.

Researchers at the university discovered this unexpected stability after sequencing the genome in different branches of the tree. Their workposted on June 13 as a bioRxiv preprint, which has not been peer reviewedmeshes with a growing body of evidence that plants are able to shield their stem cells from mutations. The practice may be valuable for sustaining their health over a lifespan that can reach hundreds of years.

If you just accumulate more and more mutations, you would eventually die of mutational meltdown, says Cris Kuhlemeier, a developmental biologist at the University of Bern in Switzerland.

Each time a cell divides, mutations can arise because of errors made while copying the genome. Animals shield their reproductive cells from these mutations by isolating them early in development. These cells, called the germline, then follow a different developmental path, and typically have a low rate of cell division.

But plants do not have a dedicated germline: the cluster of stem cells that gives rise to the reproductive parts of flowers also generates plant stems and leaves. Because of this, scientists thought that the stem cells would accumulate many mutations,and that newer branches at the top of a long-lived tree would be remarkably different from the lower branches.

Plant biologist Philippe Reymond and his team at the University of Lausanne decided to test this hypothesis using the universitys prized oak tree. They sequenced the genome from leaves on lower, older branches and upper, younger ones, and tallied the number of single-letter changes they found in the tree's DNA. (Reymond declined to be interviewed byNaturebecause the paper is currently under review at a scientific journal.)

The team found that the number of mutations was much lower than would be expected based on calculations of the number of cell divisions that occurred between the lower branch and the higher one.

Its a tantalizing study, says Daniel Schoen, a plant evolutionary biologist at McGill University in Montreal, Canada. It touches on something that was simmering always, in the back of the minds of plant biologists.

It is too soon to say how general this phenomenon will be in plants, cautions Karel ha, a plant geneticist at the Central European Institute of Technology in Brno, Czech Republic. The researchers also looked only at one kind of genetic changesingle-letter changes to the sequenceand did not evaluate other kinds of mutations, such as deleted DNA.

Mao-Lun Weng, a plant evolutionary biologist at South Dakota State University in Brookings, notes that the team used a stringent filter to weed out background noise in the sequencing data, and may have inadvertently missed some mutations as a result.

This could mean that some mutations were left out of the analysis. But ha and Weng are quick to note that the results are in line with two studies published last year. In the first, led by Kuhlemeier, researchers tracked individual stem-cell divisions in the growth region of plants called the meristem. They found that in tomato and thale cress (Arabidopsis), the meristem contains a set of three or four cells that are set aside and divide much less often than the other cells in the region. The other study, led by ha, also found few mutations between old and new leaves in thale cress.

For Kuhlemeier, the results provide an answer to a question that has troubled him ever since a trip to Oregon 20 years ago. As he looked up at a soaring, 400-year-old Douglas fir, Kuhlemeier wondered how the branches towards the top of the tree would differ from those at the bottom. I had always thought of a tree not as an organism, but as a collection of organisms with different genomesmore like a colony, he says. Many ecologists shared his view, but now he has begun to question his earlier idea.

A clearer picture of plant development could help breeders as they increasingly focus on long-lived, perennial plants, says Schoen. If, as plants age, there is this mutation accumulation that could impact vigour, we would want to know about it, he says. We need more information of this type.

This article is reproduced with permission and wasfirst publishedon June 19, 2017.

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Ancient Oak's Youthful Genome Surprises Biologists - Scientific ... - Scientific American

WASHINGTON, June 19, 2017 Scientists say they are gaining a new understanding of why corn or maize as it is widely known outside the U.S. and not some other plant, is the most productive and widely grown crop in the world, after deciphering a new, much more detailed reference genome for the plant.

Among other things, according to a paper published recently in the journal Nature, the new sequence shows that that maize individuals are much, much less alike at the level of the genome than people are.

Our new genome for maize shows how incredibly flexible this plant is, a characteristic that directly follows from the way its genome is organized, says Doreen Ware, of Cold Spring Harbor Laboratory (CSHL) and the U.S. Department of Agriculture, who led scientists at seven academic institutions and several genome technology companies in the project.

Ware says this flexibility not only helps explain why maize has been so successful since its adaptation by primitive farmers thousands of years ago, but also bodes well for its ability to grow in new places as the earths climate changes, and for increasing the plants productivity and environmental sustainability in the U.S. and abroad.

The maize genome is large, but its size is not really what is responsible for what scientists call the plants phenotypic plasticity, that is the potential range in its ability to adapt. In trying to determine what possibilities are available to a plant when adapting to new or changing conditions, it is just as much the context in which genes are activated or silenced as the identity of the genes themselves that determines what the total set of genes enables a plant to do, Ware explains.

It is precisely this context of gene activity variations in way the plants genes are regulated in different individuals across the species that the new genome is bringing to light, the researchers said in a release. By assembling a highly accurate and very detailed reference genome for an important maize line called B73, and then comparing it with genome maps for maize individuals from two other lines (W22 and Ki11), grown in different climates, the sequencing team arrived at an astonishing realization.

Maize individuals are much, much less alike at the level of the genome than people are, for one thing, Ware says. The genome maps of two people will each match the reference human genome at around 98 percent of genome positions. Humans are virtually identical, in genome terms. But weve found that two maize individuals from the W22 and Ki11 lines each align with our new reference genome for B73 maize only 35 percent, on average. Their genome organization is incredibly different, she says.

Yinping Jiao, a postdoctoral researcher in the Ware lab and first author of the paper announcing the new genome, said this difference between maize individuals is a reflection not only of changes in the sequence of the genes themselves, but also where and when genes are expressed, and at what levels.

It is possible to home in on these variabilities in gene expression in unprecedented detail in the new reference genome sequence. The first reference genome for maize, completed in 2009, was a major milestone, but owing to now outdated technology, it yielded a final genome text more akin to a speed-reading version than one fit for close reading, says Ware.

The 2009 sequence tended to miss two things. So-called first-generation sequencing technology could not solve the great number of repetitive sequences in the maize genome, and tended to miss a significant number of spaces between genes. Because so many tiny pieces had to be stitched together to form a whole, it was particularly hard to accurately capture the many places in maize where DNA letters form long repeating sequences. Repeat sequences are especially important in maize, owing to the particular way its genome evolved over millions of years.

The new sequence makes use of what biologists call long-read sequencing, which, as the name suggests, assembles a complete genome from many fewer pieces about 3,000 as opposed to the over 100,000 smaller pieces it took to build the 2009 reference genome. The new technology is also much cheaper; the just completed effort cost around $150,000, compared with more than $35 million for its predecessor.

Long-read technology, by giving scientists a granular view of the space between genes in maize, sheds revealing light on how those genes are regulated, since regulatory elements are often physically situated in regions just up- or downstream from genes.

Because of its amazing phenotypic plasticity, concludes Ware, so many more combinations are available to this plant. What does this mean to breeding? It means we have a very large variation in the regulatory component of most of the plants genes. They have lots of adaptability beyond what we see them doing now. That has huge implications for growing maize as the population increases and climate undergoes major change in the period immediately ahead of us.

The new genomes resolution of spaces between genes -- intergenic regions -- also makes it possible to read detailed histories from the texts of genomes from different maize individuals. We want to understand how the maize genome evolved, Ware says, to be able to look at the genome in an individual and have it tell us a story. Why does the expression of a given gene change, and under what circumstances?

Consider, for instance, the impact of transposons bits of DNA that jump around in genomes. This can now be assessed with specificity not previously possible. Transposons, which are present in all genomes, were first seen and described in maize in the 1940s by CSHL Nobel laureate Barbara McClintock.

The new reference genome helps scientists understand how the history and structure of the maize genome has been determined by the action of transposons more than in most plants. When they jump into a position within a gene, the gene can be compromised entirely. Other times, whether a transposon has hopped into a position just before or after a gene can determine when and how much it is expressed.

While the phenomenon of jumping genes has been understood for decades, its impact in different individuals in various maize lines provides precisely the kind of information that can help explain the plants evolutionary success.

The plants genomic plasticity is also a boon to breeders. Diversity in maize is the resource base for breeding, says Jiao. Its the key to making better maize, and more of it, in the future.

(Employees of two companies were involved in the research and co-authored the paper: Pacific Biosciences of Menlo Park (sequencing); and BioNano Genomics of San Diego (optical mapping). The paper, titled Improved maize reference genome with single molecule technologies, can be accessed by clicking here.)

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Corn genome research bodes well for plant's adaptation to climate change - Agri-Pulse