Human Genome's Breaking Points: Genetic Sequence of Large-Scale Differences Between Human Genomes

Human Genome's Breaking Points: Genetic Sequence of Large-Scale Differences Between Human Genomes

  10:04:00 AM    Science Lover

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A detailed analysis of data from 185 human genomes sequenced in the course of the 1000 Genomes Project, by scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, in collaboration with researchers at the Wellcome Trust Sanger Institute in Cambridge, UK, as well as the University of Washington and Harvard Medical School, both in the USA, has identified the genetic sequence of an unprecedented 28 000 structural variants (SVs) -- large portions of the human genome which differ from one person to another.

The work, published in Nature, could help find the genetic causes of some diseases and also begins to explain why certain parts of the human genome change more than others.

Scientists have identified the genetic sequence of an unprecedented 28,000 structural variants -- large portions of the human genome which differ from one person to another. (Credit: iStockphoto/Andrey Prokhorov)

The international team of scientists identified over a thousand SVs that disrupt the sequence of one or more genes. These gene-altering mutations may be linked to diseases, so knowing the exact genetic sequence of these variations will help clinical geneticists to narrow down their searches for disease-causing mutations.

"Knowing the exact genetic sequence of SVs and their context in the genome could help find the genetic causes for as-yet unexplained diseases," says Jan Korbel, who led the research at EMBL: "this may help us understand why some people remain healthy until old age whereas others develop diseases early in their lives."

This unprecedented catalogue of large-scale genetic variants also sheds light on why some parts of the genome mutate more frequently than others. The scientists found that deletions, where genetic material is lost, and insertions, where it is gained, tend to happen in different places in the genome and through different molecular processes. For instance, large-scale deletions are more likely to occur in regions where DNA often breaks and has to be put back together, as 'chunks' of genetic material can be lost in the process.

"We found 51 hotspots where certain SVs, such as large deletions, appear to occur particularly often" Korbel says: "Six of those hotspots are in regions known to be related to genetic conditions such as Miller-Dieker syndrome, a congenital brain disease that can lead to infant death."

Previous research had already linked SVs -- also called copy-number variants -- to many genetic conditions, such as colour-blindness, schizophrenia, and certain forms of cancer. However, because of their large size and complex DNA sequence, SVs were difficult to identify. In this study, the researchers overcame these difficulties, developing novel computational approaches that allowed them to pinpoint the exact locations of these large-scale variations in the genome, broadening the potential scope of future disease studies.

"There are many structural variants in everyone's genomes and they are increasingly being associated with various aspects of human health" says Charles Lee, a clinical cytogeneticist and associate professor at Harvard Medical School and Brigham and Women's Hospital, and joint leader of the study: "It is important to be able to identify and comprehensively characterize these genetic variants using state-of-the-art DNA sequencing technologies."

Data from this study is being made publicly available to the scientific community through the 1000 Genomes Project, an international public-private consortium to build the most detailed map of human genetic variation to date. The 1000 Genomes Project aims to sequence 2500 whole genomes by the end of 2012, resulting, by far, in the largest collection of human genomes to date.

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A New Way to Make Stem Cells Using RNA instead of DNA could avoid the health risks--and the political pitfalls--of stem-cell treatments.

A New Way to Make Stem Cells Using RNA instead of DNA could avoid the health risks--and the political pitfalls--of stem-cell treatments.

  1:27:00 AM    Science Lover

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A Harvard researcher has developed a way to make pluripotent stem cells that solves several of the major impediments to using them to treat human diseases.

New cell: This microscope image shows neurons
(colored green) created from pluripotent stem
cells using modified RNA.
Credit: Phil Manos, Cell Press

Derrick Rossi, an assistant professor at Harvard Medical School, created pluripotent stem cells--which can turn into virtually any other type of cell in the body--from non-stem cells without using viruses to tinker with a cell's genome, as conventional methods do. This means that Rossi's method could be substantially safer for treating disease. The work is published today in the journal Cell Stem Cell.

"Rossi has figured out how to turn a skin cell into a stem cell without genetic modifications, and to do it efficiently," said Doug Melton, codirector of the Harvard Stem Cell Institute, where Rossi is a principal faculty member, at a press conference.

Rossi's innovation, which has not yet been tested in people, was to use messenger RNA instead of DNA to produce the four proteins needed to reprogram the cell. He has started a company called ModeRNA to commercialize this use of messenger RNA. He said the approach may also have potential in gene therapy, which also relies on viruses to deliver treatment, but he declined to talk further about the company or possible gene therapy applications because the work is at such an early stage.

Improving the usability of man-made stem cells is key to helping patients and ending the political morass that has slowed stem-cell research. On Tuesday, a U.S. federal appeals court allowed federal funding of embryonic stem-cell research to continue while a legal case against such funding proceeds.

The human embryonic stem cells used in research were mostly derived from embryonic tissue grown a decade ago. These are the most versatile cells in the body, and the gold standard by which man-made cells are judged.

Four years ago, Japanese researcher Shinya Yamanaka showed that regular cells could be turned into embryonic-like stem cells--called induced pluripotent stem (iPS) cells--through the introduction of four specific proteins. Theoretically, this meant that doctors could take skin cells from a sick or disabled person, transform them into stem cells, and then into a specialized cell to treat them--an insulin-producing islet cell for someone with diabetes or a nerve cell for someone who is paralyzed, for instance. Using iPS cells avoids the need to destroy embryos and, because they can be derived from the patient's own cells, means less risk of rejection.

But only one in 1,000 or one in 10,000 skin cells could be transformed into a stem cell using Yamanaka's method. It also changes a cell's genes in ways that might trigger cancer or other problems.

Rossi 's idea was to produce Yamanaka's four proteins in a different way. Instead of using the DNA that holds the instructions for making proteins, he wanted to use RNA, which carries those instructions to the place in a cell where proteins are made.

His first several attempts were miserable failures. When he tried to change the messages the RNA carried, he triggered a serious immune response and most of the cells shut down or self-destructed. Rossi then tried modifying the RNA chemically and eventually figured out a way to allow his changes to escape immune detection while delivering the message. "This was key to our success," said Rossi, who is also a researcher at Children's Hospital Boston. "We could encode RNA for any protein we wanted to express and insert it into a cell."

Rossi said it was a happy coincidence that using RNA instead of changing the DNA was as much as 100-fold more efficient. He said the effect was possibly because the process more closely reflects how cells themselves transform.

Rossi successfully differentiated his stem cells into muscle cells using RNA, a process that may offer promise in gene therapy and other treatments. His method does not alter the cell's underlying genome, though Rossi admits that he does not yet understand what it does to the cell's epigenome, which controls expression of genes.

Rossi said that his cells, which he's named RiPS, for "RNA induced Pluripotent Stem" cells, are more like embryonic stem cells than traditional iPS cells because they have not been genetically altered.

Melton said the Harvard Stem Cell Institute, which includes several hundred stem-cell researchers from across Harvard University and its affiliated hospitals, will now be making its standard iPS cells with Rossi's method.

In a prepared statement, Yamanaka, now at the University of California, San Francisco, said Rossi's approach to generating stem cells seems promising, and he would like to have someone in his lab try it.

"The quality of the induced pluripotent stem cells generated by this method should be carefully examined because their characteristics vary depending on the induction methods and the origins of the resulting cells," he said. "The standard method to generate iPSCs for clinical applications has yet to be established. I think this method has the potential for it."

Jacob Hanna, a postdoctoral fellow at the Whitehead Institute for Biomedical Research in Cambridge, said he's also eager to begin working with the cells.

"I think it's a very exciting paper with a very promising method," said Hanna, who was not involved in the research. When asked if he was jealous that Rossi had developed the method first, Hanna said, "Yes, of course! It's a very nice paper," quickly adding, "Jealous in a very positive and supporting way."

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Ancestral Populations Of India And Relationships To Modern Groups Revealed

Ancestral Populations Of India And Relationships To Modern Groups Revealed

  10:55:00 AM    Science Lover

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In a study published in the September 24th issue of Nature, an international team describes how they harnessed modern genomic technology to explore the ancient history of India, the world's second most populous nation.

A map showing the groups across India included in the Nature study. 

(Credit: Photo courtesy of D. Reich, K. Thangaraj, N. Patterson, A. Price and L. Singh)

The new research reveals that nearly all Indians carry genomic contributions from two distinct ancestral populations. Following this ancient mixture, many groups experienced periods of genetic isolation from each other for thousands of years. The study, which has medical implications for people of Indian descent, was led by scientists at the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad, India together with US researchers at Harvard Medical School, the Harvard School of Public Health and the Broad Institute of Harvard and MIT.

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Why We Learn More From Our Successes Than Our Failures

Why We Learn More From Our Successes Than Our Failures

  9:10:00 PM    Science Lover

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If you've ever felt doomed to repeat your mistakes, researchers at MIT's Picower Institute for Learning and Memory may have explained why: Brain cells may only learn from experience when we do something right and not when we fail.

Given different images as cues, monkeys were trained to look right or left for rewards.
MIT neuroscientists found that neurons responded differently following correct and
incorrect responses, with correct responses setting up the brain for additional successes.
(Credit: Courtesy / Earl Miller)

In the July 30 issue of the journal Neuron, Earl K. Miller, the Picower Professor of Neuroscience, and MIT colleagues Mark Histed and Anitha Pasupathy have created for the first time a unique snapshot of the learning process that shows how single cells change their responses in real time as a result of information about what is the right action and what is the wrong one.

"We have shown that brain cells keep track of whether recent behaviors were successful or not," Miller said. Furthermore, when a behavior was successful, cells became more finely tuned to what the animal was learning. After a failure, there was little or no change in the brain — nor was there any improvement in behavior.

The study sheds light on the neural mechanisms linking environmental feedback to neural plasticity — the brain's ability to change in response to experience. It has implications for understanding how we learn, and understanding and treating learning disorders.

Rewarding success

Monkeys were given the task of looking at two alternating images on a computer screen. For one picture, the animal was rewarded when it shifted its gaze to the right; for another picture it was supposed to look left. The monkeys used trial and error to figure out which images cued which movements.

The researchers found that whether the animals' answers were right or wrong, signals within certain parts of their brains "resonated" with the repercussions of their answers for several seconds. The neural activity following a correct answer and a reward helped the monkeys do better on the trial that popped up a few seconds later.

"If the monkey just got a correct answer, a signal lingered in its brain that said, 'You did the right thing.' Right after a correct answer, neurons processed information more sharply and effectively, and the monkey was more likely to get the next answer correct as well," Miller said, "But after an error there was no improvement. In other words, only after successes, not failures, did brain processing and the monkeys' behavior improve."

Split-second influence

The prefrontal cortex orchestrates thoughts and actions in accordance with internal goals while the basal ganglia are associated with motor control, cognition and emotions. This work shows that these two brain areas, long suspected to play key roles in learning and memory, have full information available to them to do all the neural computations necessary for learning.

The prefrontal cortex and basal ganglia, extensively connected with each other and with the rest of the brain, are thought to help us learn abstract associations by generating brief neural signals when a response is correct or incorrect. But researchers never understood how this transient activity, which fades in less than a second, influenced actions that occurred later.

In this study, the researchers found activity in many neurons within both brain regions that reflected the delivery or withholding of a reward lasted for several seconds, until the next trial. Single neurons in both areas conveyed strong, sustained outcome information for four to six seconds, spanning the entire time frame between trials.

Response selectivity was stronger on a given trial if the previous trial had been rewarded and weaker if the previous trial was an error. This occurred whether the animal was just learning the association or was already good at it.

After a correct response, the electrical impulses coming from neurons in each of the brain areas was more robust and conveyed more information. "The signal-to-noise ratio improved in both brain regions," Miller said. "The heightened response led to them being more likely to get the next trial correct, too. This explains on a neural level why we seem to learn more from our successes than our failures."

In addition to Miller, authors include former MIT graduate student Mark H. Histed, now a postdoctoral fellow at Harvard Medical School, and former postdoctoral fellow Anitha Pasupathy, now an assistant professor at the University of Washington.

This work is supported by National Institute of Neurological Disorders and Stroke and the Tourette's Syndrome Association.

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New Nanoparticles Could Lead To End Of Chemotherapy

New Nanoparticles Could Lead To End Of Chemotherapy

  9:56:00 PM    Science Lover

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Nanoparticles specially engineered by University of Central Florida Assistant Professor J. Manuel Perez and his colleagues could someday target and destroy tumors, sparing patients from toxic, whole-body chemotherapies.

Dr. Manuel Perez and his team have been investigating
the use of nanoparticles for medicine for years.
(Credit: Jacque Brund)

Perez and his team used a drug called Taxol for their cell culture studies, recently published in the journal Small, because it is one of the most widely used chemotherapeutic drugs. Taxol normally causes many negative side effects because it travels throughout the body and damages healthy tissue as well as cancer cells.

The Taxol-carrying nanoparticles engineered in Perez's laboratory are modified so they carry the drug only to the cancer cells, allowing targeted cancer treatment without harming healthy cells. This is achieved by attaching a vitamin (folic acid) derivative that cancer cells like to consume in high amounts.

Because the nanoparticles also carry a fluorescent dye and an iron oxide magnetic core, their locations within the cells and the body can be seen by optical imaging and magnetic resonance imaging (MRI). That allows a physician to see how the tumor is responding to the treatment.

The nanoparticles also can be engineered without the drug and used as imaging (contrast) agents for cancer. If there is no cancer, the biodegradable nanoparticles will not bind to the tissue and will be eliminated by the liver. The iron oxide core will be utilized as regular iron in the body.

"What's unique about our work is that the nanoparticle has a dual role, as a diagnostic and therapeutic agent in a biodegradable and biocompatible vehicle," Perez said.

Perez has spent the past five years looking at ways nanotechnology can be used to help diagnose, image and treat cancer and infectious diseases. It's part of the quickly evolving world of nanomedicine.

The process works like this. Cancer cells in the tumor connect with the engineered nanoparticles via cell receptors that can be regarded as "doors" or "docking stations." The nanoparticles enter the cell and release their cargo of iron oxide, fluorescent dye and drugs, allowing dual imaging and treatment.

"Although the results from the cell cultures are preliminary, they are very encouraging," Perez said.

A new chemistry called "click chemistry" was utilized to attach the targeting molecule (folic acid) to the nanoparticles. This chemistry allows for the easy and specific attachment of molecules to nanoparticles without unwanted side products. It also allows for the easy attachment of other molecules to nanoparticles to specifically seek out particular tumors and other malignancies.

Perez's study builds on his prior research published in the prestigious journal Angewandte Chemie Int. Ed. His work has been partially funded by a National Institutes of Health grant and a Nanoscience Technology Center start-up fund.

"Our work is an important beginning, because it demonstrates an avenue for using nanotechnology not only to diagnose but also to treat cancer, potentially at an early stage," Perez said.

Perez, a Puerto Rico native, joined UCF in 2005. He works at UCF's NanoScience Technology Center and Chemistry Department and in the Burnett School of Biomedical Sciences in the College of Medicine. He has a Ph.D. from Boston University in Biochemistry and completed postdoctoral training at Massachusetts General Hospital, Harvard Medical School's teaching and research hospital.

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