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Alcohol-Induced Histone Acetylation Reveals a Gene Network Involved in Alcohol Tolerance

Alcohol-Induced Histone Acetylation Reveals a Gene Network Involved in Alcohol Tolerance | Amazing Science |

Sustained or repeated exposure to sedating drugs such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state.

Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study.

A research team now used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. They surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. The identified a network of genes that are essential for the development of tolerance to sedation by alcohol.

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Single-cell genome sequencing gets better and better

Single-cell genome sequencing gets better and better | Amazing Science |

Researchers led by bioengineers at the University of California, San Diego have generated the most complete genome sequences from single E. coli cells and individual neurons from the human brain. The breakthrough comes from a new single-cell genome sequencing technique that confines genome amplification to fluid-filled wells with a volume of just 12 nanoliters. "Our preliminary data suggest that individual neurons from the same brain have different genetic compositions. This is a relatively new idea, and our approach will enable researchers to look at genomic differences between single cells with much finer detail," said Kun Zhang, a professor in the Department of Bioengineering at the UC San Diego Jacobs School of Engineering and the corresponding author on the paper.


The researchers report that the genome sequences of single cells generated using the new approach exhibited comparatively little "amplification bias," which has been the most significant technological obstacle facing single-cell genome sequencing in the past decade. This bias refers to the fact that the amplification step is uneven, with different regions of a genome being copied different numbers of times. This imbalance complicates many downstream genomic analyses, including assembly of genomes from scratch and identifying DNA content variations among cells from the same individual.


Sequencing the genomes of single cells is of great interest to researchers working in many different fields. For example, probing the genetic make-up of individual cells would help researchers identify and understand a wide range of organisms that cannot be easily grown in the lab from the bacteria that live within our digestive tracts and on our skin, to the microscopic organisms that live in ocean water. Single-cell genetic studies are also being used to study cancer cells, stem cells and the human brain, which is made up of cells that increasingly appear to have significant genomic diversity.

Eduardo Camina Paniagua's curator insight, November 19, 2013 1:55 AM
DNA sequencing is the process of determining the precise order of nucleotides within a DNA molecule. It includes any method or technology that is used to determine the order of the four bases in a strand of DNA. The advent of rapid DNA sequencing methods has greatly accelerated biological and medical research and discovery.

Knowledge of DNA sequences has become indispensable for basic biological research, and in numerous applied fields such as diagnostic, and biological systemathics. The rapid speed of sequencing attained with modern DNA sequencing technology has been instrumental in the sequencing of complete DNA sequences, or genomes of numerous types and species of life, including the human genome and other complete DNA sequences of many animal, plant, and microbiall species.

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Girl who feels no pain could inspire new painkillers

Girl who feels no pain could inspire new painkillers | Amazing Science |

A mutation in one gene means that a girl is unable to sense pain – a discovery that could hold clues for the development of new drugs.


A girl who does not feel physical pain has helped researchers identify a gene mutation that disrupts pain perception. The discovery may spur the development of new painkillers that will block pain signals in the same way.


People with congenital analgesia cannot feel physical pain and often injure themselves as a result – they might badly scald their skin, for example, through being unaware that they are touching something hot.


By comparing the gene sequence of a girl with the disorder against those of her parents, who do not, Ingo Kurth at Jena University Hospital in Germany and his colleagues identified a mutation in a gene called SCN11A.


This gene controls the development of channels on pain-sensing neurons. Sodium ions travel through these channels, creating electrical nerve impulses that are sent to the brain, which registers pain.


Overactivity in the mutated version of SCN11A prevents the build-up of the charge that the neurons need to transmit an electrical impulse, numbing the body to pain. "The outcome is blocked transmission of pain signals," says Kurth.


To confirm their findings, the team inserted a mutated version of SCN11A into mice and tested their ability to perceive pain. They found that 11 per cent of the mice with the modified gene developed injuries similar to those seen in people with congenital analgesia, such as bone fractures and skin wounds. They also tested a control group of mice with the normal SCN11A gene, none of which developed such injuries.


The altered mice also took 2.5 times longer on average than the control group to react to the "tail flick" pain test, which measures how long it takes for mice to flick their tails when exposed to a hot light beam. "What became clear from our experiments is that although there are similarities between mice and men with the mutation, the degree of pain insensitivity is more prominent in humans," says Kurth.


The team has now begun the search for drugs that block the SCN11Achannel. "It would require drugs that selectively block this but not other sodium channels, which is far from simple," says Kurth.


"This is great science," says Geoffrey Wood of the University of Cambridge, whose team discovered in 2006 that mutations in another, closely related ion channel gene can cause insensitivity to pain. "It's completely unexpected and not what people had been looking for," he says.


Wood says that there are three ion channels, called SCN9A, 10A and 11A, on pain-sensing neurons. People experience no pain when either of the first two don't work, and agonising pain when they're overactive. "With this new gene, it's the opposite: when it's overactive, they feel no pain. So maybe it's some kind of gatekeeper that stops neurons from firing too often, but cancels pain signals completely when it's overactive," he says. "If you could get a drug that made SCN11A overactive, it should be a fantastic analgesic."


"It's fascinating that SCN11A appears to work the other way, and that could really advance our knowledge of the role of sodium channels in pain perception, which is a very hot topic," says Jeffrey Mogil at McGill University in Canada, who was not involved in the new study.


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Wide range of differences, mostly unseen, among humans: Silent mutations more significant than expected

Wide range of differences, mostly unseen, among humans: Silent mutations more significant than expected | Amazing Science |

No two human beings are the same. Although we all possess the same genes, our genetic code varies in many places. And since genes provide the blueprint for all proteins, these variants usually result in numerous differences in protein function. But what impact does this diversity have? Bioinformatics researchers at Rutgers University and the Technische Universitaet Muenchen (TUM) have investigated how protein function is affected by changes at the DNA level. Their findings bring new clarity to the wide range of variants, many of which disturb protein function but have no discernible health effect, and highlight especially the role of rare variants in differentiating individuals from their neighbors.

The slightest changes in human DNA can result in an incorrect amino acid being incorporated into a protein. In some cases, all it takes is for a single base to be substituted in a person's DNA, a variant known as a single nucleotide polymorphism (SNP). "Many of these pointmutations have no impact on human health. However, of the roughly 10,000 'missense' SNPs in the human genome – that is, SNPs affecting the protein sequence – at least a fifth can change the function of the protein," explains Prof. Yana Bromberg of the Department of Biochemistry and Microbiology at Rutgers University. "And in some cases, the affected protein is so important and the change so large that we have to wonder why the person with this mutation is still healthy."

Furthermore, two unrelated individuals have thousands of different mutations that affect proteins. Previously, scientists did not fully understand how this large number of mutations affects the coding sequences of DNA. To investigate these "silent" mutations, Bromberg joined forces with Rutgers colleague Prof. Peter Kahn and Prof. Burkhard Rost at TUM.

"We found that many of the mutations are anything but silent," declares Rost, head of the TUM Chair for Bioinformatics and a fellow of the TUM Institute for Advanced Study. The research indicates an extremely wide range of mutations. Many SNPs, for example, are neutral and do not affect protein function. Some, however, cause pathogenic disruption to protein functionality. "There is a gray area between these extremes," Rost explains. "Some proteins have a reduced biological function but are tolerated by the organism and therefore do not directly trigger any disease."


The research team analyzed over one million SNPs from a number of DNA databases. They used artificial learning methods to simulate the impact of DNA mutations on the function of proteins. This approach enabled them to investigate the impact of a large number of SNPs quickly and efficiently.


The study's findings suggest that, with respect to diversity in protein function, the individual differences between two people are greater than previously assumed. "It seems that humans can live with many small changes in protein function," says Rost. One conclusion the researchers draw is that the wide functional spectrum of proteins must play a key role in evolution. In addition, Bromberg says, "Protein functional diversity may also hold the key to developing personalized medicine."

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Researchers find that MC1R mutation that causes red hair also triggers melanoma-promoting pathway

Researchers find that MC1R mutation that causes red hair also triggers melanoma-promoting pathway | Amazing Science |

A person’s skin pigment, which determines hair color and skin tone, is influenced by the melanocortin-1 (MC1R) gene receptor. For the population’s 1 to 2 percent of redheads, a mutation in MC1R accounts for their red hair color and typical light skin. 


Now researchers from Harvard Medical School have discovered that the same MC1R mutation responsible for the red-hair phenotype also promotes an important cancer-causing pathway. The new findings, reported online August 22 in the journal Molecular Cell, help to explain the molecular mechanisms that underlie redheads’ well-known risk of developing melanoma, providing new insights for treating and preventing this dangerous type of skin cancer.


Melanoma is the least common but the most lethal of skin cancers. Accounting for 75 percent of all skin-cancer deaths, melanoma originates in pigment-producing skin cells called melanocytes. Melanoma is believed to be a multistep process (melanomagenesis) of genetic mutations that increase cell proliferation, cell differentiation and cell death and increase an individual’s susceptibility to ultraviolet (UV) radiation. Two types of UV radiation—UVA and UVB—can mutate DNA in skin cells and lead to melanoma.


“In this current study, we have demonstrated that the mutation MC1R-RHCpromotes the PI3K/Akt signaling pathway when a red-haired individual is exposed to UV radiation,” explained co-senior author Wenyi Wei, an HMS associate professor of pathology at Beth Israel Deaconess Medical Center. PI3K/Akt is a well-known cancer-causing pathway that has been implicated in breast cancer, ovarian cancer and lung cancer. 


Previous work by the study’s co-senior author, Rutao Cui of the Boston University Department of Dermatology, had demonstrated that MC1R plays a key role in protecting melanocytes from UV-induced DNA damage. In this current study, Wei and Cui wanted to find out how this was happening.


Led by co-first authors Lixin Wan, an HMS instructor in pathology at Beth Israel Deaconess, and Juxiang Cao at BU, the scientific team embarked on a series of experiments in both cell cultures and mouse models. Their experiments showed that in normal circumstances, MC1R was binding to PTEN, a well-known tumor-suppressor gene. PTEN acts to safeguard against cancer; without PTEN, the end result is elevated signaling in the cancer-causing P13K/Akt pathway.


The team then went on to demonstrate that MC1R-RHC mutations found in red-haired individuals lacked this protective mechanism. “As a result, upon UVB exposure, we saw an increased destruction of PTEN in the mutated pigment cells,” said Wei. The team additionally found that in these sameMC1R-RHC pigment cells, elevated PI3K/Akt activity was boosting cell proliferation and was synchronizing with another well-known cancer mutation in the BRAF gene (found in nearly 70 percent of human melanomas) to further accelerate cancer development. In support of these results, noted Wei and Cui, another research group at Massachusetts General Hospital recently demonstrated that expression of the BRAF gene mutation in the melanocytes of mice carrying a mutated MC1R gene led to a high incidence of invasive melanomas.

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Progeria protein lamin A dramatically accelerates aging and also prevents the spread of cancer

Progeria protein lamin A dramatically accelerates aging and also prevents the spread of cancer | Amazing Science |

Researchers from the Instituto de Medicina Oncológica y Molecular de Asturias have found that a protein responsible for accelerated aging disorders can dramatically slow down the spread of cancers.


The team revealed that prelamin A, responsible for accelerated ageing in a condition called progeria, can prevent the progression of malignant or cancerous tumours. They achieved this by using mosaic mouse models, genetically modified mice bearing the protein prelamin A in half of their cells.


Ageing and cancer are intimately related processes, but their links are complex. The risk of developing tumours increases with age, but some of the mechanisms favouring ageing can also slow down the appearance and development of cancer. The results from this study represent an advance in the understanding of the underlying biological mechanisms that link age and cancer development, as well as possible new drug targets in the future.


"Mice with prelamin A in all their cells age more quickly and do not live longer than 4-5 months, which extremely hampers the study of cancer, as there is no time for the disease to fully develop,"indicates Jorge de la Rosa.


Researchers previously developed mice that have an underactive ZMPSTE24 gene that mimic the ageing disorder progeria to test for possible treatments. This causes the protein prelamin A to accumulate and in turn results in progeria. To better study the association of ageing and cancer development, the team developed a mosaic model where ZMPSTE24 was underactive in half of the cells and working normally in the other half of the cells.


"Mosaic mice, however, live as long as normal mice, up to two to three years, and they keep 50% of cells with prelamin A in all their tissues throughout lifespan, which has permitted us to study the effect of this protein on cancer," comments Juan Cadiñanos.


The team found that the mosaic mice were completely healthy, without any of the physical deformities shown by mice with prelamin A-induced progeria: reduced size and weight, loss of fat, infertility and premature death. This suggests that it might not be necessary to correct the defects in all the cells of patients with progeria, but only some. These results provide hope for a successful treatment of patients with progeria in the future.

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Amazing Science: Genomics Postings

Amazing Science: Genomics Postings | Amazing Science |

Genomics is a discipline within genetics that applies recombinant DNA, Next generation DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the function and structure of genomes - the complete set of DNA within a single cell of an organism). The field includes efforts to determine the entire DNA sequence of organisms and studies of intragenomic phenomena such as heterosis, epistasis, pleiotropy and other interactions between loci and alleles within the genome.

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DNA Founder Closes in on Genetic Culprit for Undescribed Syndrome

DNA Founder Closes in on Genetic Culprit for Undescribed Syndrome | Amazing Science |

Hugh Rienhoff says that his nine-year-old daughter, Bea, is “a fire cracker”, “a tomboy” and “a very sassy, impudent girl”. But in a forthcoming research paper, he uses rather different terms, describing her hypertelorism (wide spacing between the eyes) and bifid uvula (a cleft in the tissue that hangs from the back of the palate). Both are probably features of a genetic syndrome that Rienhoff has obsessed over since soon after Bea’s birth in 2003. Unable to put on much muscle mass, Bea wears braces on her skinny legs to steady her on her curled feet. She is otherwise healthy, but Rienhoff has long worried that his daughter’s condition might come with serious heart problems.


Rienhoff, a biotech entrepreneur in San Carlos, California, who had trained as a clinical geneticist in the 1980s, went from doctor to doctor looking for a diagnosis. He bought lab equipment so that he could study his daughter’s DNA himself — and in the process, he became a symbol for the do-it-yourself biology movement, and a trailblazer in using DNA technologies to diagnose a rare disease (see Nature 449,773–776; 2007).


“Talk about personal genomics,” says Gary Schroth, a research and development director at the genome-sequencing company Illumina in San Diego, California, who has helped Rienhoff in his search for clues. “It doesn’t get any more personal than trying to figure out what’s wrong with your own kid.”


Now nearly a decade into his quest, Rienhoff has arrived at an answer. Through the partial-genome sequencing of his entire family, he and a group of collaborators have found a mutation in the gene that encodes transforming growth factor-β3 (TGF-β3). Genes in the TGF-β pathway control embryogenesis, cell differentiation and cell death, and mutations in several related genes have been associated with Marfan syndrome and Loeys–Dietz syndrome, both of which have symptomatic overlap with Bea’s condition. The mutation, which has not been connected to any disease before, seems to be responsible for Bea’s clinical features, according to a paper to be published in the American Journal of Medical Genetics.


Hal Dietz, a clinician at Johns Hopkins University School of Medicine in Baltimore, Maryland, where Rienhoff trained as a geneticist, isn’t surprised that the genetic culprit is in this pathway. “The overwhelming early hypothesis was that this was related,” says Dietz, who co-discovered Loeys–Dietz syndrome in 2005.


Rienhoff had long been tapping experts such as Dietz for assistance. In 2005, an examination at Johns Hopkins revealed Bea’s bifid uvula. This feature, combined with others, suggested Loeys–Dietz syndrome, which is caused by mutations in TGF-β receptors. But physicians found none of the known mutations after sequencing these genes individually. This was a relief: Loeys–Dietz is associated with devastating cardiovascular complications and an average life span of 26 years.

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A human antiviral enzyme (APOBEC3B) causes DNA mutations that lead to several forms of cancer

A human antiviral enzyme (APOBEC3B) causes DNA mutations that lead to several forms of cancer | Amazing Science |

Researchers have discovered that a human antiviral enzyme 

called APOBEC3B, is responsible for more than half of breast cancer cases. The previous study was published in Nature in February, 2013.


APOBEC3B is part of a family of antiviral proteins that Harris has studied for more than a decade. His effort to understand how these proteins work has led to these surprising discoveries that APOBEC3B is a broadly important cancer mutagen.


"We are very excited about this discovery because it indicates that a single enzyme is one of the largest known contributors to cancer mutation, possibly even eclipsing sources such as UV rays from the sun and chemicals from smoking," says Reuben Harris, a professor of biochemistry, molecular biology and biophysics based in the College of Biological Sciences. Harris, who led the study, is also a member of the Masonic Cancer Center, University of Minnesota.


For the current study, Harris, along with colleagues Michael Burns and Alpay Temiz, analyzed tumor samples from 19 different types of cancer for the presence of APOBEC3B and 10 related proteins. Results showed that APOBEC3B alone was significantly elevated in six types (bladder, cervix, two forms of lung cancer, head & neck, and breast). Levels of the enzyme, which is present in low levels in most healthy tissues, were elevated in several other types of cancer as well.


A second key finding was that the mutational signature of APOBEC3B is a close match to the actual mutation pattern in these cancers. "Much like we each have unique written signatures, these enzymes each leave a unique mark," Harris says.


Findings from both studies are counterintuitive because the enzyme, which is produced by the immune system, is supposed to protect cells from HIV and other viruses, not harm our own genomic DNA.


While it's well known that sunlight and chemical carcinogens can mutate DNA, and that mutations are essential for cancer to develop, Harris is the first to discover that this human enzyme is a major cause mutation in cancer. He believes that APOBEC3B is a biological "double-edged sword" that protects some cells from viruses such as HIV and produces mutations that give rise to cancer in others.


Harris hopes to find a way to block APOBEC3B from mutating DNA, just as sunscreen blocks mutations that lead to melanoma. Many cancer mutations have been identified, but discovering a common source of mutation such as APOBEC3B is expected to help researchers to move "upstream" and look for a way to stop carcinogenesis closer to its source, he says, "like damming a river before it wreaks havoc on downstream areas." It's also possible that a simple test for APOBEC3B could be used to detect cancer earlier.

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Cancer-Linked Fam190a Gene Found to Regulate Cell Division and Chromosomal Stability

Cancer-Linked Fam190a Gene Found to Regulate Cell Division and Chromosomal Stability | Amazing Science |

Johns Hopkins cancer scientists have discovered that a little-described gene known as FAM190A plays a subtle but critical role in regulating the normal cell division process known as mitosis, and the scientists’ research suggests that mutations in the gene may contribute to commonly found chromosomal instability in cancer.


In laboratory studies of cells, investigators found that knocking down expression of FAM190A disrupts mitosis. In three pancreatic cancer-cell lines and a standard human-cell line engineered to be deficient in FAM190A, researchers observed that cells often had difficulty separating at the end of mitosis, creating cells with two or more nuclei. The American Journal of Pathology published a description of the work online May 17, which comes nearly a century after German scientist Theodor Boveri linked abnormal mitosis to cancer. Until now, there had been no common gene alteration identified as the culprit for cancer-linked mitosis.


“These cells try to divide, and it looks like they succeed, except they wind up with a strand that connects them,” explains Scott Kern, M.D., professor of oncology and pathology at Johns Hopkins University School of Medicine and its Kimmel Cancer Center. “The next time they try to divide, all the nuclei come together, and they try to make four cells instead of two. Subsequently, they try to make eight cells, and so on.” Movies of the process taken by Kern’s laboratory are available on the journal Web site.


Kern’s group previously reported that deletions in the FAM190A gene could be found in nearly 40 percent of human cancers. That report, published in 2011 in the journal Oncotarget, and the current one are believed to be the only published papers focused solely on FAM190A, which is frequently altered in human cancers but whose function has been unknown. Alterations in FAM190A messages may be the third most common in human cancers after those for the more well-known genes p53 and p16, Kern says.


“We don’t think that a species can exist without FAM190, but we don’t think severe defects in FAM190A readily survive among cancers,” Kern says. “The mutations seen here are very special – they don’t take out the whole gene but instead remove an internal portion and leave what we call the reading frame. We think we’re finding a more subtle defect in human cancers, in which mitosis defects can occur episodically, and we propose it may happen in about 40 percent of human cancers.”


Abnormalities in FAM190A may cause chromosomal imbalances seen so commonly in cancers, Kern says. Multipolar mitosis is one of the most common functional defects reported in human cancers, and more than 90 percent of human cancers have abnormal numbers of chromosomes.

Kern says he plans to study FAM190A further by creating lab models of the subtle defects akin to what actually is tolerated by human cancer cells.

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World's Largest Blood and Urine Freezer at Biobank is Aiming to Create Trove of Genetic Data

World's Largest Blood and Urine Freezer at Biobank is Aiming to Create Trove of Genetic Data | Amazing Science |
The goal is to put the vast collection of data on genetic variations and health into databases open to researchers and doctors all over the world.


More than 70 medical, research and advocacy organizations active in 41 countries and including the National Institutes of Health announced Wednesday that they had agreed to create an organized way to share genetic and clinical information. Their aim is to put the vast and growing trove of data on genetic variations and health into databases — with the consent of the study subjects — that would be open to researchers and doctors all over the world, not just to those who created them.

Millions more people are expected to get their genes decoded in coming years, and the fear is that this avalanche of genetic and clinical data about people and how they respond to treatments will be hopelessly fragmented and impede the advance of medical science. This ambitious effort hopes to standardize the data and make them widely available.

“We are strong supporters of this global alliance,” said Dr. Francis Collins, director of the National Institutes of Health. “There is lots of momentum now, and we really do want to move quickly.”


In just the past few years, the price of determining the sequence of genetic letters that make up human DNA has dropped a millionfold, said Dr. David Altshuler, deputy director and chief academic officer at the Broad Institute of Harvard and M.I.T. As a result, instead of having access to just a few human genomes — the complete genetic material of a person, including genes and regions that control genes — researchers can now study tens of thousands of them, along with clinical data on peoples’ health and how they fared on various treatments.


In the next few years, Dr. Altshuler said, researchers expect that millions of people will have their genomes sequenced.


“The question is whether and how we make it possible to learn from these data as they grow, in a manner that respects the autonomy and privacy choices of each participant,” he said. No one wants to put DNA sequences and clinical data on the Internet without the permission of patients, he said, so it also is important to allow people to decide if they want their data — with no names or obvious identifiers attached — to be available to researchers.


Medical researchers say the best way forward is to have shared databases. Do patients with a particular genetic aberration tend to do well with a particular therapy? Do patients with another mutation have greater odds of developing cancer?


Dr. Collins said that cancers are so genetically complex that, most of the time, a mutation seen in a cancer patient will be uncommon. To figure out its significance, data from hundreds of thousands of patients — the world’s collected data — on that mutation are needed.

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Genetics of white tigers pinpointed - due to a single gene, SLC45A2

Genetics of white tigers pinpointed - due to a single gene, SLC45A2 | Amazing Science |

Chinese scientists trace the rare white coloration in Bengal tigers to a single change in a gene that affects a host of animals, including humans.


White tigers are a rare variant of the customary orange Bengal sub-species. Today, they are found exclusively in captive programmes where the limited numbers are interbred to maintain the distinctive fur color.


Shu-Jin Luo of Peking University and colleagues investigated the genetics of a family of tigers living in Chimelong Safari Park in Panyu, Guangzhou Province. This ambush of tigers included both white and orange individuals.


The study zeroed in on the pigment gene called SLC45A2, which has long been associated with the light colouration seen in some human populations, and in a range of other animals including horses, chickens, and fish.


The team identified a small alteration in the white-tiger version of SLC45A2 that appears to inhibit the production of red and yellow pigments. This change has no effect on the generation of black pigment - explaining why the whites still have their characteristic dark stripes.


A number of the white tigers found in zoos have health issues, such as eyesight problems and some deformities.


However, Luo and colleagues say these deficiencies are a consequence of inbreeding by humans and that the white coats are in no way indicative of a more general weakness in the Bengal variant.


Establishing this fact means that re-introducing them to the wild under a carefully managed conservation programme might be worth considering.

"The last known free-ranging white tiger was shot in 1958, before which sporadic sightings were made in India," the researchers write.


"Reasons for the extinction of wild white tigers were likely the same as those accounting for the dramatic decline in wild tigers in general: uncontrolled trophy hunting, habitat loss, and habitat fragmentation.


"However, the fact that many white tigers captured or shot in the wild were mature adults suggests that a white tiger in the wild is able to survive without its fitness being substantially compromised."

Kate Richmond's curator insight, June 10, 2013 10:34 AM

This article could be an excellent content-reading activity for students while also bringing up issues of ethics in genetics and single-gene vs. polygenic traits.

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Non-coding Repeats Cause Peptide Clumps

Non-coding Repeats Cause Peptide Clumps | Amazing Science |
Protein aggregates in the brains of some people with dementia or motor neuron disease have a surprising origin.


A repetitive DNA sequence that was not believed to encode proteins is, in fact, the source of insoluble peptide chains that aggregate in the brain cells of patients displaying certain types of neurodegeneration, according to a recent study. These aggregates occur in a wide range of neurodegenerative disorders, so determining their identity is an important first step towards understanding how they might contribute to various pathologies.


FTLD-ALS spectrum disorders are a range of related neurodegenerative disorders from frontotemporal lobar degeneration (FTLD) right through to amyotrophic lateral sclerosis (ALS). Most cases are of unknown origin, but an expanded repeat region in a non-coding part of a gene called C9orf72 “is the most prevalent cause we know of for both FTLD and ALS,” Miller said. Almost all patients with FTLD-ALS have characteristic protein aggregates, or inclusions, in their brain cells, but patients with the C9orf72 mutation have an additional, more prominent type of inclusion.


When the mutation was first discovered, two principle hypotheses arose as to how it might cause disease, said Dieter Edbauer, a professor of translational neurobiochemistry at the Ludwig Maximilians Universität in Munich, Germany, who led the study. One idea is that the RNA transcript containing the repeats might sequester important RNA-binding proteins in aggregates, preventing their proper function. The other hypothesis posits that the repeats might inhibit correct transcription or RNA splicing of C9orf72. The possibility that the repeats might be translated into peptides was a bit of a shot in the dark, Edbauer admitted. “I thought, a lot of big labs will look into [the two main hypotheses], and I don’t have a real chance to compete with them,” he joked.


Although the repeats are in a non-coding region of the C9orf72 gene and thus should not be translated at all, there were precedents for such illegitimate translation and, moreover, the possibility was “so attractive,” said Edbauer. He realized that if translation did occur, the proteins “would be extremely hydrophobic, so it would really make sense that they would aggregate in patients.”


The repeating DNA sequence is 6 nucleotides long, and researchers estimate that several hundred copies of the sequence exist in FTLD-ALS patients carrying the C9orf72 mutation, with healthy people carrying fewer than 25. If translated, the sequence would encode chains of two-amino-acid, or dipeptide, repeats. And, depending on where in the sequence translation is initiated, those dipeptides could be glycine-alanine, glycine-proline, or glycine-arginine.


Edbauer created antibodies to detect all three possible dipeptide chains, and found that all three were present in protein aggregates in the postmortem brains of C9orf72 mutation-carrying patients. The peptide chains were not present in patients without the mutation, however.


Identifying the nature of the inclusions was an important issue to resolve, said Ian Mackenzie, a professor of pathology and laboratory medicine at the University of British Columbia in Vancouver, Canada, who was not involved in the study. But “even if the finding is correct, is it at all relevant from a pathogenic point of view?” he asked. Indeed, it is still possible that the other hypotheses about the C9orf72 mutation are correct and that the aggregates are a by-product.


The mutation could even cause disease by a combination of mechanisms, Mackenzie said. “The next set of experiments [should] be to see whether clearing these peptides or blocking them will protect cells,” Miller added.

Edbauer thinks it is likely the inclusions will turn out to be toxic. “We don’t know in what way they are toxic, but it is unlikely that they are doing anything good,” he said. “Normal people don’t have these proteins at all.”


The absence of the peptides in healthy people also “makes them an attractive target for therapy,” said Edbauer. “One could imagine it might be easier to find a specific strategy to block their synthesis, their toxicity, or their aggregation . . . without causing side effects.”

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BGI to Sequence 2,200 Geniuses in Search for the "Genome Of The Genius"

BGI to Sequence 2,200 Geniuses in Search for the "Genome Of The Genius" | Amazing Science |
In the world of genomics, Chinese biotech giant BGI is big and getting bigger. The firm agreed to purchase Bay Area juggernaut Complete Genomics for a bargain basement $117 million in 2012.

BGI owns 156 DNA sequencers and produces 10% to 20% of the world’s genetic information. Now the firm is putting their DNA sequencing might behind an investigation into the genetics of genius.

Suitably, one of BGI’s homegrown savants, 20-year-old Zhao Bowen, will head up the study. According to his bio, Zhao dropped out of high school to join BGI “after a startlingly productive internship contributing to BGI’s cucumber sequencing project.” His smart gene study promises to be a bit more challenging.

According to the Wall Street Journal, 1,600 of the study’s 2,200 genomes were provided by Dr. Robert Plomin of King’s College, London. Plomin collected the DNA of individuals with IQs over 160 (average IQ is said to be around 100) who had previously participated in a program called the Study of Mathematically Precocious Youth. BGI signed up another 500 on their website. (The WSJ doesn’t account for the remaining 100.)

Zhao’s team is already busy sequencing the genomes and optimistically says they’ll be done in three months. The team will compare their genius genomes to a random selection of the population to see if they can isolate differences between the two.

Will they find anything useful? The WSJ compares the study to the genetics of height which depends on “1,000 genetic variations that partly explain why some people are taller than others.” It took 10,000 genomes for scientists to see results. If the genetic determinants of height are subtle and complicated, intelligence must be out of the ballpark, down at the pub, mumbling into a pint of ale.

BGI very clearly gets all this stuff. They know it’s a difficult and controversial topic. Sections of their FAQ read like a financial services disclaimer. “We do not claim that our study design is capable of identifying all g-associated alleles given enough participants, let alone all loci linked with other components of intelligence; or that g is a perfect measurement of intelligence, brain health, etc. We simply wish to start the process of discovery, and believe that this is a good place to begin.”

And maybe that’s enough for now. It’ll be fascinating, and probably controversial, when the team announces their findings. After all, if someone thinks they’ve found the genes behind intelligence—what then will they do with that information?

Thomas Faltin's curator insight, December 31, 2013 6:23 AM

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Genome-wide signatures of convergent evolution in echolocating mammals

Genome-wide signatures of convergent evolution in echolocating mammals | Amazing Science |
Evolution is typically thought to proceed through divergence of genes, proteins and ultimately phenotypes. However, similar traits might also evolve convergently in unrelated taxa owing to similar selection pressures.


Adaptive phenotypic convergence is widespread in nature, and recent results from several genes have suggested that this phenomenon is powerful enough to also drive recurrent evolution at the sequence level. Where homoplasious substitutions do occur these have long been considered the result of neutral processes. However, recent studies have demonstrated that adaptive convergent sequence evolution can be detected in vertebrates using statistical methods that model parallel evolution, although the extent to which sequence convergence between genera occurs across genomes is unknown.


A group of scientists recently analyzed genomic sequence data in mammals that have independently evolved echolocation and show that convergence is not a rare process restricted to several loci but is instead widespread, continuously distributed and commonly driven by natural selection acting on a small number of sites per locus.


Systematic analyses of convergent sequence evolution in 805,053 amino acids within 2,326 orthologous coding gene sequences compared across 22 mammals (including four newly sequenced bat genomes) revealed signatures consistent with convergence in nearly 200 loci. Strong and significant support for convergence among bats and the bottlenose dolphin was seen in numerous genes linked to hearing or deafness, consistent with an involvement in echolocation. Unexpectedly, we also found convergence in many genes linked to vision: the convergent signal of many sensory genes was robustly correlated with the strength of natural selection. 



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Inner Ear Dysfunction Due to a Mutation of SLC12A2 Linked to Hyperactivity

Inner Ear Dysfunction Due to a Mutation of SLC12A2 Linked to Hyperactivity | Amazing Science |

Hyperactivity can be a frustrating experience for children as well as for their parents, teachers and other caregivers. The state typically is viewed simply as abnormal behavior, with little understanding of its causes. Now, research with mice points to an unlikely source: a defective inner ear.


The physiological link between hyperactivity and the inner ear lies within a mutation in a gene called Slc12a2. Normally, the gene encodes an SLC12A2 protein important in maintaining proper ionic balance and cell volume. This protein is broadly expressed in tissues, including in the central nervous system (CNS) and the inner ear.


The mechanism behind the biological link occurs when Slc12a2 holds a specific mutation that turns a codon (a genetic sequence) for potassium lysine into a stop codon (which terminates protein production). Researchers at Albert Einstein College of Medicine in New York City found that when this mutation took place there was a loss of detectable SLC12A2 protein. Its deficit in the inner ear resulted in a collapse of Reissner’s membrane inside the cochlea as well as additional membranes in the inner ear’s vestibular compartments (which deal with balance and spatial orientation). They were surprised to find, however, that when the mutation occurred in the genes within the particular brain regions such as the cortex, striatum (forebrain), cerebellum or throughout the CNS, neither abnormal behavior nor inner ear dysfunction resulted.


Michelle Antoine, then a neuroscience PhD student, suspected a physiological link when she noticed a set of mice in geneticist Jean Hébert’s lab behaving abnormally—chasing their tails and almost always moving. After analyzing the mice’s CNS and peripheral nervous systems, she found that the animal’s inner ears were defective and their brains exhibited some abnormalities. She realized the mice provided an opportunity to study the association between ear defects and abnormal behavior.


Hébert hopes that the finding could shift the focus of hyperactivity treatment from altering simple behavior to biology. Still, he thinks further research must be done before the gap can be bridged between treating mice and treating humans.

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Unusual Mechanism of DNA Synthesis Could Explain Certain Genetic Mutations

Unusual Mechanism of DNA Synthesis Could Explain Certain Genetic Mutations | Amazing Science |
Researchers have discovered how cells repair a potentially devastating kind of DNA damage.


The repair of chromosomal double strand breaks (DSBs) is crucial for the maintenance of genomic integrity. However, the repair of DSBs can also destabilize the genome by causing mutations and chromosomal rearrangements, the driving forces for carcinogenesis and hereditary diseases.


Break-induced replication (BIR) is one of the DSB repair pathways that is highly prone to genetic instability. BIR proceeds by invasion of one broken end into a homologous DNA sequence followed by replication that can copy hundreds of kilobases of DNA from a donor molecule all the way through its telomere. The resulting repaired chromosome comes at a great cost to the cell, as BIR promotes mutagenesis, loss of heterozygosity, translocations, and copy number variations, all hallmarks of carcinogenesis. BIR uses most known replication proteins to copy large portions of DNA, similar to S-phase replication. It has therefore been suggested that BIR proceeds by semiconservative replication; however, the model of a bona fide, stable replication fork contradicts the known instabilities associated with BIR such as a 1,000-fold increase in mutation rate compared to normal replication.


The collaborative work of graduate students working under Anna Malkova, associate professor of biology at Indiana University-Purdue University Indianapolis (IUPUI) and Kirill Lobachev, associate professor of biology at the Georgia Institute of Technology have now discovered that in budding yeast the mechanism of replication during BIR is significantly different from S-phase replication, as it proceeds via an unusual bubble-like replication fork that results in conservative inheritance of the new genetic material. They provide evidence that this atypical mode of DNA replication, dependent on Pif1 helicase, is responsible for the marked increase in BIR-associated mutations.


Lobachev’s lab used cutting-edge analysis techniques and equipment available at only a handful of labs around the world. This allowed the researchers to see inside yeast cells and freeze the break-induced DNA repair process at different times. They found that this mode of DNA repair doesn’t rely on the traditional replication fork — a Y-shaped region of a replicating DNA molecule — but instead uses a bubble-like structure to synthesize long stretches of missing DNA. This bubble structure copies DNA in a manner not seen before in eukaryotic cells.


Traditional DNA synthesis, performed during the S-phase of the cell cycle, is done in semi-conservative manner as shown by Matthew Meselson and Franklin Stahl in 1958 shortly after the discovery of the DNA structure. They found that two new double helices of DNA are produced from a single DNA double helix, with each new double helix containing one original strand of DNA and one new strand.


“We demonstrated that break-induced replication differs from S-phase DNA replication as it is carried out by a migrating bubble instead of a normal replication fork and leads to conservative DNA synthesis promoting highly increased mutagenesis,” Malkova said.


This desperation replication triggers “bursts of genetic instability” and could be a contributing factor in tumor formation. “From the point of view of the cell, the whole idea is to survive, and this is a way for them to survive a potentially lethal event, but it comes at a cost,” Lobachev said. “Potentially, it’s a textbook discovery.”


During break-induced replication, one broken end of DNA is paired with an identical DNA sequence on its partner chromosome. Replication that proceeds in an unusual bubble-like mode then copies hundreds of kilobases of DNA from the donor DNA through the telomere at the ends of chromosomes.


“Surprisingly, this is a way of synthesizing DNA in a very robust manner,” Saini said. “The synthesis can take place and cover the whole arm of the chromosome, so it’s not just some short patches of synthesis.”


The bubble-like mode of DNA replication can operate in non-dividing cells, which is the state of most of the body’s cells, making this kind of replication a potential route for cancer formation. “Importantly, the break-induced replication bubble has a long tail of single-stranded DNA, which promotes mutations,” Ramakrishnan said.


The single-stranded tail might be responsible for the high mutation-rate because it can accumulate mutations by escaping the other repair mechanisms that quickly detect and correct errors in DNA synthesis. “When it comes to cancer, other diseases and even evolution, what seems to be happening are bursts of instability, and the mechanisms promoting such bursts were unclear,” Malkova said.


The molecular mechanism of break-induced replication unraveled by the new study provides one explanation for the generation of mutations. We propose that the BIR mode of synthesis presents a powerful mechanism that can initiate bursts of genetic instability in eukaryotes, including humans.

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Distinct brain disorders like Schizophrenia and Learning Disorder biologically linked

Distinct brain disorders like Schizophrenia and Learning Disorder biologically linked | Amazing Science |

A team of researchers have shown that schizophrenia and a disorder associated with autism and learning difficulties share a common biological pathway. This is one of the first times that researchers have uncovered genetic evidence for the underlying causes of schizophrenia.


The team found that a disruption of the gene TOP3B, an exceedingly rare occurrence in most parts of the world, is fairly common in a uniquely genetically distinct founder population from North-eastern Finland. In this population, which has grown in relative isolation for several centuries, the disruption of TOP3B is associated with an increased risk of schizophrenia as well as with impairment in intellectual function and learning.


Furthermore, the biochemical investigation of the protein encoded by the TOP3B gene allowed the researchers to gain first insight into the cellular processes that might be disturbed in the affected individuals.


Although the past two decades have revealed a wealth of information about the genetics of disease, we still know little about the biology behind schizophrenia. Many associations between schizophrenia and genetic risk factors have been reported, but only a very few can be considered schizophrenia susceptibility genes. This study uncovers an important biological pathway that appears to underlie schizophrenia and could contribute to the cognitive impairment that is an important component of this disorder.


"This is a tremendous discovery for our team; not only have we uncovered vital information about the biology behind schizophrenia, but we have also linked this same biological process to a disorder associated with learning difficulties," says Dr Aarno Palotie, lead author from the Wellcome Trust Sanger Institute, the Broad Institute of MIT and Harvard and the Institute for Molecular Medicine Finland. "Our findings offer great hope for future studies into the genetic basis of schizophrenia and other brain disorders, potentially finding new drug targets against them."

The North-eastern population of Finland has three times the frequency of schizophrenia compared to the national average in Finland, as well as a higher rate of intellectual impairment and learning difficulties. The team used data collected from this unique population to sift through genomic data for genetic deletions that may influence people's susceptibility to schizophrenia.

The team identified a rare genetic deletion affecting TOP3B in the North-eastern Finnish population that increases a person's susceptibility to schizophrenia two-fold and that also is associated with an increased frequency of other disorders of brain development such as intellectual impairment. They speculate that this deletion directly disrupts the TOP3B gene to cause its effects on the brain.


TOP3B encodes a type of protein that typically helps the cell to unwind and wind DNA helices - essential to normal cell function. Quite unexpectedly for an enzyme of this class, however, TOP3B was found to act on messenger-RNA rather than DNA.


In their further biochemical investigation into TOP3B, the team found that the TOP3B protein interacts with a protein known as FMRP. The deactivation or disruption of this protein is responsible for Fragile X syndrome, a disorder associated with autism and learning difficulties, primarily in men.


Within the northern Finnish population, the team identified four people who did not have a functioning copy of the TOP3B gene. These four people were either diagnosed as having learning difficulties or as having schizophrenia, solidifying the evidence that this gene is important in these brain disorders and that they are biologically linked.


"These two disorders, schizophrenia and Fragile X syndrome, although they may seem drastically different, share key features, particularly the cognitive impairment that is frequently associated with both conditions," says Dr Nelson Freimer, author from UCLA. "So, it is not unexpected that they could share some of the same biological processes.

"What is fantastic about this study is that through investigations in an isolated corner of Finland we are contributing to concerted international efforts that are beginning to unravel the genetic root of schizophrenia, a debilitating disorder that affects so many people throughout the world."

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Mutated Genes in Schizophrenia Map to Brain Networks

Mutated Genes in Schizophrenia Map to Brain Networks | Amazing Science |
People with schizophrenia have a high number of spontaneous mutations in genes that form a network in the front region of the brain. The findings reveal new clues about the disorder.


Researchers found that people with schizophrenia have a high number of spontaneous mutations in genes that form a network in the front region of the brain. The findings reveal further clues about the causes of the disorder.

Schizophrenia networks in the prefrontal cortex area of the brain.Image courtesy of Dr. Mary-Claire King, University of Washington.


Schizophrenia is a chronic, severe brain disorder. People with schizophrenia may hear voices or see things that aren’t there. They may believe that people are reading their minds or controlling their thoughts.


The disorder occurs in 1% of the general population. However, it occurs in 10% of people who have a parent, brother or sister with the disorder, indicating that genetics plays a role in its cause.


Previous studies have shown that many people with schizophrenia have de novo, or new, genetic mutations. These misspellings in a gene’s DNA sequence occur spontaneously and so aren’t shared by their close relatives.


Dr. Mary-Claire King of the University of Washington in Seattle and colleagues set out to identify spontaneous genetic mutations in people with schizophrenia and to assess where and when in the brain these misspelled genes are turned on, or expressed. The researchers sequenced the exomes (protein-coding DNA regions) of 399 people—105 with schizophrenia plus their unaffected parents and siblings. Gene variations that were found in a person with schizophrenia but not in either parent were considered spontaneous.


The likelihood of having a spontaneous mutation was associated with the age of the father in both affected and unaffected siblings. Significantly more mutations were found in people whose fathers were 33-45 years at the time of conception compared to 19-28 years.


Among people with schizophrenia, the scientists identified 54 genes with spontaneous mutations predicted to cause damage to the function of the protein they encode. The researchers used newly available database resources that show where in the brain and when during development genes are expressed. The genes, they found, form an interconnected expression network with many more connections than that of the genes with spontaneous damaging mutations in unaffected siblings.


The spontaneously mutated genes in people with schizophrenia were expressed in the prefrontal cortex, a region in the front of the brain. The genes are known to be involved in important pathways in brain development. Fifty of these genes were active mainly during the period of fetal development.

“Processes critical for the brain’s development can be revealed by the mutations that disrupt them,” King says. “Mutations can lead to loss of integrity of a whole pathway, not just of a single gene.”


These findings support the concept that schizophrenia may result, in part, from disruptions in development in the prefrontal cortex during fetal development.

Via Agãpe Lenõre
Linus Ridge's comment, August 15, 2013 5:08 AM
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Amazing Science: Genetics Postings

Amazing Science: Genetics Postings | Amazing Science |

Genetics concerns the process of trait inheritance from parents to offspring, including the molecular structure and function of genes, gene behavior in the context of a cell or organism (e.g. dominance and epigenetics), gene distribution, and variation and change in populations such as through Genome-Wide Association Studies (GWAS). Given that genes are universal to living organisms, genetics can be applied to the study of all living systems; including bacteria, plants, animals, and humans. Modern genetics seeks to understand this process which began with the work of Gregor Mendel.

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Overweight? Blame Your Genes -- Gene discovered that controls how fast calories are burned

Overweight? Blame Your Genes -- Gene discovered that controls how fast calories are burned | Amazing Science |
Researchers have found a genetic mutation that may help explain why some people can eat the same amount as others but gain more weight.


Scientists have long thought explanations for why some people get fat might lie in their genes. They knew body weight was strongly inherited. Years ago, for example, they found that twins reared apart tended to have similar weights and adoptees tended to have weights like their biological parents, not the ones who reared them. As researchers developed tools to look for the actual genes, they found evidence that many — maybe even hundreds — of genes may be involved, stoking appetites, making people voraciously hungry.

In a recent study, Dr. Majzoub and his colleagues describe figuring out how the gene they deleted, known as MRAP2, acts in the brain to control weight. They discovered that it is a helper gene. It normally acts in the brain to signal another gene already known to be involved in controlling appetite. So they developed a hypothesis. If the helper gene was deleted, the brakes should come off the gene that controls appetite. Animals should eat voraciously.

The first thing they noticed was that the mice got fat, ending up weighing twice as much as their normal siblings, with most of that extra weight due to fat accumulation.


“During the mouse equivalent of childhood and adolescence they were becoming rapidly obese,” Dr. Majzoub said.


The surprise came when the researchers figured out why. When the mice were young, they had normal appetites. The researchers measured what they and their normal siblings ate and determined they were eating the same amount of food. Yet the mice with the deleted gene still gained weight. The only way the obesity-prone mice could be kept slim was to be fed 10 to 15 percent less than their siblings.

But as adults, the mice with the missing gene developed monstrous appetites. Given a chance, they ate much more than their siblings, exacerbating the effects of their tendency to turn food into fat.


That led the researchers to ask if the same genetic phenomenon could be making people obese. They contacted Dr. Sadaf Farooqui of the University of Cambridge, whose group has been mapping the genes of massively obese children, and studied the data on 500 of the children, searching for mutations that disabled the same gene they had deleted in mice.


One child clearly had a gene-disabling mutation and three others had mutations that the investigators suspect might render the gene nonfunctional. None of the normal-weight children who served as controls had a mutation in the helper gene.


“From a basic science point of view, this is really interesting and exciting,” said David Allison, an obesity researcher at the University of Alabama in Birmingham who was not involved in the study. Any discovery that helps fill in the details of how the brain controls eating and weight gain is important, he added.


Jeffrey Friedman, an obesity researcher at Rockefeller University, who also was not involved in the study, said, “It is another piece in a very important puzzle.”


Dr. Majzoub and his colleagues are now trying to determine whether additional mutations in the gene they discovered — ones that hinder its function but do not completely disable it — might explain why some people gain weight.


“All we can do is hope,” Dr. Majzoub said.

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Multifunctional Genes: Taste Receptor Gene Inactivation Causes Male Sterility

Multifunctional Genes: Taste Receptor Gene Inactivation Causes Male Sterility | Amazing Science |
Two proteins called TAS1R3 and GNAT3, which have been previously known to be involved in oral taste detection, also play a crucial role in sperm development.


While breeding mice for taste-related studies, Dr Bedrich Mosinger from Monell Chemical Senses Center and his colleagues discovered that they were unable to produce offspring that were simultaneously missing two taste-signaling proteins – TAS1R3 and GNAT3.


TAS1R3 is a component of both the sweet and umami (amino acid) taste receptors. GNAT3 is a molecule needed to convert the oral taste receptor signal into a nerve cell response.


The researchers determined that fertility was affected only in males. Both taste proteins had previously been found in testes and sperm, but until now, their function there was unknown.


This study “highlights a connection between the taste system and male reproduction. It is one more demonstration that components of the taste system also play important roles in other organ systems,” Dr Mosinger explained.

 In order to explore the reproductive function of TAS1R3 and GNAT3, the team engineered mice that were missing genes for the mouse versions of the two proteins but expressed the human form of the TAS1R3 receptor – these mice were fertile. 


However, when the human TAS1R3 was blocked in the engineered mice by adding the drug clofibrate to their diet, thus leaving the mice without any functional TAS1R3 or GNAT3 proteins, the males became sterile due to malformed and fewer sperm.


The sterility was quickly reversed after clofibrate was removed from the diet.

Clofibrate belongs to a class of drugs called fibrates that frequently are prescribed to treat lipid disorders such as high blood cholesterol or triglycerides. Previous studies had revealed that it is a potent inhibitor of the human, but not mouse, TAS1R3 receptor.


“Noting the common use of fibrates in modern medicine and also the widespread use in modern agriculture of the structurally-related phenoxy-herbicides, which also block the human TAS1R3 receptor,” Dr Mosinger said, “these compounds could be negatively affecting human fertility, an increasing problem worldwide.”


“If our pharmacological findings are indeed related to the global increase in the incidence of male infertility, we now have knowledge to help us devise treatments to reduce or reverse the effects of fibrates and phenoxy-compounds on sperm production and quality. This knowledge could further be used to design a male non-hormonal contraceptive,” Dr Mosinger concluded.

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Epigenetics raises the possibility that a smoker can cause grandchildren to get asthma via genetics

Epigenetics raises the possibility that a smoker can cause grandchildren to get asthma via genetics | Amazing Science |

The adverse health effects of smoking can be passed down through multiple generations, according to new experiments conducted at the Los Angeles Biomedical Research Institute. In one experiment, pregnant rats were given nicotine injections that produced asthma in their offspring. What surprised researchers is that third-generation rats (the grandchildren of the smoker rats) also developed asthma. "Nicotine is not only affecting lung cells, [say researchers], but also affecting sex cells in ways that cause the lungs which ultimately develop from those cells to express their genes in the same abnormal ways."

Some biologists are highly skeptical of the recent findings because they appear to run contrary to Darwin's theory of evolution. The suggestion that learned traits, such as a smoking addiction, can be passed down genetically to future generations was initially a theory put forth by the French naturalist Jean-Baptiste Lamarck that rivaled Darwin's evolution. Today, genetic inheritances of learned traits are known as epigenetic changes, a term that refers to the regulation of gene expression by the chemical modification of DNA, or of the histone proteins in which DNA is usually wrapped. 

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Genetic Scientists Eliminate Schizophrenia Symptoms in Mice by Targeting Neuregulin-1 (NRG1)

Genetic Scientists Eliminate Schizophrenia Symptoms in Mice by Targeting Neuregulin-1 (NRG1) | Amazing Science |

Geneticists writing in the journal Neuron reversed schizophrenia-like symptoms in adult mice by restoring normal expression to the gene Neuregulin-1 (NRG1).


Targeting expression of NRG1, which makes a protein important for brain development, may hold promise for treating at least some patients with the brain disorder. Like patients with schizophrenia, adult mice biogenetically-engineered to have higher NRG1 levels showed reduced activity of the brain messenger chemicals glutamate and γ-aminobutyric acid (GABA). The mice also showed behaviors related to aspects of the human illness.

“They genetically engineered mice so they could turn up levels of NRG1 to mimic high levels found in some patients then return levels to normal,” explained senior author Dr Lin Mei from the Medical College of Georgia at Georgia Regents University.


“They found that when elevated, mice were hyperactive, couldn’t remember what they had just learned and couldn’t ignore distracting background or white noise. When they returned NRG1levels to normal in adult mice, the schizophrenia-like symptoms went away.”


While schizophrenia is generally considered a developmental disease that surfaces in early adulthood, the team found that even when they kept NRG1 levels normal until adulthood, mice still exhibited schizophrenia-like symptoms once higher levels were expressed. Without intervention, they developed symptoms at about the same age humans do.


“This shows that high levels of NRG1 are a cause of schizophrenia, at least in mice, because when you turn them down, the behavior deficit disappears,” Dr Mei said. “Our data certainly suggests that we can treat this cause by bringing down excessive levels of NRG1 or blocking its pathologic effects.”


“Schizophrenia is a spectrum disorder with multiple causes – most of which are unknown – that tends to run in families, and high NRG1 levels have been found in only a minority of patients. To reduce NRG1 levels in those individuals likely would require development of small molecules that could, for example, block the gene’s signaling pathways,” Dr Mei said.


“Current therapies treat symptoms and generally focus on reducing the activity of two neurotransmitters since the bottom line is excessive communication between neurons.”


The good news is it’s relatively easy to measure NRG1 since blood levels appear to correlate well with brain levels. To genetically alter the mice, the scientists put a copy of the NRG1 gene into mouse DNA then, to make sure they could control the levels, they put in front of the DNA a binding protein for doxycycline, a stable analogue for the antibiotic tetracycline, which is infamous for staining the teeth of fetuses and babies. The mice are born expressing high levels of NRG1 and giving the antibiotic restores normal levels.


“If you don’t feed the mice tetracycline, the NRG1 levels are always high. Endogenous levels of the gene are not affected. High-levels of NRG1 appear to activate the kinase LIMK1, impairing release of the neurotransmitter glutamate and normal behavior. The LIMK1 connection identifies another target for intervention,” Dr Mei concluded.

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Researchers Identify 4 New Genetic Risk Factors For Testicular Cancer

Researchers Identify 4 New Genetic Risk Factors For Testicular Cancer | Amazing Science |

Tapping into three genome-wide association studies (GWAS), the researchers, including Peter A. Kanetsky, PhD, MPH, an associate professor in the department of Biostatistics and Epidemiology, analyzed 931 affected individuals and 1,975 controls and confirmed the results in an additional 3,211 men with cancer and 7,591 controls. The meta-analysis revealed that testicular germ cell tumor (TGCT) risk was significantly associated with markers at four loci—4q22, 7q22, 16q22.3, and 17q22, none of which have been identified in other cancers. Additionally, these loci pose a higher risk than the vast majority of other loci identified for some common cancers, such as breast and prostate.


This brings the number of genomic regions associated with testicular cancer up to 17—including eight new ones reported in another study in this issue of Nature Genetics.


Testicular cancer is relatively rare; however, incidence rates have doubled in the past 40 years. It is also highly heritable. If a man has a father or son with testicular cancer, he has a four-to six-fold higher risk of developing it compared to a man with no family history. That increases to an eight-to 10-fold higher risk if the man has a brother with testicular cancer.

Given this, researchers continue to investigate genetic variants and their association with cancer.


In 2009, Dr. Nathanson and colleagues uncovered variation around two genes—KITLG and SPRY4—found to be associated with an increased risk of testicular cancer. The two variants were the first striking genetic risk factors found for this disease at the time. Since then, several more variants have been discovered, but only through single GWAS studies.


"This analysis is the first to bring several groups of data together to identify loci associated with disease," said Dr. Nathanson, "and represent the power of combining multiple GWAS to better identify genetic risk factors that failed to reach genome-wide significance in single studies."

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