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Scooped by Dr. Stefan Gruenwald!

FDA permits marketing of first direct-to-consumer genetic carrier test for Bloom syndrome

FDA permits marketing of first direct-to-consumer genetic carrier test for Bloom syndrome | Amazing Science |

The U.S. Food and Drug Administration today authorized for marketing 23andMe’s Bloom Syndrome carrier test, a direct-to-consumer (DTC) genetic test to determine whether a healthy person has a variant in a gene that could lead to their offspring inheriting the serious disorder.

Along with this authorization, the FDA is also classifying carrier screening tests as class II. In addition, the FDA intends to exempt these devices from FDA premarket review. The agency plans to issue a notice that announces the intent to exempt these tests and that provides a 30-day period for public comment. This action creates the least burdensome regulatory path for autosomal recessive carrier screening tests with similar uses to enter the market.

“The FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information. Today’s authorization and accompanying classification, along with FDA’s intent to exempt these devices from FDA premarket review, supports innovation and will ultimately benefit consumers,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “These tests have the potential to provide people with information about possible mutations in their genes that could be passed on to their children.”

In general, carrier testing is a type of genetic testing performed on people who display no symptoms for a genetic disorder but may be at risk for passing it on to their children. A carrier for a genetic disorder has inherited one normal and one abnormal allele for a gene associated with the disorder. A child must inherit two abnormal alleles, one copy from each parent, in order for symptoms to appear.

No test is perfect. Given the probability of erroneous results and the rarity of these mutations, professional societies typically recommend that only prospective parents with a family history of a genetic disorder undergo carrier screening. For example, when a gene mutation is expected to be very rare, a positive result for the mutation may have a high probability of being wrong.

Like other home-use tests for medical purposes, the FDA requires the results to be conveyed in a way that consumers can understand and use. This is the same approach the FDA has taken with other over-the-counter consumer products such as pregnancy, cholesterol and HIV tests for home use

While the FDA is not limiting who should or should not use these tests, it is requiring that the company explain to the consumer in the product labeling what the results might mean for prospective parents interested in seeing if they carry a genetic disorder.  

If sold over the counter, the FDA is also requiring 23andMe to provide information to consumers about how to obtain access to a board-certified clinical molecular geneticist or equivalent to assist in pre- and post-test counseling. 23andMe performed two separate studies to demonstrate that their test is accurate in detecting Bloom syndrome carrier status. One study conducted at two laboratories tested a total of 123 samples, including samples from known carriers of the disease. An additional study evaluated 105 samples at two additional laboratories. Both studies showed equivalent results in detecting carrier status of Bloom syndrome when the same samples were tested.

The company also conducted a usability study with 295 people not familiar with the 23andMe saliva collection device to demonstrate consumers could understand the test instructions and collect an adequate saliva sample.

Finally, the company conducted a user study of 302 randomly recruited participants representing the U.S. general population in age, gender, race and education level to show the test instructions and results were easy to follow and understand.

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Human ancestors may have begun evolving the knack for consuming alcohol about 10 million years ago

Human ancestors may have begun evolving the knack for consuming alcohol about 10 million years ago | Amazing Science |

The ability to break down alcohol likely helped human ancestorsmake the most out of rotting, fermented fruit that fell onto the forest floor, the researchers said. Therefore, knowing when this ability developed could help researchers figure out when these human ancestors began moving to life on the ground, as opposed to mostly in trees, as earlier human ancestors had lived. "A lot of aspects about the modern human condition — everything from back pain to ingesting too much salt, sugar and fat — goes back to our evolutionary history," said lead study author Matthew Carrigan, a paleogeneticist at Santa Fe College in Gainesville, Florida. "We wanted to understand more about the modern human condition with regards to ethanol," he said, referring to the kind of alcohol found in rotting fruit and that's also used in liquor and fuel.

To learn more about how human ancestors evolved the ability to break down alcohol, scientists focused on the genes that code for a group of digestive enzymes called the ADH4 family. ADH4 enzymes are found in the stomach, throat and tongue of primates, and are the first alcohol-metabolizing enzymes to encounter ethanol after it is imbibed. The researchers investigated the ADH4 genes from 28 different mammals, including 17 primates. They collected the sequences of these genes from either genetic databanks or well-preserved tissue samples.

The scientists looked at the family trees of these 28 species, to investigate how closely related they were and find out when their ancestors diverged. In total, they explored nearly 70 million years of primate evolution. The scientists then used this knowledge to investigate how the ADH4 genes evolved over time and what the ADH4 genes of their ancestors might have been like.

Then, Carrigan and his colleagues took the genes for ADH4 from these 28 species, as well as the ancestral genes they modeled, and plugged them into bacteria, which read the genes and manufactured the ADH4 enzymes. Next, they tested how well those enzymes broke down ethanol and other alcohols. This method of using bacteria to read ancestral genes is "a new way to observe changes that happened a long time ago that didn't fossilize into bones," Carrigan said.

The results suggested there was a single genetic mutation 10 million years ago that endowed human ancestors with an enhanced ability to break down ethanol. "I remember seeing this huge difference in effects with this mutation and being really surprised," Carrigan said. The scientists noted that the timing of this mutation coincided with a shift to a terrestrial lifestyle. The ability to consume ethanol may have helped human ancestors dine on rotting, fermenting fruit that fell on the forest floor when other food was scarce.

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Sequenced genomes reveal mutations that disable single genes and can help to identify new drugs

Sequenced genomes reveal mutations that disable single genes and can help to identify new drugs | Amazing Science |
On average, every person carries mutations that inactivate at least one copy of 200 or so genes and both copies of around 20 genes. However, knockout mutations in any particular gene are rare, so very large populations are needed to study their effects. These ‘loss of function’ mutations have long been implicated in certain debilitating diseases, such as cystic fibrosis. Most, however, seem to be harmless — and some are even beneficial to the persons carrying them. “These are people we’re not going to find in a clinic, but they’re still really informative in biology,” says MacArthur.

His group and others had been focusing on genome data, but they are now also starting to mine patient-health records to determine the — sometimes subtle — effects of the mutations. In a study of more than 36,000 Finnish people, published in July (E. T. Lim et al. PLoS Genet. 10, e1004494; 2014), MacArthur and his team discovered that people lacking a gene called LPA might be protected from heart disease, and that another knockout mutation, carried in one copy of a gene by up to 2.4% of Finns, may cause fetuses to miscarry if it is present in both copies.

Bing Yu of the University of Texas Health Science Center in Houston told the meeting how he and his collaborators had compared knockout mutations found in more than 1,300 people with measurements of around 300 molecules in their blood. The team found that mutations in one gene, called SLCO1B1, were linked to high levels of fatty acids, a known risk factor for heart failure. And a team from the Wellcome Trust Sanger Institute in Hinxton, UK, reported that 43 genes whose inactivation is lethal to mice were found to be inactivated in humans who are alive and apparently well.

The poster child for human-knockout efforts is a new class of drugs that block a gene known as PCSK9 (see Nature 496, 152–155; 2013). The gene was discovered in French families with extremely high cholesterol levels in the early 2000s. But researchers soon found that people with rare mutations that inactivate one copy of PCSK9 have low cholesterol and rarely develop heart disease. The first PCSK9-blocking drugs should hit pharmacies next year, with manufacturers jostling for a share of a market that could reach US$25 billion in five years.

“I think there are hundreds more stories like PCSK9 out there, maybe even thousands,” in which a drug can mimic an advantageous loss-of-function mutation, says Eric Topol, director of the Scripps Translational Science Institute in La Jolla, California. Mark Gerstein, a bio­informatician at Yale University in New Haven, Connecticut, predicts that human knockouts will be especially useful for identifying drugs that treat diseases of ageing. “You could imagine there’s a gene that is beneficial to you as a 25-year-old, but the thing is not doing a good job for you when you’re 75.”

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Schizophrenia is not a single disease but rather consists of eight different genetically distinct classes

Schizophrenia is not a single disease but rather consists of eight different genetically distinct classes | Amazing Science |

New research shows that schizophrenia isn’t a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. The finding could be a first step toward improved diagnosis and treatment for the debilitating psychiatric illness.

The research at Washington University School of Medicine in St. Louis is reported online Sept. 15 in The American Journal of Psychiatry. About 80 percent of the risk for schizophrenia is known to be inherited, but scientists have struggled to identify specific genes for the condition.

Now, in a novel approach analyzing genetic influences on more than 4,000 people with schizophrenia, the research team has identified distinct gene clusters that contribute to eight different classes of schizophrenia.

“Genes don’t operate by themselves,” said C. Robert Cloninger, MD, PhD, one of the study’s senior investigators. “They function in concert much like an orchestra, and to understand how they’re working, you have to know not just who the members of the orchestra are but how they interact.” 

Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms in individual patients. In all, the researchers analyzed nearly 700,000 sites within the genome where a single unit of DNA is changed, often referred to as a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and 3,800 healthy controls, learning how individual genetic variations interacted with each other to produce the illness. 

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Single gene (Lhx1) found to control jet lag

Single gene (Lhx1) found to control jet lag | Amazing Science |

The discovery of the role of this gene, called Lhx1, provides scientists with a potential therapeutic target to help night-shift workers or jet lagged travelers adjust to time differences more quickly. The results, published in eLife, can point to treatment strategies for sleep problems caused by a variety of disorders.

“It’s possible that the severity of many dementias comes from sleep disturbances,” says Satchidananda Panda, a Salk associate professor who led the research team. “If we can restore normal sleep, we can address half of the problem.”

Every cell in the body has a “clock” – an abundance of proteins that dip or rise rhythmically over approximately 24 hours. The master clock responsible for establishing these cyclic circadian rhythms and keeping all the body’s cells in sync is the suprachiasmatic nucleus (SCN), a small, densely packed region of about 20,000 neurons housed in the brain’s hypothalamus.

More so than in other areas of the brain, the SCN’s neurons are in close and constant communication with one another. This close interaction, combined with exposure to light and darkness through vision circuits, keeps this master clock in sync and allows people to stay on essentially the same schedule every day. The tight coupling of these cells also helps make them collectively resistant to change. Exposure to light resets less than half of the SCN cells, resulting in long periods of jet lag.

In the new study, researchers disrupted the light-dark cycles in mice and compared changes in the expression of thousands of genes in the SCN with other mouse tissues. They identified 213 gene expression changes that were unique to the SCN and narrowed in on 13 of these that coded for molecules that turn on and off other genes. Of those, only one was suppressed in response to light: Lhx1.

“No one had ever imagined that Lhx1 might be so intricately involved in SCN function,” says Shubhroz Gill, a postdoctoral researcher and co-first author of the paper. Lhx1 is known for its role in neural development: it’s so important, that mice without the gene do not survive. But this is the first time it has been identified as a master regulator of light-dark cycle genes.

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Friends Are the Family You Choose: Genome-Wide Analysis Reveals Genetic Similarities Among Friends

Friends Are the Family You Choose: Genome-Wide Analysis Reveals Genetic Similarities Among Friends | Amazing Science |

If you consider your friends family, you may be on to something. A study from the University of California, San Diego, and Yale University finds that friends who are not biologically related still resemble each other genetically.

Published in the Proceedings of the National Academy of Sciences, the study is coauthored by James Fowler, professor of medical genetics and political science at UC San Diego, and Nicholas Christakis, professor of sociology, evolutionary biology, and medicine at Yale.

“Looking across the whole genome,” Fowler said, “we find that, on average, we are genetically similar to our friends. We have more DNA in common with the people we pick as friends than we do with strangers in the same population.”

The study is a genome-wide analysis of nearly 1.5 million markers of gene variation, and relies on data from the Framingham Heart Study. The Framingham dataset is the largest the authors are aware of that contains both that level of genetic detail and information on who is friends with whom.

The researchers focused on 1,932 unique subjects and compared pairs of unrelated friends against pairs of unrelated strangers. The same people, who were neither kin nor spouses, were used in both types of samples. The only thing that differed between them was their social relationship.

The findings are not, the researchers say, an artifact of people’s tendency to befriend those of similar ethnic backgrounds. The Framingham data is dominated by people of European extraction. While this is a drawback for some research, it may be advantageous to the study here: because all the subjects, friends and not, were drawn from the same population. The researchers also controlled for ancestry, they say, by using the most conservative techniques currently available. The observed genetic go beyond what you would expect to find among people of shared heritage – these results are “net of ancestry,” Fowler said.

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Genetic cause behind hemifacial microsomia found: Transcription factor OTX2 is to blame

Genetic cause behind hemifacial microsomia found: Transcription factor OTX2 is to blame | Amazing Science |

Whitehead Institute scientists have identified a genetic cause of a facial disorder known as hemifacial microsomia (HFM). The researchers find that duplication of the geneOTX2 induces HFM, the second-most common facial anomaly after cleft lip and palate. HFM affects approximately one in 3,500 births. While some cases appear to run in families, no gene had been found to be causative. That is until Whitehead Fellow Yaniv Erlich and his lab set out to do just that. Their work is described in this week’s issue of the journal PLOS ONE.

Patients with HFM tend to have asymmetrical faces—typically with one side of the upper and lower jaws smaller than the opposite side—a smaller or malformed ear on the affected side, and, in some cases, neurological or developmental abnormalities. Thought to be brought on by circulation difficulties during embryonic development, HFM is also thought to be sporadic—meaning that it occurs spontaneously rather than through inheritance. However, one family in northern Israel has more than its share of the anomaly.

To identify the origin of this family’s disorder, Erlich and lab technician Dina Zielinski began studying the genomes of a five-year-old female member of the family, along with those of her mother, grandmother, and male cousin, who all exhibited traits of HFM. Later, the genetic information from the grandmother’s Russian cousin, who resides in the Philadelphia area, was recruited to the study.

“What’s unique here is that this is the largest family with this disorder described in the literature,” says Erlich. “Most of the time, you see one person affected, or perhaps two people—a parent and a child. Such a large family increases the power of the genetic study and clearly signals that there is a genetic component to a disease.”

Within this large piece of DNA, Zielinski identified eight candidate genes that could cause the type of HFM running in this family. She then used two algorithms to compare the molecular signatures of these eight genes to other genes known to be responsible for various facial malformations with features similar to HFM. After this analysis, the gene OTX2 that codes for a transcription factor rose above the seven other candidates.

These results are supported by what is known of OTX2’s function. Previous data indicates that the gene codes for a protein that is expressed in the heads and pharyngeal arches of mouse embryos in developmental stages corresponding to the periods when HFM abnormalities are thought to arise in humans.

Although this is a tantalizing hint as to OTX2’s activity during development, Zielinski cautions that little is known about its overall role, in part because it serves as a transcription factor that regulates other genes.

OTX2’s activity is very complicated,” says Zielinski, who is first author of the PLOS ONE paper. “Development is dependent on tight control of these transcription factors that turn other genes on and off. The feedback between OTX2 and other transcription factors is complex but we know thatOTX2 plays a critical role in craniofacial patterning.”

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The milk revolution: A single genetic mutation first let ancient Europeans drink milk

The milk revolution: A single genetic mutation first let ancient Europeans drink milk | Amazing Science |

When a single genetic mutation first let ancient Europeans drink milk, it set the stage for a continental upheaval. During the most recent ice age, milk was essentially a toxin to adults because — unlike children — they could not produce the lactase enzyme required to break down lactose, the main sugar in milk. But as farming started to replace hunting and gathering in the Middle East around 11,000 years ago, cattle herders learned how to reduce lactose in dairy products to tolerable levels by fermenting milk to make cheese or yogurt. Several thousand years later, a genetic mutation spread through Europe that gave people the ability to produce lactase — and drink milk — throughout their lives.

Young children almost universally produce lactase and can digest the lactose in their mother's milk. But as they mature, most switch off the lactase gene. Only 35% of the human population can digest lactose beyond the age of about seven or eight (2). “If you're lactose intolerant and you drink half a pint of milk, you're going to be really ill.

Most people who retain the ability to digest milk can trace their ancestry to Europe, where the trait seems to be linked to a single nucleotide in which the DNA base cytosine changed to thymine in a genomic region not far from the lactase gene. There are other pockets of lactase persistence in West Africa (see Nature 444994996; 2006), the Middle East and south Asia that seem to be linked to separate mutations3 (so called 'Lactase hotspots').

The single-nucleotide switch in Europe happened relatively recently. Thomas and his colleagues estimated the timing by looking at genetic variations in modern populations and running computer simulations of how the related genetic mutation might have spread through ancient populations4. They proposed that the trait of lactase persistence, dubbed the LP allele, emerged about 7,500 years ago in the broad, fertile plains of Hungary.

AckerbauHalle's curator insight, February 13, 2014 1:55 AM

Woher kommt die Fähigkeit zur Verdauung von Laktase? Neue genetische Studien bringen hier Licht ins Dunkel.

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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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Birdsong and human speech turn out to be controlled by the same genes

Birdsong and human speech turn out to be controlled by the same genes | Amazing Science |

New research on the bird genome has revealed that the same genes that give humans the ability to speak give birds the ability to sing. Because of this similarity, researchers will be able to use birds as lab subjects to better understand how speech evolved.

Duke University neuroscientist Erich Jarvis led a study on birdsong and speech published recently in Science. But he also co-led the greater effort that made it possible -- the mapping of 48 bird genomes. This unprecedented look at the genetic make-up of all kinds of birds allowed researchers to answer questions on everything from crocodile evolution to bird teeth. But Jarvis was always driven by avian musicality.

"I've always been interested in how the brain controls complex behaviors, and I became most interested in speech," Jarvis said. But it's hard to study speech in humans -- you can't keep someone in a lab for their entire life or perform invasive experiments on them. Non-human primates are usually the best choice for study, but other primates don't learn to mimic vocal sounds the way humans do. But birds fit the bill.

Several papers on vocal learning in birds were released as part of the genome study, but Jarvis's favorite is one that describes how a computational biologist in his lab crunched all of the data sets together to find genes that lined up between birds. They found a consistent set of around 50 genes that seem to correlate with vocal learning: If a gene was more active in humans, it was also more active in birds who could learn songs (and the same held true if the gene was less active). These changes weren't seen in birds who don't learn songs or in non-speaking primates.

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Genetic factors behind surviving or dying from Ebola shown in mouse study

Genetic factors behind surviving or dying from Ebola shown in mouse study | Amazing Science |

A newly developed mouse model suggests that genetic factors are behind the mild-to-deadly range of responses to the Ebola virus. The frequency of different manifestations of the disease across the lines of these mice are similar in variety and proportion to the spectrum of clinical disease observed in the 2014 West African outbreak. The new mouse model might be useful in testing candidate therapeutics and vaccines for Ebola, and in finding genetic markers for susceptibility and resistance to the disease.

Research on Ebola prevention and treatment has been hindered by the lack of a mouse model that replicates the main characteristics of human Ebola hemorrhagic fever. The researchers had originally obtained this genetically diverse group of inbred laboratory mice to study locations on mouse genomes associated with influenza severity.

The research was conducted in a highly secure, state-of-the-art biocontainment safety level 4 laboratory in Hamilton, Mont. The scientists examined mice that they infected with a mouse form of the same species of Ebola virus causing the 2014 West Africa outbreak. The study was done in full compliance with federal, state, and local safety and biosecurity regulations. This type of virus has been used several times before in research studies. Nothing was done to change the virus.

Interestingly, conventional laboratory mice previously infected with this virus died, but did not develop symptoms of Ebola hemorrhagic fever.

In the present study, all the mice lost weight in the first few days after infection. Nineteen percent of the mice were unfazed. They not only survived, but also fully regained their lost weight within two weeks. They had no gross pathological evidence of disease. Their livers looked normal. Eleven percent were partially resistant and less than half of these died. Seventy percent of the mice had a greater than 50 percent mortality. Nineteen percent of this last group had liver inflammation without classic symptoms of Ebola, and thirty-four percent had blood that took too long to clot, a hallmark of fatal Ebola hemorrhagic fever in humans. Those mice also had internal bleeding, swollen spleens and changes in liver color and texture.

The scientists correlated disease outcomes and variations in mortality rates to specific genetic lines of mice.

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Genes don't just influence your IQ—they determine how well you do in school

Genes don't just influence your IQ—they determine how well you do in school | Amazing Science |

Twin study shows that many different inherited traits shape a person's grades and test scores.

If you sailed through school with high grades and perfect test scores, you probably did it with traits beyond sheer smarts. A new study of more than 6000 pairs of twins finds that academic achievement is influenced by genes affecting motivation, personality, confidence, and dozens of other traits, in addition to those that shape intelligence. The results may lead to new ways to improve childhood education.

“I think this is going to end up being a really classic paper in the literature,” says psychologist Lee Thompson of Case Western Reserve University in Cleveland, Ohio, who has studied the genetics of cognitive skills and who was not involved in the work. “It’s a really firm foundation from which we can build on.”

Researchers have previously shown that a person’s IQ is highly influenced by genetic factors, and have even identified certain genes that play a role. They’ve also shown that performance in school has genetic factors. But it’s been unclear whether the same genes that influence IQ also influence grades and test scores.

In the new study, researchers at King’s College London turned to a cohort of more than 11,000 pairs of both identical and nonidentical twins born in the United Kingdom between 1994 and 1996. Rather than focus solely on IQ, as many previous studies had, the scientists analyzed 83 different traits, which had been reported on questionnaires that the twins, at age 16, and their parents filled out. The traits ranged from measures of health and overall happiness to ratings of how much each teen liked school and how hard they worked. Then, the researchers collected data on how well each individual scored on the General Certificate of Secondary Education (GCSE) exam, an exam that all students in the United Kingdom must take and which is used for admission to advanced classes or colleges.

The team found nine general groups of traits that were all highly hereditary—the identical twins were more likely to share the traits than nonidentical twins—and also correlated with performance on the GCSE. Not only were traits other than intelligence correlated with GCSE scores, but these other traits also explained more than half of the total genetic basis for the test scores.

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Case of a missing gene may help future Alzheimer's treatment

Case of a missing gene may help future Alzheimer's treatment | Amazing Science |
Research suggests that reducing or neutralizing one variety of the APOE gene would not harm the brain, while making Alzheimer’s less likely.

The 40-year-old man showed up in Dr. Mary Malloy’s clinic with sadly disfiguring symptoms. His hands, elbows, ears and feet were blemished with protruding pustules and tuber-like welts, some so painful it was hard for him to walk. He suffered from a rare genetic condition called dysbetalipoproteinemia, which caused his cholesterol levels to soar so high that pools of fatty tissue seemed to bubble up under his skin.

But there was something else about this patient. He was missing a gene that, when present in one form, greatly increases the risk of developing Alzheimer’s disease. Dr. Malloy, who co-directs the Adult Lipid Clinic at the University of California, San Francisco, and her colleagues saw an opportunity to answer an important neurological riddle: Does the absence of the gene — named apolipoprotein E, or APOE, after the protein it encodes — hurt the brain?

If a person with this rare condition were found to be functioning normally, that would suggest support for a new direction in Alzheimer’s treatment. It would mean that efforts — already being explored by dementia experts — to prevent Alzheimer’s by reducing, eliminating or neutralizing the effects of the most dangerous version of APOE might succeed without causing other problems in the brain.

The researchers, who reported their findings on Monday in the journal JAMA Neurology, discovered exactly that. They ran a battery of tests, including cognitive assessments, brain imaging and cerebrospinal fluid analyses. The man’s levels of beta-amyloid and tau proteins, which are markers of Alzheimer’s, gave no indication of neurological disease. His brain size was unaffected, and the white matter was healthy. His thinking and memory skills were generally normal.

“This particular case tells us you can actually live without any APOE in the brain,” said Dr. Joachim Herz, a neuroscientist and molecular geneticist at University of Texas Southwestern Medical Center, who was not involved in the research. “So if they were to develop anti-APOE therapies for Alzheimer’s, we would not have to worry about serious neurological side effects.”

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Who's your daddy? Researchers program computer to find out

Who's your daddy? Researchers program computer to find out | Amazing Science |
A University of Central Florida research team has developed a facial recognition tool that promises to be useful in rapidly matching pictures of children with their biological parents and in potentially identifying photos of missing children as they age.

The work verifies that a computer is capable of matching pictures of parents and their children. The study will be presented at the nation's premier event for the science of computer vision - the IEEE Computer Vision and Pattern Recognition conference in Columbus, Ohio, which begins Monday, June 23. Graduate Student Afshin Dehfghan and a team from UCF's Center for Research in Computer Vision started the project with more than 10,000 online images of celebrities, politicians and their children.

"We wanted to see whether a machine could answer questions, such as 'Do children resemble their parents?' 'Do children resemble one parent more than another?' and 'What parts of the face are more genetically inspired?'" he said.

Anthropologists have typically studied these questions. However Dehghan and his team are advancing a new wave of computational science that uses the power of a mechanical "mind" to evaluate data completely objectively – without the clutter of subjective human emotions and biases. The tool could be useful to law enforcement and families in locating missing children.

"As this tool is developed I could see it being used to identify long-time missing children as they mature," said Ross Wolf, associate professor of criminal justice at UCF.

Wolf said that facial recognition technology is already heavily used by law enforcement, but that it has not been developed to the point where it can identify the same characteristics in photos over time, something this technology could have the capability to do. Dehghan said he is planning to expand on the work in that area by studying how factors such as age and ethnicity affect the resemblance of facial features.

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Single nucleotide mutation in c-KIT ligand gene is responsible for blond hair trait

Single nucleotide mutation in c-KIT ligand gene is responsible for blond hair trait | Amazing Science |
HHMI researchers find that a single-letter change in the genetic code is enough to generate blond hair in humans.

Genomic surveys by other groups had revealed that the gene – Kit ligand – is indeed evolutionarily significant among humans. “The very same gene that we found controlling skin color in fish showed one of the strongest signatures of selection in different human populations around the world,” Kingsley says. His team went on to show that in humans, different versions of Kit ligand were associated with differences in skin color.

Furthermore, in both fish and humans, the genetic changes associated with pigmentation differences were distant from the DNA that encodes the Kit ligand protein, in regions of the genome where regulatory elements lie. “It looked like regulatory mutations in both fish and humans were changing pigment,” Kingsley says.

Kingsley's subsequent stickleback studies have shown that when new traits evolve in different fish populations, changes in regulatory DNA are responsible about 85 percent of the time. Genome-wide association studies have linked many human traits to changes in regulatory DNA, as well. Tracking down specific regulatory elements in the vast expanse of the genome can be challenging, however.

“We have to be kind of choosy about which regulatory elements we decide to zoom in on,” Kingsley says. “We thought human hair color was at least as interesting as stickleback skin color.” So his team focused its efforts on a human pigmentation trait that has long attracted attention in history, art, and popular culture.

Kit ligand encodes a protein that aids the development of pigment-producing cells, so it made sense that changing its activity could affect hair or skin color. But the Kit ligand protein also plays a host of other roles throughout the body, influencing the behavior of blood stem cells, sperm or egg precursors, and neurons in the intestine. Kingsley wanted to know how alterations to the DNA surrounding this essential gene could drive changes in coloration without comprising Kit ligand's other functions.

Catherine Guenther, an HHMI research specialist in Kingsley's lab, began experiments to search for regulatory switches that might specifically control hair color. She snipped out segments of human DNA from the region implicated in previous blond genetic association studies, and linked each piece to a reporter gene that produces a telltale blue color when it is switched on. When she introduced these into mice, she found that one piece of DNA switched on gene activity only in developing hair follicles.

“When we found the hair follicle switch, we could then ask what's different between blonds and brunettes in northern Europe,” Kingsley said. Examining the DNA in that regulatory segment, they found a single letter of genetic code that differed between individuals with different hair colors.

Their next step was to test each version's effect on the activity of the Kit ligand gene. Their preliminary experiments, conducted in cultured cells, indicated that placing the gene under the control of the “blond” switch reduced its activity by about 20 percent, as compared to the "brunette" version of the switch. The change seemed slight, but Kingsley and Guenther suspected they had identified the critical point in the DNA sequence.

The scientists next engineered mice with a Kit ligand gene placed under the control of the brunette or the blond hair enhancer. Using technology developed by Liqun Luo, who is also an HHMI investigator at Stanford, they were able to ensure that each gene was inserted in precisely the same way, so that a pair of mice differed only by the single letter in the hair follicle switch—one carrying the ancestral version, the other carrying the blond version.

“Sure enough, when you look at them, that one base pair is enough to lighten the hair color of the animals, even though it is only a 20 percent difference in gene expression,” Kingsley says. “This is a good example of how fine-tuned regulatory differences may be to produce different traits. The genetic mechanism that controls blond hair doesn't alter the biology of any other part of the body. It's a good example of a trait that's skin deep—and only skin deep.”

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Germline EGFR T790M mutation results in a rare and unique lung cancer hereditary syndrome associated with a 31% risk

Germline EGFR T790M mutation results in a rare and unique lung cancer hereditary syndrome associated with a 31% risk | Amazing Science |

Two studies found that germline EGFR T790M mutation results in a rare and unique lung cancer hereditary syndrome associated with an estimated 31% risk for the disease in never-smokers. Lead author Adi Gazdar, MD, of the Department of Pathology, UT Southwestern Medical Center, Dallas, TX, and colleagues studied a family with germline EGFR T790M mutations over five generations (14 individuals) and combined their observations with data obtained from a literature search (15 individuals). They found that the mutation occurred in approximately 1% of NSCLCs and in less than one in 7,500 subjects without lung cancer.

Female never-smokers were overrepresented in the family cohort. Among 13 patients for whom gender and smoking status were known, nine were female never-smokers, two were male never-smokers, and two were ever-smokers (one male and one female).

“The risk of lung cancer development in never-smoking carriers is greater than the risk of heavy smokers with or without the mutation,” says Dr. Gazdar, who is an IASLC member. “Unaffected carriers with this mutation are at increased risk for the development of lung cancer irrespective of their smoking status and should be followed by increased surveillance, including low-dose computed tomography,” he adds.

The cancers associated with germline EGFR T790M mutations share several similar features with lung cancers containing sporadic EGFR mutations, such as a predominance for adenocarcinoma histology, female gender, and never-smoking status. However, a difference with lung cancers having sporadic EGFR mutations is a predominance for white ethnicity (compared with East Asian). 

“Germline EGFR T790M mutations are present in approximately 50% of all patients with baseline EGFR T790M identified in their tumor specimens before treatment,” says Dr. Yu, also an IASLC member. “In our practice, we recommend that all patients with baseline  EGFR T790M identified in their lung tumor tissue be referred to clinical genetics to discuss EGFR T790M germline testing. Carriers of this mutation need to be prospectively studied to better understand the clinical implications of this germline mutation.

The presence of a germline EGFR T790M mutation also predicts for resistance to standard tyrosine kinase inhibitors (TKIs), which adds complexity to treatment. Until newer third- and fourth-generation TKIs designed to overcome T790M-mediated resistance become available, standard chemotherapy may be the preferred first-line therapy option in the absence of another known or suspected molecular target.

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Why hospitals will soon sequence the genes of every single patient

Why hospitals will soon sequence the genes of every single patient | Amazing Science |

We are now on the verge of a health data breakthrough, in which computers will be able to do similar diagnostic tasks, by analyzing massive amounts of data, including genome sequences, risk factors, medical histories, drug interactions, and more.

Looking at this trend last year, venture capitalist Vinod Khosla made the bold claim that technology will replace 80 percent of companies eventually. The reality is probably more nuanced: Far from threatening to put doctors out of jobs, the falling prices of data analysis and genome sequencing are enabling them with tools they could only dream of even a few years ago.

At the Mount Sinai Hospital in New York, Joel Dudley, Ph.D. uses Ayasdi’s products to discover how patients with certain genes are more likely to develop some diseases (diabetes, cardiovascular conditions…) as well as how genes influence the performance of a treatment, or may reveal risks of later relapses that can be prepared for.

Already 11,000 patients at Mount Sinai have had their genome sequenced, a pool large enough for meaningful analysis, although Ayasdi tells us “those are still early days for the industry. There are no plans to act on that data directly with individual patients just yet.”

Right now the Mount Sinai community is working at organizing itself to make the useful information available to the frontline staff. And another 30,000 patients may soon sign the consent form and opt in to participate in this new way to explore which care is best for them.

The exploration of big data by the enterprise is becoming less of a competitive edge and turning into more of a must-have. Similarly, hospitals may have to adopt genetic analysis as a rule of thumb sooner rather than later.  Mount Sinai is unusual today in pioneering regular genetic screenings, but it soon may become commonplace.

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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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