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Scooped by Dr. Stefan Gruenwald!

What Can You Do With the World's Largest Family Tree of 13 Million People?

What Can You Do With the World's Largest Family Tree of 13 Million People? | Amazing Science |

Your family tree might contain a few curious revelations. It might alert you to the existence of long-lost third cousins. It might tell you your 10-times-great-grandfather once bought a chunk of Brooklyn. It might reveal that you have royal blood. But when family trees includes millions of people—maybe even tens of millions of people—then we’re beyond the realm of individual stories.


When genealogies get so big, they’re not just the story of a family anymore; they contain the stories of whole countries and, at the risk of sounding grandiose, even all of humanity.


Last week, scientists using data from and each unveiled papers analyzing the genealogies for patterns like migrations, lifespan, and when people stopped marrying family members. sells both subscriptions to its genealogy research site and a popular genetic test through its subsidiary AncestryDNA. Its geneticists— along with a historian—used the genetic data of 770,000 AncestryDNA customers along with the genealogy records of their ancestors to map migrations in North America.


The team first analyzed the DNA tests to find clusters of closely related people in the present. Then, they matched up the people in those clusters with genealogy records containing 20 million people, which included the birthplaces of several generations of ancestors. With that, they could march backwards in time to see how those ancestors migrated across the U.S.

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Molecular patterns of complex diseases

Molecular patterns of complex diseases | Amazing Science |

The Helmholtz Zentrum München has published results of the largest genome-wide association study on proteomics to date. An international team of scientists reports 539 associations between protein levels and genetic variants in ‘Nature Communications’. These associations overlap with risk genes for 42 complex diseases.


Genome-wide association studies (GWAS) provide an opportunity to associate concentration changes in certain proteins or metabolic products with gene loci. Knowledge of these genes makes it possible to establish connections to complex diseases. Scientists utilize the fact that to date, hundreds of associations between genetic variants and complex diseases have been demonstrated. These associations are immensely important because they do help uncover the underlying molecular mechanisms.


"In the world's largest proteomics GWAS to date, we worked with colleagues* to examine blood samples from 1,000 participants in the KORA study**," reports Dr. Gabi Kastenmüller. She is acting director and head of the Metabolomics Group at the Institute of Bioinformatics and Systems Biology (IBIS) at the Helmholtz Zentrum München. The team quantified a total of 1,100 proteins. Dr. Christian Gieger, head of the Molecular Epidemiology Research Unit (AME) at the Helmholtz Zentrum München, adds: "We found 539 independent associations between protein levels and genetic variants." These overlap with genetic risk variants for 42 complex conditions, such as cardiovascular diseases and Alzheimer's disease.


"Our results provide new insights into the biological processes that are influenced by a very wide range of complex diseases and that can be used as a basis for the development of new strategies to predict and prevent these diseases," Gieger states. The team is now planning to investigate the exact mechanisms behind the new gene-protein associations.

Via Integrated DNA Technologies
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Set of uncombable hair genes discovered (PADI3, TGM3 and TCHH)

Set of uncombable hair genes discovered (PADI3, TGM3 and TCHH) | Amazing Science |
Some children suffer from completely tangled hair, which cannot be combed at all. In German, the phenomenon bears the apt name “uncombable hair syndrome” or even “Struwwelpeter syndrome”. Researchers have identified mutations in three genes that are responsible for this.


Scientists from a total of eight countries were involved in the work. The results were published in the American Journal of Human Genetics.


Many parents know from their own experience that it is not always easy to comb children's hair. Yet with patience and nerves of steel, even the toughest of knots can usually be undone. In the case of "uncombable hair syndrome," brushes and combs don't stand even the hint of a chance. Those affected have extremely frizzy, dry, generally light blonde hair with a characteristic shine, which successfully resists any attempt to tame it. These symptoms are most pronounced in childhood and then ease over time. In adulthood, the hair can more or less be styled normally.


Virtually nothing has so far been known about the causes -- particularly because the phenomenon is relatively rare. It was described in the specialist literature for the first time in 1973; since then, around one hundred cases have been documented worldwide. "However, we assume that there are much more people affected," explains Professor Regina Betz from the Institute for Human Genetics at the University of Bonn. "Those who suffer from uncombable hair do not necessarily seek help for this from a doctor or hospital." Nevertheless, it is known that the anomaly occurs more frequently in some families -- it thus appears to have genetic causes.


Betz is a specialist for rare hereditary hair disorders. A few years ago, she was approached at a conference by a British colleague. He had recently examined a family with two affected children. The Bonn-based human geneticist's interest was piqued. "Via contact with colleagues from around the world, we managed to find nine further children," she explains. The scientists in Bonn sequenced all the genes of those affected. When comparing large databases, they thus came across mutations in three genes that are involved in forming the hair.


The changed genes bear the identifiers PADI3, TGM3 and TCHH. The first two contain the assembly instructions for enzymes, while the third -- TCHH -- contains an important protein for the hair shaft. In healthy hair, the TCHH proteins are joined to each other with extremely fine strands of keratin, which are responsible for the shape and structure of the hair. During this process, the two other identified genes play an important role: "PADI3 changes the hair shaft protein TCHH in such a way that the keratin filaments can adhere to it," explains the lead author of the study, Dr. Fitnat Buket Basmanav Ünalan. "The TGM3 enzyme then produces the actual link."

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The Genetic Components of Rare Diseases

The Genetic Components of Rare Diseases | Amazing Science |

In fall 2015, the conclusion of the 1000 Genomes Project revealed 88 million variants in the human genome. What most of them mean for human health is unclear. Of the known associations between a genetic variant and disease, many are still tenuous at best. How can scientists determine which genes or genetic variants are truly detrimental?


Patients with rare diseases are often caught in the crosshairs of this uncertainty. By the time they have their genome, or portions of it, sequenced, they’ve endured countless physician visits and tests. Sequencing provides some hope for an answer, but the process of uncovering causal variants on which to build a treatment plan is still one of painstaking detective work with many false leads. Even variants that are known to be harmful show no effects in some individuals who harbor them, says Adrian Liston, a translational immunologist at the University of Leuven in Belgium who works on disease gene discovery.


Exome sequencing, which covers the 1 percent to 2 percent of the genome that codes for protein, typically turns up some 30,000 genetic variants, which need to be carefully assessed. Advances in bioinformatics tools have allowed researchers to rapidly whittle numerous variants or genes down to a manageable list. From there, other web-based platforms are helping investigators build a case for causation. These steps are important, Liston says, because testing a gene candidate in animal models or cell lines consumes a vast amount of resources.

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First gene mutation explaining development of multiple sclerosis found

First gene mutation explaining development of multiple sclerosis found | Amazing Science |

MS is a neurodegenerative disease in which the immune system attacks the myelin that protects nerve fibers, upsetting the flow of information between the brain and the body. It affects about 2 million people worldwide, and in its more severe, progressive form, no good treatments are available.


About 10% to 15% of MS cases appear to have a hereditary component, but until now researchers conducting genetic studies have found only weak associations between the risk of developing MS and particular gene variants. In contrast, people who carry the newly discovered mutation have a 70% chance of developing the disease, the team determined.


In the current study, the investigators reviewed materials from the Canadian Collaborative Project on Genetic Susceptibility to MS, a large database that contains genetic material from almost 2,000 families across Canada. They looked at a family that had multiple cases of the disease--five cases over two generations--and did exome sequencing to look for rare coding mutations that were present in all family members who had the disease.


After identifying a gene of interest, they went back to the database and found the same mutation in another family with multiple cases of MS. Interestingly, all patients in these families with the mutation presented with the progressive form of MS. "The mutation we found, in a gene called NR1H3, is a missense mutation that causes loss of function of its gene product, LXRA protein," says neuroscientist Weihong Song, Canada Research Chair in Alzheimer's Disease at UBC and the study's other senior author. Together with other members of the same family, LXRA controls transcriptional regulation of genes involved in lipid homeostasis, inflammation, and innate immunity.


Mice with this gene knocked out are known to have neurological problems, including a decrease in myelin production. "There is clear evidence to support that this mutation has consequences in terms of biological function, and the defective LXRA protein leads to familial MS development," Song says.


"One thing that's important to note is that although this mutation is present in only about 1 in 1,000 people with MS, by doing association analysis we've also found common variants in the same gene that are risk factors for progressive MS," Vilariño-Güell adds. "So even if patients don't have the rare mutation, treatments that target this pathway would likely be able to help them."

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The gene hunters 

The gene hunters  | Amazing Science |

Criss-crossing the globe on a quest for unusual DNA, researchers have discovered a rare mutation that promises insights into both epilepsy and autism — and points to a treatment.

Via Integrated DNA Technologies
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Scientists find link between genome and microbiome in Crohn’s disease patients

Scientists find link between genome and microbiome in Crohn’s disease patients | Amazing Science |
Genes linked to Crohn’s disease, an inflammatory bowel disease, might make people’s immune cells miss out on helpful messages sent by friendly gut bacteria.


Good gut bacteria might not help people with Crohn’s disease.

Protective microbial messages go unread in mice and in human immune cells with certain defective genes, researchers report online May 5 in Science. The findings are the first to tie together the roles of genes and beneficial microbes in the inflammatory bowel disease, says biologist Brett Finlay of the University of British Columbia in Vancouver, who was not involved in the new work.


“This is a major step forward in this area,” he says. Human genes and friendly microbes work together to control inflammation, he says. “And when you muck that up, things can go awry.”


In Crohn’s disease, the immune system riles up too easily, trigging chronic inflammation. Scientists don’t know why exactly people’s immune systems go haywire. But researchers have linked the disease to glitches in nearly 200 genes, including ATG16L1 and NOD2, which typically help kill bad bacteria in the gut.


Researchers have also reported that people with Crohn’s have a different collection of gut microbes compared with that of healthy people, says study coauthor and Caltech microbiologist Sarkis Mazmanian.But though “there’s a huge body of literature on the genome and on the microbiome,” he says, “no one knew what the interplay was between the two.”


So his team explored a potential link using a friendly gut microbe called Bacteroides fragilis. The bacteria send out calming messages that tell the immune system to tone down inflammation. Like letters inside envelopes, these messages travel in protective pouches called outer membrane vesicles, or OMVs.


Feeding OMVs to mice typically protects them from developing inflamed colons, or colitis — but not mice lacking the Crohn’s-linked genes ATG16L1 and NOD2. When researchers treated those mice with a colitis-causing chemical, they succumbed to the disease, even after eating OMVs.


Mice with defective versions of ATG16L1 and NOD2 “can’t reap the benefits of the beneficial microbiota,” Mazmanian says.Immune cells from human patients with the defective genes didn’t respond to OMVs either.


The findings suggest that the genes that kill bad bacteria also work with good bacteria to keep people’s immune systems from going out of control, says gastroenterologist Balfour Sartor of the University of North Carolina School of Medicine in Chapel Hill. The work “opens up a new mechanism for protection,” he says.

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Do 'genetic superheroes' exist? Or did media overhype Resilience Project?

Do 'genetic superheroes' exist? Or did media overhype Resilience Project? | Amazing Science |
Genetic Superheroes. Hitting the genetic lottery. 13 Incredibly lucky people. Bulletproof genomes.


That’s just a few of the ways people have described the results from a recent analysis of the genomes of over half a million people which found that 13 lucky people have disease causing mutations, but don’t exhibit any symptoms.


The study is the largest effort, to date, to identify so called ‘resilient’ individuals. These are healthy people who possess a mutation in their genome that is known to be disease causing. Many believe the DNA of these resilient people hold the key to treating genetic diseases, like cystic fibrosis, that today are incurable.


The existence of these 13 genetic Herculeses has created much excitement in the media:

  • STAT: Genetic ‘unicorns’ defy their own DNA — and hint at treatments
  • NPR: How Do ‘Genetic Superheroes’ Overcome Their Bad DNA?
  • BBC‘Superhero DNA’ Keeps Diseases at Bay


But did the study really identify a few lucky winners of the genome lottery? What’s the real story here? The study published in the journal Nature Biotechnology by a team of international scientists led by researchers at Icahn School of Medicine at Mount Sinai in New York City searched the genomes of 589,306 people—all over the age of 30—for 874 genes that are linked to 584 genetic diseases. All of these diseases begin to affect a person during childhood, like cystic fibrosis, Tay-sachs and Pfeiffer syndrome.


The team obtained these sequences from a variety of previous studies, but most of the data—nearly 400,000 samples—came from the at-home, personal genetics test 23andMe. (On the 23andMe consent forms, customers can select a box to allow their DNA to be used in such research.) Pooling all of this data, the scientists identified 15,597 potentially resilient individuals, but after a rigorous screen of these candidates, they eliminated almost all of them, settling on just 13, they believed were resilient.


The study is considered, by the Resilience Project leaders to be a ‘proof of concept’ study which means they modestly set out to prove their methods could identify resilient individuals. The study’s leader, Stephen Friend, says the idea to look for resilient people came out of frustration from the lack of success he had in looking at the problem from the other way. He and other biotech researchers usually search for genetic variants common in a number of sick individuals and then look for ways to fix the defect, but Friend admits they have been largely unsuccessful using this approach. He hopes that by looking for resilient people instead, he will discover why they are resilient and then use that knowledge to treat those who do exhibit symptoms.


But some have begun to question the validity of the resilience of these candidates, which could blow a hole in the conclusions. The study was a retrospective analysis, meaning the authors looked over data from other studies to establish connections, but they did not personally examine any of the participants. More importantly, for many they never can. In several of the studies they borrowed data from, recontact was not even considered when asking for participant consent. For participant’s samples from 23andMe, the consent for recontact falls into a gray area because the company does not specifically ask for permission to recontact on its consent form.


Nature Biotechnology published an independent commentary from Daniel MacArthur, a geneticist who teaches at Harvard University and conducts research at Massachusetts General Hospital. MacArthur explains why this data collection flaw hurts the study’s validity: "Perhaps most unfortunately, the researchers could not recontact the majority of resilient individuals for further study because of a lack of necessary consent forms. This means that some of their resilient cases may be mirages (the result of undisclosed disease cases, sample swaps, or somatic mosaicism), and this lack of consent precluded the collection of further clinical and genetic data to explore possible resilience mechanisms."

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We're finally cracking the secrets of what makes us sick

We're finally cracking the secrets of what makes us sick | Amazing Science |

For the data in our genome to be useful, we need to process not just the 3 billion base pairs of DNA that make up each person's genome but also the genomes of many people. The Precision Medicine Initiative is starting with the genomes of at least one million people. That's a mind-boggling amount of data already, and we'll eventually end up needing even more: "many millions" of genomes, saysDr. Eric Schadt, founding director of the Icahn Institute for Genomics and Multiscale Biology at Mount Sinai.

We're still figuring out how to decode it all.


At Mount Sinai, scientists are trying to "collect as much information on as many patients as we can, integrate it, build predictive models from it, and then derive from those models more refined diagnoses, risk assessments, and plans for treatment than has been possible before," Schadt told Nature Biotechnology in 2012.


The team at Icahn is collecting genetic information from patients and trying to incorporate that data with everything from their clinical history to the bacteria on and around them in order to develop predictive models that will calculate how a disease will affect a person.


"The technology advances [that make that possible] have been astounding," says Schadt. "The ability to generate sequencing data has moved at a super-Moore's law rate," faster than even computing technology, he says. The supercomputers we have now can process genetic information in ways that would have been "just impossible 10 years ago." Scientists all over the country are pushing for new ways to understand genomic data.


Deep Genomics, a startup run by Brendan Frey, is leveraging artificial intelligence to help decode the meaning of the genome.

Specifically, the company is using deep learning: the process by which a computer takes in data and then, based on its extensive knowledge drawn from analyzing other data, interprets that information.

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Rare single gene mutation in SETD1A increases risk of schizophrenia 35-fold

Rare single gene mutation in SETD1A increases risk of schizophrenia 35-fold | Amazing Science |

Genetic factors play a major role in schizophrenia but scientists are only now beginning to identify the specific genes involved. A new study published in Nature Neuroscience shows that rare mutations in the SETD1A gene dramatically increase the risk of developing schizophrenia. This implicates a specific biological pathway in schizophrenia, which may also be of significance beyond the condition.


Patients with schizophrenia can experience hallucinations and delusions, as well as a lack of motivation and problems with social interactions. Schizophrenia affects around 1% of the population. There is no cure and better treatments are desperately needed. Most scientists believe that the symptoms seen in patients with schizophrenia result from changes in the way in which the brain develops. These changes result in part from environmental factors (such as birth complications), but genes also play a major role.


The genetic basis of schizophrenia is complex. There are hundreds, if not thousands, of genes that contribute to a person’s risk of becoming ill, meaning that genetic samples from huge numbers of patients and healthy people are needed to prove the involvement of a given gene.


The new study by researchers at The Wellcome Trust Sanger Institute looked for rare, small-scale genetic changes that are associated with schizophrenia. To do this scientists used a technique called “whole-exome sequencing” which examines the full DNA “letter” sequence of the parts of genes that encode the proteins that perform tasks in cells.


They then examined the sequence data for mutations that are predicted to be particularly disruptive: those that either reduce or abolish the resulting protein (so-called “loss-of-function”, or LoF, mutations), or which dramatically alter its sequence (“missense mutations”).


They found, like a previous study, that patients with schizophrenia had, on average, a higher number of these rare but disruptive LoF mutations compared to healthy people. Most strikingly, they found that these mutations in one particular gene – SETD1A – were associated with schizophrenia and a 35-fold increase in risk of developing the condition. Although extremely rare, SETD1A LoF mutations were only found in schizophrenia patients – none were seen in healthy people.


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First gene for grey hair found

First gene for grey hair found | Amazing Science |

Published in Nature Communications, the BBSRC-funded study analysed a population of over 6,000 people with varied ancestry across Latin America to identify new genes associated with hair color, greying, density and shape, i.e. straight or curly. “We already know several genes involved in balding and hair color but this is the first time a gene for greying has been identified in humans, as well as other genes influencing hair shape and density,” said lead author, Dr Kaustubh Adhikari, UCL Cell & Developmental Biology.


“It was only possible because we analysed a diverse melting pot of people, which hasn’t been done before on this scale. These findings have potential forensic and cosmetic applications as we increase our knowledge on how genes influence the way we look.”


The findings could help develop forensic DNA technologies that build visual profiles based on an individual’s genetic makeup. Research in this field has previously used samples from people of European descent, but these new results could help forensic reconstructions in Latin America and East Asia.


The gene identified for grey hair – IRF4 – is known to play a role in hair color but this is the first time it has been associated with the greying of hair. This gene is involved in regulating production and storage of melanin, the pigment that determines hair, skin and eye color.


Hair greying is caused by an absence of melanin in hair so the scientists want to find out IRF4’s role in this process. Understanding how IRF4 influences hair greying could help the development of new cosmetic applications that change the appearance of hair as it grows in the follicle by slowing or blocking the greying of hair.

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KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome

KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome | Amazing Science |

Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures.

Using autozygome and exome analyses, scientists have recently identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556 (-/-) null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in C. elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions.

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Genetics: Big hopes for big data

Genetics: Big hopes for big data | Amazing Science |

Technology is allowing researchers to generate vast amounts of information about tumors. The next step is to use this genomic data to transform patient care.

Adrian Lee has dedicated his career to studying breast cancer, which is to say he is actually tackling many different diseases at once. “No two breast cancers are the same,” says Lee, a pharmacologist and chemical biologist at the University of Pittsburgh in Pennsylvania. “Cancer is way more complex than we know.”

Lee is using genomic technology to fully describe cancers of the breast and apply that knowledge to guide treatment decisions for individual patients. “We can now analyse multiple variables from a single specimen, such as changes in DNA, changes in RNA and changes in methylation,” he says. “Genome-wide scans allow for better systems biology and allow us to learn what's gone wrong in a particular tumor.”

Sequencing tumors is faster, cheaper and easier than ever. With many researchers collecting sequence data and uploading these to public databases such as the The Cancer Genome Atlas (TCGA), opportunities to describe the many different cancers that arise in breast tissue are upon us. “The challenge used to be generating the data,” says Nicholas Navin, a geneticist at The University of Texas MD Anderson Cancer Center in Houston. “Those issues have been resolved. Now the challenge is data processing and data analysing — interpreting the mutations and communicating those to oncologists.”

At the University of Pittsburgh, researchers are working to link the molecular signatures of people with breast cancer to a host of clinical data, including demographic information associated with risk such as age, ethnicity and body weight. They are mining electronic health records for clinical correlates, treatment interactions and outcomes. “We've got a big haystack and we're trying to find the needle,” says Lee. “But we're also trying to incriminate the needle, by linking it to lots of things.” Collecting all that data from patients' electronic records adds up, Lee says. It takes infrastructure — Pittsburgh has already accumulated 5 petabytes, or 5 million gigabytes, which is enough data to overload around 40,000 new iPhone 6 devices.

Making the connection between the reams of data coming out of sequencing laboratories and the individual women fighting breast cancer takes big-time computing power. Big data needs researchers who are comfortable with statistical noise and those who are old hands at the iterative process required to create flexible computer programs.

Big-data researchers take a large data set and look for patterns. The idea is to identify mutations that can be targeted with drug treatment. It is the essence of personalized medicine: screen a patient's tumour for a set of biomarkers to choose the best treatment to fight the cancer. Big-data researchers believe that analysing the data of the thousands of tumours that have come before will reveal patterns that can improve screening and diagnosis, and inform treatment.

Lee and his colleagues have illustrated how big-data science led to a rethink of breast cancer1. They used two public databases — TCGA and METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), which contain data on the entire set of genes, RNA transcripts and proteins of thousands of breast-cancer tumours — to parse out potential differences in the molecular signatures of breast tumours in younger compared with older women. Women who are diagnosed before the age of 40 tend to have worse disease: they are more likely to have later-stage cancers, poorer prognoses and worse survival outcomes than older women.

Via Integrated DNA Technologies
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Diabetes in your DNA? Scientists zero in on the genetic signature of risk

Diabetes in your DNA? Scientists zero in on the genetic signature of risk | Amazing Science |

Why do some people get Type 2 diabetes, while others who live the same lifestyle never do?


For decades, scientists have tried to solve this mystery – and have found more than 80 tiny DNA differences that seem to raise the risk of the disease in some people, or protect others from the damagingly high levels of blood sugar that are its hallmark.

But no one “Type 2 diabetes signature” has emerged from this search. Now, a team of scientists has reported a discovery that might explain how multiple genetic flaws can lead to the same disease.


They’ve identified something that some of those diabetes-linked genetic defects have in common: they seem to change the way certain cells in the pancreas “read” their genes. The discovery could eventually help lead to more personalized treatments for diabetes. But for now, it’s the first demonstration that many Type 2 diabetes-linked DNA changes have to do with the same DNA-reading molecule. Called Regulatory Factor X, or RFX, it’s a master regulator for a number of genes.


The team reporting the findings in a new paper in the Proceedings of the National Academy of Sciences(link is external) comes from the University of Michigan, National Institutes of Health, Jackson Laboratory for Genomic Medicine, University of North Carolina, and the University of Southern California.

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How a tiny mutation in the ARHGAP11B gene helped grow our big human brain

How a tiny mutation in the ARHGAP11B gene helped grow our big human brain | Amazing Science |

After splitting from the chimpanzee lineage, a single letter of our genome switched to another – and likely shaped the evolutionary expansion of the human.


The gene ARHGAP11B promotes basal progenitor amplification and is implicated in neocortex expansion. It arose on the human evolutionary lineage by partial duplication ofARHGAP11A, which encodes a Rho guanosine triphosphatase–activating protein (RhoGAP). However, a lack of 55 nucleotides in ARHGAP11B mRNA leads to loss of RhoGAP activity by GAP domain truncation and addition of a human-specific carboxy-terminal amino acid sequence.


Scientists now show that these 55 nucleotides are deleted by mRNA splicing due to a single C→G substitution that creates a novel splice donor site. They reconstructed an ancestral ARHGAP11B complementary DNA without this substitution. Ancestral ARHGAP11B exhibits RhoGAP activity but has no ability to increase basal progenitors during neocortex development. Hence, a single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex.

Carlos Garcia Pando's comment, December 11, 2016 12:23 PM
Is this a case of progressive evolution? I think this is a clear case of random error: just a sigle base change (C for G) with such a great impact.
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Catalog of genetic information from 60,000 people reveals unexpected surprises

Catalog of genetic information from 60,000 people reveals unexpected surprises | Amazing Science |

More than one million people have now had their genome sequenced, or its protein-coding regions (the exome). The hope is that this information can be shared and linked to phenotype — specifically, disease — and improve medical care. An obstacle is that only a small fraction of these data are publicly available:



In an important step, we report this week the first publication from the Exome Aggregation Consortium (ExAC), which has generated the largest catalogue so far of variation in human protein-coding regions. It aggregates sequence data from some 60,000 people. Most importantly, it puts the information in a publicly accessible database that is already a crucial resource (


There are challenges in sharing such data sets — the project scientists deserve credit for making this one open access. Its scale offers insight into rare genetic variation across populations. It identifies more than 7.4 million (mostly new) variants at high confidence, and documents rare mutations that independently emerged, providing the first estimate of the frequency of their recurrence. And it finds 3,230 genes that show nearly no cases of loss of function. More than two-thirds have not been linked to disease, which points to how much we have yet to understand.


The study also raises concern about how genetic variants have been linked to rare disease. The average ExAC participant has some 54 variants previously classified as causal for a rare disorder; many show up at an implausibly high frequency, suggesting that they were incorrectly classified. The authors review evidence for 192 variants reported earlier to cause rare Mendelian disorders and found at a high frequency by ExAC, and uncover support for pathogenicity for only 9. The implications are broad: these variant data already guide diagnoses and treatment (see, E. V. Minikel et al. Sci. Transl. Med. 8, 322ra9; 2016 and R. Walsh et al. Genet. Med.; 2016).


These findings show that researchers and clinicians must carefully evaluate published results on rare genetic disorders. And it demonstrates the need to filter variants seen in sequence data, using the ExAC data set and other reference tools — a practice widely adopted in genomics.


The ExAC project plans to grow over the next year to include 120,000 exome and 20,000 whole-genome sequences. It relies on the willingness of large research consortia to cooperate, and highlights the huge value of sharing, aggregation and harmonization of genomic data. This is also true for patient variants — there is a need for databases that provide greater confidence in variant interpretation, such as the US National Center for Biotechnology Information’s ClinVar database.

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Mystery Solved: Muffs and Beard in Chickens

Mystery Solved: Muffs and Beard in Chickens | Amazing Science |
Hip humans aren't the only ones growing outrageous facial hair. Some chickens do, too. And now, geneticists in China have discovered the cause.


Muffs and beard (Mb) is a phenotype in chickens where groups of elongated feathers gather from both sides of the face (muffs) and below the beak (beard). It is an autosomal, incomplete dominant phenotype encoded by the Muffs and beard (Mb) locus. A group of scientists have now used genome-wide association (GWA) analysis, linkage analysis, Identity-by-Descent (IBD) mapping, array-CGH, genome re-sequencing and expression analysis to show that the Mb allele is causing the Mb phenotype which is a derived allele where a complex structural variation (SV) on GGA27 leads to an altered expression of the gene HOXB8. This Mb allele was shown to be completely associated with the Mb phenotype in nine other independent Mb chicken breeds. The Mb allele differs from the wild-type mb allele by three duplications, one in tandem and two that are translocated to the tandem repeat around 1.70 Mb away on GGA27. The duplications contain a total of seven annotated genes and their expression was tested during distinct stages of Mb morphogenesis. A continuous high ectopic expression of HOXB8 was found in the facial skin of Mb chickens only, strongly suggesting that HOXB8 directs this regional feather-development.


In conclusion, the results provide an interesting example of how genomic structural rearrangements of homeobox genes alter the regulation of genes leading to novel phenotypes. Further, it again illustrates the value of utilizing derived phenotypes in domestic animals to dissect the genetic basis of developmental traits, herein providing novel insights into the likely role of HOXB8 in feather development and differentiation.

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Five genes identified that give your nose its shape

Five genes identified that give your nose its shape | Amazing Science |

Whether you have a huge honker, a puny proboscis, or a snubbed schnoz, the shape of your nose is in your genes. Now, researchers have sniffed out five of those stretches of DNA that control nose and chin shape. The team sequenced the genomes of more than 6000 men and women in Central and South America and used photographs of the participants to categorize 14 of their facial features—from cheekbone protrusion to lip shape. Then, the scientists analyzed whether any of the features were associated with certain genes. GLI3 and PAX1, both known to be involved in cartilage growth, were linked to the breadth of a person’s nostrils;DCHS2, also related to cartilage, controlled nose pointiness; RUNX2, which drives bone development, was associated with the width of the nose bridge, the upper area of the nose; and EDAR, which has previously been linked to ear and tooth shape and hair texture, affected chin protrusion. The results, published online today in Nature Communications, may help shed light on how the human face evolved and why different ethnicities have distinct facial features. Moreover, the research could help forensic scientists reconstruct faces based on genetic samples.

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There is no single 'clever gene' – there are thousands

There is no single 'clever gene' – there are thousands | Amazing Science |

Thousands of genes are involved in intelligence, according to a new study which effectively shatters any hopes of eugenicists that babies can be genetically designed to be clever. In one of the largest studies of the human genome to date, a group of 253 scientists from around the world identified 74 genetic variants that are associated with the number of years spent in formal education.


Humans’ genetic make-up is believed to be responsible for at least 20 per cent of the difference in educational attainment between individuals, with the rest down to social factors and the environment in which they are raised. But the researchers found that the largest effect of any one genetic variant was tiny – just 0.035 per cent. This suggests that there must be at least several thousand of genes that are involved.


An Oxford University geneticist asked to comment on the research said it was a “great relief” because it showed there was little chance that people would be able to genetically modify children to be smart. The researchers, who published a paper in the journal Nature, said that the total effect of the 74 genetic variants on educational attainment was 0.43 per cent.


One of the authors of the paper, Dr Daniel Benjamin, an associate professor at the University of Southern California, said: “The fact that the genetic variant we identify with the largest effect accounts for only 0.035 of one per cent of the variation tells us that there must be at least thousands of genetic variants that influence education but have not yet been detected.” However he said the “most exciting result” of their research was that they could construct an index of genetic variants from across the genome, called a polygenic score, that could predict about six per cent of the variation.


“That’s not large enough to be useful for predicting any particular individual’s educational attainment, but it’s important because it is large enough to be useful in social science studies, which focus on average behavior in the population,” Dr Benjamin said.

Via Campaign for Social Science
Campaign for Social Science's curator insight, May 12, 2016 4:35 AM

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Thousands of genes are involved in intelligence, according to a new study which effectively shatters any hopes of eugenicists that babies can be genetically designed to be clever.
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Skeletal stem cells form the blueprint of the face structure

Skeletal stem cells form the blueprint of the face structure | Amazing Science |

Timing is everything when it comes to the development of the vertebrate face. In a new study published in PLoS Genetics, USC Stem Cell researcher Lindsey Barske from the laboratory of Gage Crump and her colleagues identify the roles of key molecular signals that control this critical timing.


Previous work from the Crump and other labs demonstrated that two types of molecular signals, called Jagged-Notch and Endothelin1 (Edn1), are critical for shaping the face. Loss of these signals results in facial deformities in both zebrafish and humans, revealing these as essential for patterning the faces of all vertebrates.


Using sophisticated genetic, genomic and imaging tools to study zebrafish, the researchers discovered that Jagged-Notch and Edn1 work in tandem to control where and when stem cells turn into facial cartilage. In the lower face, Edn1 signals accelerate cartilage formation early in development. In the upper face, Jagged-Notch signals prevent stem cells from making cartilage until later in development. The authors found that these differences in the timing of stem cells turning into cartilage play a major role in making the upper and lower regions of the face distinct from one another.


"We've shown that the earliest blueprint of the facial skeleton is set up by spatially intersecting signals that control when stem cells turn into cartilage or bone. Logically, therefore, small shifts in the levels of these signals throughout evolution could account for much of the diversity of shapes we see within the skulls of different animals, as well as the wonderful array of facial shapes seen in humans," said Barske, lead author and A.P. Giannini postdoctoral research fellow.

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Small handheld device tracks disease mutations within minutes

QuantuMDx Group is one of the most exciting biotechs to emerge from the UK and is developing a low cost, simple-to-use, handheld laboratory for 15-minute diagnosis of disease at the patient's side, for commercialisation in 2015. The robust device, which reads and sequences DNA and converts it into binary code using a tiny computer chip, is ideally suited to help address the humanitarian health burden by offering molecular diagnostics at a fraction of the price of traditional testing.


Rapidly & accurately detecting and monitoring emerging drug resistance of infectious diseases such as malaria, TB and HIV will enable health professionals to immediately prescribe the most effective drug against that disease. Once the device has passed regulatory approval, it will be available in developed countries for infectious disease testing and rapid cancer profiling and, in time, be available over-the-counter at pharmacies.


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Seeing cell to cell differences for first time explains symptoms of rare genetic disorders

Seeing cell to cell differences for first time explains symptoms of rare genetic disorders | Amazing Science |

Every cell in the body has two genomes, one from the mother and one from the father. Until now, researchers have lacked the tools to examine -- in a single cell --the exact readout from each genome to make RNA. Using a new technology that allows researchers to do just that, an interdisciplinary University of Pennsylvania team examined a rare disease in which these two genomes are expressed differently throughout the body, even sometimes in the same organ. They found that at the single-cell level gene expression was highly variable and quite different than expected, which is now shedding light on the molecular causes of rare diseases and perhaps the complex nature of tumors.


"This is a great example of cross-school collaboration," said co-senior author Marisa Bartolomei, PhD, a professor of Cell and Developmental Biology in the Perelman School of Medicine. Her colleagues are co-first author Jennifer M. Kalish, MD, PhD, an expert in rare growth disorders from The Children's Hospital of Philadelphia, and co-first author Paul Ginart, an MD/PhD candidate, and co-senior author Arjun Raj, PhD, both from the School of Engineering and Applied Sciences at Penn, who devised the technology to image single genes in individual cells. The team published their findings in Genes & Development.


"With this new technique, we can now see which cells express which genome," Bartolomei said.

Via Mariaschnee
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Discovery of a gene associated with a set of poorly understood rare diseases

Discovery of a gene associated with a set of poorly understood rare diseases | Amazing Science |

The EMBO Journal has published a study on mice by Travis Stracker and his team, in collaboration with Vincenzo Costanzo’s laboratory at the FIRC Institute of Molecular Oncology (IFOM) in Milan, in which they reveal a gene candidate for a subtype of human ciliopathy. The gene in question, GEMC1, is indispensable for the generation of multiciliated cells specific to tissues such as the brain, trachea, lungs and oviducts.


The surface of multiciliated cells is covered by hundreds of cilia. These tiny, hairlike structures serve to circulate cerebrospinal fluid, remove mucus from the respiratory tract, and transport ovum through the oviduct, among other functions. Defects in the generation or function of these cells causes a subtype of ciliopathies called Mucociliary Clearance Disorders.


Specifically, GEMC1-deficient mice produced by Stracker reproduce the symptoms of a rare disease called RGMC (Reduced Generation of Multiple Motile Cilia) — a condition that causes hydrocephaly, severe respiratory infections, and infertility. The work, led by IRB Barcelona PhD student Berta Terré and IFOM postdoctoral researcher Gabriele Piergiovanni, reports that GEMC1 regulates the only two genes known to date that underlie this disease, Multicilin and Cyclin O, thus making it a potential candidate gene for RGMC.


In addition, the study has revealed that GEMC1 is one of the most important genes in the gene signalling cascade for the production of multiciliated cells. This means that this gene affects many others that depend on its expression. The gene expression analysis of this first study has revealed at least 10 new candidate genes related to cilia, as well as dozens that were already known or suspected of being involved in the function of cilia.


“The mice are a particular model of RGMC but we believe that this model will allow us to identify many new genes involved in motile cilia, which affect other types of ciliopathies. We are now performing new gene expression analyses of specific cell populations to shed more light on a field about which little is known,” says Stracker, who studied GEMC1 because of its function in DNA replication and potential contribution to cancer.

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ATF6 Gene Mutation: A New Color Blindness Cause Identified

ATF6 Gene Mutation: A New Color Blindness Cause Identified | Amazing Science |
A rare eye disorder marked by color blindness, light sensitivity, and other vision problems can result from a newly discovered gene mutation identified by an international research team, including scientists from Columbia University Medical Center (CUMC). The findings, which were published today in the online edition of Nature Genetics, could lead to new, targeted treatments for this form of color blindness.

The researchers found that mutations to a gene called ATF6, a key regulator of the unfolded protein response, can lead to achromatopsia, a hereditary visual disorder characterized by color blindness, decreased vision, light sensitivity, and uncontrolled eye movement in children.

The unfolded protein response is a mechanism cells use to prevent the dangerous accumulation of unfolded or mis-folded proteins.

Based on mouse studies, the researchers suspect that the cone cells of people with achromatopsia are not permanently damaged and could be revived by enhancing the pathway that regulates the unfolded protein response. “Several drugs that activate this pathway have already been approved by the FDA for other conditions and could potentially benefit patients with achromatopsia,” said one of the study leaders, Stephen Tsang, MD, PhD, who is the Laszlo Z. Bito Associate Professor of Ophthalmology, and is affiliated with the Institute of Human Nutrition, at CUMC.

“Dr. Tsang’s innovative research continues to unfold the genetic basis for a variety of ocular diseases. This finding is an example of the finest clinically based science that will ultimately allow us to overcome preventable vision loss,” said George A. Cioffi, MD, Edward S. Harness Chairman and Ophthalmologist-in-Chief at NewYork-Presbyterian Hospital/Columbia University Medical Center.

“Five genes had previously been linked to achromatopsia; however, they accounted for only about half of all cases,” said Dr. Tsang. “Using next-generation gene sequencing on a small group of patients, we found that mutations in a sixth gene—ATF6—can independently lead to the disease.”
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New genetic clues found for major cause of blindness in the elderly

New genetic clues found for major cause of blindness in the elderly | Amazing Science |
An international team of scientists, that includes researchers from the University of Michigan, has identified 16 new genetic variations for age-related macular degeneration (AMD). Their findings nearly double the number of regions, or loci, associated with the disease.

Their findings nearly double the number of regions, or loci, associated with the disease. The International AMD Genomics Consortium with its 26 participating institutions also confirmed several previously reported AMD risk genes in the study involving 43,000 people. With its large sample size and high density of genetic variants, the study was able to prioritize candidate variants within identified risk loci, which in turn will help to plan more efficient follow-up experiments.

Furthermore, the study detected an enrichment of very rare protein coding variants in AMD cases within three of the known AMD risk genes, CFH, CFIand TIMP3. With observed frequencies in controls below 0.1 percent and strong risk effects, these findings indicate that there exist very personal situations that noticeably can shift the risk of developing the disease. 

The research brings to 52 the number of identified common and rare variants associated with the disease that causes vision loss in people 50 and older. Together these could explain up to 60 percent of the inherited genetic risk for the disease.

The consortium's findings are reported today in Nature Genetics.

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