Amazing Science

The psychiatric illnesses seem very different — schizophrenia, bipolar disorder, autism, major depression and attention deficit hyperactivity disorder. Yet they share several genetic glitches that can nudge the brain along a path to mental illness, researchers report. Which disease, if any, develops is thought to depend on other genetic or environmental factors.

 

Their study analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, they applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. The research team examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. They undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders and used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.Findings: SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10−8) in the primary analysis, Regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.The new study does not mean that the genetics of psychiatric disorders are simple. Researchers say there seem to be hundreds of genes involved and the gene variations discovered in the new study confer only a small risk of psychiatric disease.

 

Steven McCarroll, director of genetics for the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and M.I.T., said it was significant that the researchers had found common genetic factors that pointed to a specific signaling system. “It is very important that these were not just random hits on the dartboard of the genome,” said Dr. McCarroll, who was not involved in the new study.

The human skin is a complex ecosystem that hosts a heterogeneous flora. Until recently, the diversity of the cutaneous microbiota was mainly investigated for bacteria through culture based assays subsequently confirmed by molecular techniques. There are now many evidences that viruses represent a significant part of the cutaneous flora as demonstrated by the asymptomatic carriage of beta and gamma-human papillomaviruses on the healthy skin. Furthermore, it has been recently suggested that some representatives of the Polyomavirusgenus might share a similar feature. In the present study, the cutaneous virome of the surface of the normal-appearing skin from five healthy individuals and one patient with Merkel cell carcinoma was investigated through a high throughput metagenomic sequencing approach in an attempt to provide a thorough description of the cutaneous flora, with a particular focus on its viral component. The results emphasize the high diversity of the viral cutaneous flora with multiple polyomaviruses, papillomaviruses and circoviruses being detected on normal-appearing skin.

 

Moreover, this approach resulted in the identification of new Papillomavirusand Circovirus genomes and confirmed a very low level of genetic diversity within human polyomavirus species. Although viruses are generally considered as pathogen agents, our findings support the existence of a complex viral flora present at the surface of healthy-appearing human skin in various individuals. The dynamics and anatomical variations of this skin virome and its variations according to pathological conditions remain to be further studied. The potential involvement of these viruses, alone or in combination, in skin proliferative disorders and oncogenesis is another crucial issue to be elucidated.

 

Further information on the total virome inside of us: http://tinyurl.com/av22d9o

In a SPIEGEL interview, synthetic biology expert George Church of Harvard University explains how DNA will become the building material of the future -- one that can help create virus-resistant human beings and possibly bring back lost species like the Neanderthal.

 

George Church, 58, is a pioneer in synthetic biology, a field whose aim is to create synthetic DNA and organisms in the laboratory. During the 1980s, the Harvard University professor of genetics helped initiate the Human Genome Project that created a map of the human genome. In addition to his current work in developing accelerated procedures for sequencing and synthesizing DNA, he has also been involved in the establishing of around two dozen biotech firms. In his new book, "Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves," which he has also encoded as strands of DNA and distributed on small DNA chips, Church sketches out a story of a second, man-made Creation.

 

SPIEGEL recently sat down with Church to discuss his new tome and the prospects for using synthetic biology to bring the Neanderthal back from exctinction as well as the idea of making humans resistant to all viruses.

Next-generation sequencing allows detection of minor variants in a heterogeneous sample. However, errors in PCR and sequencing pose limits on its sensitivity. A group at University of Washington developed a method, called Duplex Sequencing, to dramatically improve accuracy by sequencing both strands of each DNA duplex. Mutations that are detected in the consensus sequence of one strand but not the other are discounted as technical errors.

 

The authors adopted the method to Illumina sequencing. It involves the use of modified adaptors that have a tag with random sequence attached. After ligation of these modified adaptors, each duplex DNA fragment is flanked by two different tags and subjected to paired-end sequencing. Sequences of the same duplex from the complementary strands can therefore be uniquely identified by having the same tags on either ends. Comparing sequences of the two strands allows identification of true mutations. The authors estimated that Duplex sequencing has a theoretical background error rate of less than one per 10^9 nucleotides sequenced.

Full text article can be accessed here: http://www.pnas.org/content/early/2012/07/31/1208715109.full.pdf

One of the most difficult problems in the field of genomics is assembling relatively short "reads" of DNA into complete chromosomes. In a new paper published in Proceedings of the National Academy of Sciences an interdisciplinary group of genome and computer scientists has solved this problem, creating an algorithm that can rapidly create "virtual chromosomes" with no prior information about how the genome is organized.

 

The powerful DNA sequencing methods developed about 15 years ago, known as next generation sequencing (NGS) technologies, create thousands of short fragments. In species whose genetics has already been extensively studied, existing information can be used to organize and order the NGS fragments, rather like using a sketch of the complete picture as a guide to a jigsaw puzzle. But as genome scientists push into less-studied species, it becomes more difficult to finish the puzzle.

 

To solve this problem, a team led by Harris Lewin, distinguished professor of evolution and ecology and vice chancellor for research at the University of California, Davis and Jian Ma, assistant professor at the University of Illinois at Urbana-Champaign created a computer algorithm that uses the known chromosome organization of one or more known species and NGS information from a newly sequenced genome to create virtual chromosomes.

 

"We show for the first time that chromosomes can be assembled from NGS data without the aid of a preexisting genetic or physical map of the genome," Lewin said. The new algorithm will be very useful for large-scale sequencing projects such as G10K, an effort to sequence 10,000 vertebrate genomes of which very few have a map, Lewin said.

 

"As we have shown previously, there is much to learn about phenotypic evolution from understanding how chromosomes are organized in one species relative to other species," he said. The algorithm is called RACA (for reference-assisted chromosome assembly), co-developed by Jaebum Kim, now at Konkuk University, South Korea, and Denis Larkin of Aberystwyth University, Wales. Kim wrote the software tool which was evaluated using simulated data, standardized reference genome datasets as well as a primary NGS assembly of the newly sequenced Tibetan antelope genome generated by BGI (Shenzhen, China) in collaboration with Professor Ri-Li Ge at Qinghai University, China.

 

Larkin led the experimental validation, in collaboration with scientists at BGI, proving that predictions of chromosome organization were highly accurate. Ma said that the new RACA algorithm will perform even better as developing NGS technologies produce longer reads of DNA sequence. "Even with what is expected from the newest generation of sequencers, complete chromosome assemblies will always be a difficult technical issue, especially for complex genomes. RACA predictions address this problem and can be incorporated into current NGS assembly pipelines," Ma said.

Southern Africa's bushmen, and their relatives the Khoe, veered off on their own path of genetic development 100,000 years ago, according to a new study.

 

The split, gleaned from an analysis of genetic data, is the earliest divergence scientists have discovered in the evolution of modern humans.

The Khoe and the San peoples - who speak click languages, and live across a wide swath of southern Africa from Namibia to Mozambique to South Africa - have long fascinated scientists.

 

The San, in particular, were one of the last remaining hunter-gatherer societies, living well into the 20th century in a style anthropologists think was similar to humans' most ancient ancestors.

 

The study published in the journal Science analyses the genes of 220 members of the Khoe and San groups. Researchers looked at 2.3 million genetic variations for each participant, learning important information about the Khoe-San and, more generally, the origins of modern humans.

 

Although comb jellies seem to be little more than tennis ball-sized blobs in the sea, these organisms are relatively sophisticated in how they use light. The creatures flash a blue-green light at predators, for example, possibly to startle them. Researchers studying the genome of the comb jelly, also known as a ctenophore, have discovered that the bioluminescent creatures pack in 10 proteins for generating light. They have other proteins called opsins that detect light, even though comb jellies lack eyes. It's not clear what these opsins do in this animal. The genome is the first to be sequenced from a bioluminescent animal. Because ctenophores appear to sit at the base of the animal tree of life, the findings suggest that light-generating and sensing proteins evolved at the same time as multicellularity. Such proteins may have given rise to the diversity of light-sensing molecules seen in animals today, such as in the rods and cones in human eyes. And studying them, the researchers say, could lead to new insights into the origin of eyes and therapies for treating sight disorders.

Studies in mice confirm that mutations in the gene, UBE3B, cause a rare genetic disorder in children.

 

Researchers have defined the gene responsible for a rare developmental disorder in children. The team showed that rare variation in a gene involved in brain development causes the disorder. This is the first time that this gene, UBE3B, has been linked to a disease. By using a combination of research in mice and sequencing the DNA of four patients with the disorder, the team showed that disruption of this gene causes symptoms including brain abnormalities and reduced growth, highlighting the power of mouse models for understanding the biology behind rare diseases.

 

"Ubiquitination, the biological pathway UBE3B is involved in, is crucial in neurodevelopment," says Dr Guntram Borck, lead author from the University of Ulm. "We have studied several patients with this rare condition, and by sequencing the coding regions of the genome of these patients we found mutations implicating the gene UBE3B. This result was confirmed by studies performed in mice by our collaborators at the Sanger Institute. At the Sanger researchers deleted the gene in mice and found that they had symptoms that were quite similar to those in the patients with UBE3B mutations including; reduced body weight and size, and reduced size of the brain.

 

The studies in mice also uncovered other defects underlying the disorder. Mice with the gene deletion had reduced cholesterol levels, a symptom that was seen by the team in three of the patients. This observation suggests that a defect in cholesterol metabolism is associated with this syndrome. "Both techniques, DNA sequencing and deleting the gene in mice, support the finding that disruption of UBE3B causes this syndrome," says Dr David Adams, lead author from the Wellcome Trust Sanger Institute. "We can now learn much more about this syndrome by studying these mice. They also represent a pre-clinical model in which we may trial potential new therapies.

 

"This is the first time that this gene has been implicated in any disorder." DNA sequencing has greatly improved the identification of variants associated with developmental disorders. But the challenge still remains for researchers to identify which of these variants, there are usually several hundred identified in each patient, cause the disorder. Animal models are a complementary approach for determining the causal gene and for understanding the biology behind genetic disorders.

Curator: Dr. Aviva Lev-Ari

One decade following the completion of the  Sequencing of the Human Genome – the field of Genomics, the discipline that has emerged as a result of project completion has FOUR sections: Comparative Genomics, Genome Sequencing and Annotation, Functional Genomics, and Translational Genomics.

Nearsightedness—also known as myopia—is a major cause of blindness and visual impairment worldwide, affecting 30 percent of Western populations and up to 80 percent of Asian people. At present, there is no cure.

 

During visual development in childhood and adolescence the eye grows in length, but in people with myopia the eye grows too long. Light entering the eye is then focused in front of the retina rather than on it, resulting in a blurred image.

 

The refractive error can be corrected with glasses, contact lenses, or surgery. But the eye remains longer and the retina is thinner, and could lead to retinal detachment, glaucoma, or macular degeneration, especially with higher degrees of myopia. Myopia is highly heritable, although up to now, little was known about the genetic background.

 

To find the genes responsible, researchers from Europe, Asia, Australia, and the United States analyzed genetic and refractive error data of over 45,000 people from 32 different studies, and found 24 new genes for this trait, and confirmed two previously reported genes.

 

Interestingly, the genes did not show significant differences between the European and Asian groups, despite the higher prevalence among Asian people. The new genes include those which function in brain and eye tissue signaling, the structure of the eye, and eye development. The genes lead to a high risk of myopia and carriers of the high-risk genes had a tenfold increased risk.

 

It was already known that environmental factors, such as reading, lack of outdoor exposure, and a higher level of education can increase the risk of myopia. The condition is more common in people living in urban areas.

An unfavorable combination of genetic predisposition and environmental factors appears to be particularly risky for development of myopia. How these environmental factors affect the newly identified genes and cause myopia remains intriguing, and will be further investigated.

Many people have trouble believing that chromosome number can change and stay changed in a species. Their first thought is often of Down syndrome or the other problems that usually come with missing or extra chromosomes. It can be hard to imagine how a living thing could end up with a new chromosome number without these problems.

And yet it happens all the time in creatures as varied as yeast, corn, butterflies, voles and even mice. And now it has been seen in people.

 In a recent report, a doctor in China has identified a man who has 44 chromosomes instead of the usual 46. Except for his different number of chromosomes, this man is perfectly normal in every measurable way.

His chromosomes are arranged in a stable way that could be passed on if he met a nice girl who had 44 chromosomes too. And this would certainly be possible in the future given his family history.

 

But why doesn't he have any problems? A loss of one let alone two chromosomes is almost always fatal because so many essential genes are lost. In this case, he has fewer chromosomes but is actually missing very few genes. Instead, he has two chromosomes stuck to two other chromosomes. More specifically, both his chromosome 14's are stuck to his chromosome 15's. So he has almost all the same genes as any other person. He just has them packaged a bit differently.

 

This is an important finding because it tells us about a key genetic event in human prehistory. All the evidence points to humans, like their relatives the chimpanzees, having 48 chromosomes a million or so years ago. Nowadays most humans have 46.

 

What happened to this 44 chromosome man shows one way that the first step in this sort of change might have happened in our past. Scientists could certainly predict something like this. But now there is proof that it can actually happen.

Brooke Greenberg (born January 8, 1993), is a now 20 year old girl from Reisterstown, Maryland, who has remained physically and cognitively similar to a toddler. She is about 30 inches (76 cm) tall, weighs about 16 pounds (7.3 kg), and has an estimated mental age of 9 months to 1 year. Brooke’s doctors have termed her condition Syndrome X.

 

Brooke was born on January 8, 1993 at Sinai Hospital in Baltimore, Maryland, one month prior to her due date, weighing just four pounds (1.8 kg). She was born with anterior hip dislocation, a condition which caused her legs to be swiveled upwards, awkwardly, toward her shoulders; this was corrected surgically. Otherwise, Brooke appeared to be a normal infant.

In her first six years, Brooke Greenberg went through a series of unexplained medical emergencies from which she recovered. She had seven perforated stomach ulcers. She also suffered a seizure. This was followed by what was later diagnosed as a stroke; weeks later, no damage was detected. At age five, Brooke had a mass in her brain that caused her to sleep for 14 days. The doctors diagnosed the mass as a brain tumor. However, Brooke later awoke, and physicians found no tumor present. Brooke’s pediatrician, Dr. Lawrence Pakula, states that the source of her sudden illness remains a mystery.

Over the past several years, the Greenbergs visited many specialists, looking for an explanation for their daughter’s strange condition, and found she has a mutation in Chromosome 1. In 2001, when Dateline documented Brooke, she was still the size of a six-month-old infant, weighing just 13 lb (5.9 kg) at 27 inches (69 cm) tall. The family still had no explanation. Brooke Greenberg’s mother Melanie said: “They [the specialists] just said she’ll catch up. Then we went to the nutritionist, the endocrinologist. We tried the growth hormone…”. The growth hormone treatment had no effect. Howard, Brooke’s father, said: “I mean she did not put on an ounce or she did not grow an inch … That’s when I knew there was a problem.” After the growth hormone administration failed, the doctors, unable to diagnose a known condition, named her condition Syndrome X.

The Greenbergs made many visits to nearby Johns Hopkins Children’s Center, and even took Brooke to New York’s Mount Sinai Hospital, searching for information about their daughter’s condition. When geneticists sequenced Greenberg’s DNA, they found that the genes associated with the premature aging diseases were normal, unlike the mutated versions in patients with Werner syndrome and progeria.

In 2006, Dr. Richard Walker of the University of South Florida College of Medicine, said that Brooke’s body is not developing as a coordinated unit, but as independent parts that are out of sync. She has never been diagnosed with any known genetic disorder or chromosomal abnormality that would help explain why.

In 2009, Walker said: “There’ve been very minimal changes in Brooke’s brain … Various parts of her body, rather than all being at the same stage, seem to be disconnected.” Walker noted that Greenberg’s brain, for example, is not much more mature than that of a newborn infant. He estimates her mental age at around 9 months to a year old. Brooke can make gestures and recognize sounds, but cannot speak. Her bones are like those of a ten-year-old, and she still has her baby teeth, which have an estimated developmental age of about 8 years. Said Walker, “We think that Brooke’s condition presents us with a unique opportunity to understand the process of aging.”
Her telomeres seem to be shortening at the normal rate.

Yesterday, Brooke Greenberg and her family appeared on the Katie Couric Show as part of a show focused on medical mysteries. Greenberg, who is 20 years old, appears to be the age of a toddler. While the family does not know the root of Greenberg's apparent inability to age, Mount Sinai's Eric Schadt, who also appeared on the show with host Katie Couric, has been studying her genome. As Schadt notes in the clip below, in addition to figuring out the source of her disorder, Greenberg's genome could also help researchers learn more about the aging process.

Video Link: http://bcove.me/uesqzs6d

There are lots of popular articles I could point to, but let’s start with a recent series in Time that included eight online features and the Dec. 13 cover story, ominously titled “The DNA Dilemma.”

 

The series, written by Bonnie Rochman, is thoroughly reported, balanced, and full of fascinating personal stories about children whose genomes have been sequenced. It’s also timely: The primary question Rochman raises—how much information is too much information?—has been dominating commentaries about genetic testing in the medical literature.

 

But this is the wrong question, or at least one that’s becoming increasingly irrelevant. The personal genomics horse has bolted, and yet many paternalistic members of the medical community are still trying to shut the barn door. In doing so, they’re fostering a culture of DNA fear when what we really need is a realistic and nuanced genetics education.

 

There are many kinds of genetic tests, but most of the hoopla revolves around whole-genome sequences—the impossibly long, letter-by-letter readouts of the DNA inside the nucleus of each of your cells. In 2003, the first human genome was fully sequenced for just shy of $3 billion. Today a doctor can order yours for around $10,000.

 

Though dropping every day, the cost is still prohibitive enough that most people who get their genome sequenced are part of a medical research study. But the technology is beginning to seep into everyday clinical settings, especially for children with rare diseases. In either situation, the doctor or researcher might inadvertently discover genomic information—known as “incidental findings” in the scientific literature and “dark DNA secrets” in one of the Timearticles—that has nothing to do with the child’s sickness or the study at hand. Hence the big dilemma: How much do patients want to know? How much do they need to know?

A newly identified form of DNA—small circles of non-repetitive sequences—may be widespread in somatic cells of mice and humans, according to a study in this week’s issue of Science. These extrachromosomal bits of DNA, dubbed microDNA, may be the byproducts of microdeletions in chromosomes, meaning that cells all over the body may have their own constellation of missing pieces of DNA.

 

“It’s an intriguing finding,” said James Lupski, a geneticist at Baylor College of Medicine in Houston who did not participate in the research. Most DNA studies use cells drawn from blood, but that snapshot of a person’s genome may not be giving a complete picture, Lupski explained, if cells in other organs have their own set of chromosomal snippets missing.

 

But the findings do not surprise Sabine Mai, who studies genomic instability at the University of Manitoba. Extrachromosomal DNA is a well-studied phenomenon in cells ranging from plants to humans, she says. This research is just renaming an old phenomenon, previously referred to small polydispersed DNA. Small circles of DNA have been identified before, Mai says, though new deep sequencing techniques will allow for a “deeper characterization” of these extrachromosomal snippets.

We all know that nobody's perfect. But now scientists have documented that fact on a genetic level. Researchers discovered that normal, healthy people are walking around with a surprisingly large number of mutations in their genes.

 

It's been well known that everyone has flaws in their DNA, though, for the most part, the defects are harmless. It's been less clear, however, just how many mistakes are lurking in someone's genes. "It's such an interesting question that people had been trying to make estimates from indirect approaches for a long time," says Chris Tyler-Smith of the Wellcome Trust Sanger Institute in Cambridge, England. "There were estimates that ranged from just a handful up to 100 or more serious disease-associated mutations."

 

But Tyler-Smith and his colleagues wanted to get a more precise, direct estimate. So they analyzed the DNA of 179 people from the United States, Japan, China and Nigeria who had volunteered to have their entire genetic blueprints deciphered through the 1,000 Genomes project. Now, in a paper appearing in the American Journal of Human Genetics, the researchers are reporting a big surprise.

"We found quite amazingly large numbers of deleterious and known disease-causing mutations," Tyler-Smith says. According to their analysis, the average person has around 400 defects in his or her genes, including at least a couple that are associated with disease.

 

The weird thing is, none of the people whose DNA was studied were severely sick. They all seemed perfectly happy and healthy. "It could be that in many cases the other copy of that gene or a similar gene within a multi-gene family takes over," Tyler-Smith says. "It's a bit surprising that people should be walking around apparently healthy yet we're seeing known disease-causing mutations in their genomes," he says. "But the answer was that these tended to be for mild and very often late-onset conditions. Things like heart disease, an increased risk of developing cancer."