Combining two genome analysis approaches supports immune system contribution to autism

Researchers using novel approaches and methodologies of identifying genes that contribute to the development of autism have found evidence that disturbances in several immune-system-related pathways contribute to development of autism spectrum disorders. The report published December 4 in the open-access journal PLOS ONE powerfully supports a role for the immune function in autism by integrating analysis of autism-associated DNA sequence variations with that of markers identified in studies of families affected by autism.

"Others have talked about immune function contributions to autism, but in our study immune involvement has been identified through a completely nonbiased approach," says Vishal Saxena, PhD, of the Massachusetts General Hospital (MGH) Department of Neurology, first, corresponding and co-senior author of the PLOS ONE paper. “We let the data tell us what was most important; and most tellingly, viral infection pathways were most important in this immune-related mechanism behind autism.”

Genetic studies of families including individuals with autism have indentified linkages with different locations in the genome. Since traditional interpretation methods implicate the gene closest to a marker site as the cause of a condition, those studies appeared to point to different genes affecting different families. However, Saxena’s team realized that, since autism has typical symptoms and affects the same biological processes, a common molecular physiology must be affecting the different families studied. To search for genetic pathways incorporating these autism-associated sites, they developed a methodology called Linkage-ordered Gene Sets (LoGS) that analyzes all of the genes within a particular distance from marker sites and ranks them according to their distance from the marker.

Genetic cause discovered for rare disorder of motor neurones

Scientists have identified an underlying genetic cause for a rare disorder of motor neurones, and believe this may help find causes of other related diseases.

Disorders of motor neurones are a group of progressive neuromuscular disorders that damage the nervous system, causing muscle weakness and wasting. These diseases affect many thousands of people in the UK. A number are inherited but the causes of the majority remain unknown, and there are no cures.

The new study has discovered a gene mutation that causes a rare disorder of motor neurones called distal hereditary motor neuropathy (dHMN). The researchers say their findings raise a possibility that mutations of the same gene or genes with similar roles might underlie other disorders of motor neurones. This could open up the potential for new treatment options, not only for dHMN but also for the wider group of these disorders.

dHMN principally affects muscles of the hands and feet, and sometimes causes a hoarse voice. Symptoms usually begin during adolescence although this can vary from infancy to the mid-thirties.

The study to investigate possible genetic causes of dHMN was led by Professor Andrew Crosby and Dr Meriel McEntagart at St George’s, University of London. It has been published in the American Journal of Human Genetics.

We all have hundreds of DNA flaws, UK geneticists say

Everyone has on average 400 flaws in their DNA, a UK study suggests. Most are “silent” mutations and do not affect health, although they can cause problems when passed to future generations. Others are linked to conditions such as cancer or heart disease, which appear in later life, say geneticists.

The evidence comes from the 1,000 Genomes project, which is mapping normal human genetic differences, from tiny changes in DNA to major mutations.

In the study, 1,000 seemingly healthy people from Europe, the Americas and East Asia had their entire genetic sequences decoded, to look at what makes people different from each other, and to help in the search for genetic links to diseases.

The new research, published in The American Journal of Human Genetics, compared the genomes of 179 participants, who were healthy at the time their DNA was sampled, with a database of human mutations developed at Cardiff University.

It revealed that a normal healthy person has on average about 400 potentially damaging DNA variations, and two DNA changes known to be associated with disease.

"Ordinary people carry disease-causing mutations without them having any obvious effect," said Dr Chris Tyler-Smith, a lead researcher on the study from the Wellcome Trust Sanger Institute, Cambridge.

He added: “In a population there will be variants that have consequences for their own health.”

The research gives an insight into the “flaws that make us all different, sometimes with different expertise and different abilities, but also different predispositions in diseases,” said Prof David Cooper of Cardiff University, the other lead researcher of the study.

Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson’s disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [¹¹C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson’s disease.

Are You Smarter Than Your Grandfather? Probably Not.

In the mid-1980s, James Flynn made a groundbreaking discovery in human intelligence. The political scientist at the University of Otago in New Zealand found that over the last century, in every nation in the developing world where intelligence-test results are on record, IQ test scores had significantly risen from one generation to the next.

“Psychologists faced a paradox: either the people of today were far brighter than their parents or, at least in some circumstances, IQ tests were not good measures of intelligence,” writes Flynn.  

Now, in a new book, Are We Getting Smarter? Rising IQ in the Twenty-First Century, Flynn unpacks his original finding, explaining the causes for this widespread increase in IQ scores, and reveals some new ones, regarding teenagers’ vocabularies and the mental decline of the extremely bright in old age. Ultimately, Flynn concludes that human beings are not smarter—just more modern.

Malcolm Gladwell explains why the “Flynn effect,” as the trend is now called, is so surprising. “If we work in the opposite direction, the typical teenager of today, with an IQ of 100, would have grandparents with average IQs of 82—seemingly below the threshold necessary to graduate from high school,” he wrote in a New Yorker article in 2007. “And, if we go back even farther, the Flynn effect puts the average IQs of the schoolchildren of 1900 at around 70, which is to suggest, bizarrely, that a century ago the United States was populated largely by people who today would be considered mentally retarded.”

New Genetic Disorder of Balance and Cognition Discovered

The family of disorders known as ataxia can impair speech, balance and coordination, and have varying levels of severity. Scientists from the Universities of Oxford and Edinburgh have identified a new member of this group of conditions which is connected to ‘Lincoln ataxia’, so called because it was first found in the relatives of US President Abraham Lincoln. The results are published in the journal PLOS Genetics.

Lincoln ataxia affects the cerebellum, a crucial part of the brain controlling movement and balance. It is caused by an alteration in the gene for ‘beta-III spectrin’, a protein found in the cerebellum. Each person has two copies of a gene, and in Lincoln ataxia there is an alteration in only one of the two copies. Unexpectedly, the British scientists have found cases of alterations in both copies of the gene, causing a novel disorder called ‘SPARCA1’ which is associated with a severe childhood ataxia and cognitive impairment.

This is the first report of any spectrin-related disorder where both copies of the gene are faulty and has given important insights into both Lincoln ataxia and SPARCA1.

The work was done using whole genome sequencing, a relatively new technology which allows all of a person’s genetics information to be analysed. In addition to sequencing work, the scientists characterized the condition using mice lacking beta-III spectrin. This analysis, combined with previous work, links the protein defect to changes in nerve-cell shape in the brain areas associated with cognition and coordinated movements. The work shows that loss of normal beta-III spectrin function underlies both SPARCA 1 and Lincoln ataxia, but a greater loss of beta-III spectrin is required before cognition problems arise.

Ultrasound Can Be Tweaked to Stimulate Different Sensations

A century after the world’s first ultrasonic detection device – invented in response to the sinking of the Titanic – Virginia Tech Carilion Research Institute scientists have provided the first neurophysiological evidence for something that researchers have long suspected: ultrasound applied to the periphery, such as the fingertips, can stimulate different sensory pathways leading to the brain.

And that’s just the tip of the iceberg. The discovery carries implications for diagnosing and treating neuropathy, which affects millions of people around the world.

“Ideally, neurologists should be able to tailor treatments to the specific sensations their patients are feeling,” said William “Jamie” Tyler, an assistant professor at the Virginia Tech Carilion Research Institute, who led the study published this week in PLOS ONE.

“Unfortunately, even with today’s technologies, it’s difficult to stimulate certain types of sensations without evoking others. Pulsed ultrasound allows us to selectively activate functional subsets of nerve fibers so we can study what happens when you stimulate, for example, only the peripheral fibers and central nervous system pathways that convey the sensation of fast, sharp pain or only those that convey the sensation of slow, dull, throbbing pain.”

Scripps Research Institute Scientists Identify Molecules in the Ear that Convert Sound into Brain Signals

For scientists who study the genetics of hearing and deafness, finding the exact genetic machinery in the inner ear that responds to sound waves and converts them into electrical impulses, the language of the brain, has been something of a holy grail.

Now this quest has come to fruition. Scientists at The Scripps Research Institute (TSRI) in La Jolla, CA, have identified a critical component of this ear-to-brain conversion—a protein called TMHS. This protein is a component of the so-called mechanotransduction channels in the ear, which convert the signals from mechanical sound waves into electrical impulses transmitted to the nervous system.

“Scientists have been trying for decades to identify the proteins that form mechanotransduction channels,” said Ulrich Mueller, PhD, a professor in the Department of Cell Biology and director of the Dorris Neuroscience Center at TSRI who led the new study, described in the December 7, 2012 issue of the journal Cell.

Not only have the scientists finally found a key protein in this process, but the work also suggests a promising new approach toward gene therapy. In the laboratory, the scientists were able to place functional TMHS into the sensory cells for sound perception of newborn deaf mice, restoring their function. “In some forms of human deafness, there may be a way to stick these genes back in and fix the cells after birth,” said Mueller.

TMHS appears to be the direct link between the spring-like mechanism in the inner ear that responds to sound and the machinery that shoots electrical signals to the brain. When the protein is missing in mice, these signals are not sent to their brains and they cannot perceive sound.

Specific genetic forms of this protein have previously been found in people with common inherited forms of deafness, and this discovery would seem to be the first explanation for how these genetic variations account for hearing loss.

Valuable Tool for Predicting Pain Genes in People: ‘Network Map’ of Genes Involved in Pain Perception

Scientists in Australia and Austria have described a “network map” of genes involved in pain perception. The work, published in the journal PLOS Genetics should help identify new analgesic drugs.

Dr Greg Neely from the Garvan institute of Medical Research in Sydney and Professor Josef Penninger from the Austrian Academy of Sciences in Vienna had previously screened the 14,000 genes in the fruit fly genome and identified 580 genes associated with heat perception. In the current study, using a database from the US National Centre for Biotechnology Information, they noted roughly 400 equivalent genes in people, 35% of which are already suspected to be pain genes.

The map they constructed using fly and human data includes many known genes, as well as hundreds of new genes and pathways, and demonstrates exceptional evolutionary conservation of molecular mechanisms across species. This should not be surprising, as every creature must be able to identify a source of pain or danger in order to survive.

Comparing fly with human data, they could see that a particular kind of molecular signaling (phospholipid signaling), already implicated in pain processing, appeared in the pain network. Further, they demonstrated the importance of two enzymes that make phospholipids, by removing those enzymes from mice, making them hypersensitive to heat pain.

"Pain affects hundreds of millions of people, and is a research field badly in need of new approaches and discoveries," said Dr Neely.

"The fact that evolution has done such a remarkable job of conserving pain genes across species makes our fly data very useful, because much of it translates to rodents and people.

"We are able to test our hypotheses in mice, and if a gene or pathway or process functions as we predict, there is a good chance it will also apply to people.

"By cross-referencing fly data with human information already in the public domain — like gene expression profiling or genetic association studies — we know we’ll be able to pinpoint new therapeutic targets."