Autism is an agonizing puzzle, a complex mixture of genetic and environmental factors. One piece of this puzzle that has emerged in recent years is a biochemical cascade called the mTOR pathway that regulates growth in the developing brain. A mutation in one of the genes that controls this pathway, PTEN (also known as phosphatase and tensin homolog), can cause a particular form of autism called macrocephaly/autism syndrome.

Using an animal model of this syndrome, scientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered that mutations in PTEN affect the assembly of connections between two brain areas important for the processing of social cues: the prefrontal cortex, an area of the brain associated with complex cognitive processes such as moderating social behavior, and the amygdala, which plays a role in emotional processing.

 “When PTEN is mutated, we find that neurons that project from the prefrontal cortex to the amygdala are overgrown and make more synapses,” said TSRI Associate Professor Damon Page. “In this case, more synapses are not necessary a good thing because this contributes to abnormal activity in the amygdala and deficits in social behavior.”

The study also showed that targeting the activity of the mTOR pathway shortly after birth, a time when neurons are forming connections between these brain areas, can block the emergence of abnormal amygdala activity and social behavioral deficits. Likewise, reducing activity neurons that project between these areas in adulthood can also reverse these symptoms.

‘Given that the functional connectivity between the prefrontal cortex and amygdala is largely conserved between mice and humans,” said TSRI Graduate Student Wen-Chin Huang, the first author of the study, “we anticipate the therapeutic strategies suggested here may be relevant for individuals on the autism spectrum.”

Although caution is warranted in extrapolating findings from animal models to humans, these findings have implications for individualized approaches to treating autism. “Even within individuals exposed to the same risk factor, different strategies may be appropriate to treat the symptoms of autism in early development versus maturity,” said Page.

The Scripps Research Institute www.scripps.edu/news/press/2016/20161115page.html

Many of the genetic variations that increase risk for schizophrenia are rare, making it difficult to study their role in the disease. To overcome this, the Psychiatric Genomics Consortium, an international team led by Jonathan Sebat, PhD, at University of California San Diego School of Medicine, analysed the genomes of more than 41,000 people in the largest genome-wide study of its kind to date. Their study reveals several regions of the genome where mutations increase schizophrenia risk between four- and 60-fold.

These mutations, known as copy number variants, are deletions or duplications of the DNA sequence. A copy number variant may affect dozens of genes, or it can disrupt or duplicate a single gene. This type of variation can cause significant alterations to the genome and lead to psychiatric disorders, said Sebat, who is a professor and chief of the Beyster Center for Genomics of Neuropsychiatric Diseases at UC San Diego School of Medicine. Sebat and other researchers previously discovered that relatively large copy number variants occur more frequently in schizophrenia than in the general population.

In this latest study, Sebat teamed up with more than 260 researchers from around the world, part of the Psychiatric Genomics Consortium, to analyse the genomes of 21,094 people with schizophrenia and 20,227 people without schizophrenia. They found eight locations in the genome with copy number variants associated with schizophrenia risk. Only a small fraction of cases (1.4 percent) carried these variants. The researchers also found that these copy number variants occurred more frequently in genes involved in the function of synapses, the connections between brain cells that transmit chemical messages.
With its large sample size, this study had the power to find copy number variants with large effects that occur in more than 0.1 percent of schizophrenia cases. However, the researchers said they are still missing many variants. More analyses will be needed to detect risk variants with smaller effects, or ultra-rare variants.

“This study represents a milestone that demonstrates what large collaborations in psychiatric genetics can accomplish,” Sebat said. “We’re confident that applying this same approach to a lot of new data will help us discover additional genomic variations and identify specific genes that play a role in schizophrenia and other psychiatric conditions.”

University of California San Diego Health health.ucsd.edu/news/releases/Pages/2016-11-22-study-finds-rare-genetic-variations-linked-to-schizophrenia.aspx

Most melanomas are driven by mutations that spur out-of-control cell replication, while nevi (moles composed of non-cancerous cells at the skin surface) harbouring the same mutations do not grow wildly. However, changes in the level of gene expression can cause nevi to become melanomas.

Dermatologists surmise that 30 to 40 percent of melanomas (approximately 30,000 cases per year) may arise in association with a nevus. However, clinicians would like to be able to better distinguish between the two, especially in borderline cases when they examine skin tissue after a patient biopsy.

Senior author John T. Seykora, MD, PhD, a professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, led a study that found that decreased levels of the gene p15 represents a way to determine if a nevus is transitioning to a melanoma. The protein p15 functions to inhibit nevus cell proliferation.

“We showed that p15 expression is a robust biomarker for distinguishing nevus from melanoma,” said Seykora. “Making this distinction has been a long-standing issue for dermatologists. We hope that this new finding will help doctors determine if a nevus has transformed to melanoma. This could help doctors and patients in difficult cases. Current research will hopefully move this into the realm of standard practice in about one to two years.”

Decreased expression in the related protein p16 has also been associated with melanoma, but p15 appears to be a primary driver of oncogene-induced cell senescence in nevus cells. When p15 levels drop, then nevus cells begin to grow.

The team stained human nevus and melanoma tissue samples with p15 and p16 antibodies.  Staining was evaluated and graded for percentage and intensity to determine an “H score,” which correlates with the level of protein in the cells. This approach could also form the basis of a clinical determination, taking the form of an antibody test for p15 from a patient’s biopsy specimen. “If the staining level is high then that would be most consistent with a benign nevus,” Seykora said. “If the staining level is low then that would be consistent with a melanoma.”

RNA was also extracted from 14 nevus and melanoma tissue samples to determine levels of p15 mRNA.  The expression of p15 mRNA was significantly increased in melanocytic nevi compared with melanomas as determined by real-time quantitative RT-PCR analysis.

Penn Medicine www.uphs.upenn.edu/news/News_Releases/2016/11/seykora/

24 research studies from the landmark BLUEPRINT project and IHEC consortia reveal how variation in blood cells’ characteristics and numbers can affect a person’s risk of developing complex diseases such as heart disease, and autoimmune diseases including rheumatoid arthritis, asthma, coeliac disease and type 1 diabetes.

The papers, along with another 17 in high-impact journals, represent the culmination of a five-year, £25 million (€30 million) project that brought together 42 leading European universities, research institutes and industry partners and the work of IHEC. The project’s goals were to explore and describe the range of epigenetic changes that take place in bone marrow as stem cells develop into different types of mature blood cell. It also sought to match epigenetic changes and genetic differences to the physical characteristics of each cell type and use this knowledge to understand how these can lead to blood disorders, cancer and other complex diseases*.

In the first study, Sanger Institute researchers worked closely with colleagues at the University of Cambridge and the University of Oxford to carry out the largest and most in-depth study of DNA and blood cell characteristics using the UK BioBank resource and the INTERVAL study. By comparing almost 30 million DNA sequence differences in more than 173,000 people with variation in the physical properties of blood cells the scientists identified 2,500 previously undiscovered locations in the genome that influence blood cell characteristics and functions. Further work showed that genetic differences affecting some of these characteristics are linked to increased risk of heart attack, or to rheumatoid arthritis and other common autoimmune diseases.

“The scale, resolution and homogeneity of our work were vital. Because we examined so many people we were able to discover important ‘rare and low frequency’ genetic differences that are present in fewer than 10 per cent of the population. We found that these can have a much larger impact on the characteristics of blood cells than the common differences studied previously. Of the more than 300 rare and low frequency difference we found, 74 appear to affect the structure of proteins. These give us important clues as to which biological pathways are involved in controlling the production, function and characteristics of blood cells.”

The team found that genetic differences that cause people to have more young red blood cells in their peripheral bloodstreams also increase the risk they will have a heart attack.

“When mature red blood cells rupture in our blood the body replaces them with new, young red cells – a process known as haemolysis. So we think that increased haemolysis and increased risk of coronary heart disease are affected by the same biological pathways. Identifying these pathways may offer new treatment possibilities.”

Dr Adam Butterworth, one of the study’s senior authors, from the University of Cambridge
‘By combining our detailed genetic information with data from the BLUEPRINT project, we were able to identify with high certainty ‘active’ regions of the human genome that are more likely to be involved in disease mechanisms.’

Heather Elding, one of the paper’s first authors, from the Sanger Institute
For example, in another new finding, the research team showed that genetic differences that increased the amount of certain white blood cells, known as eosinophils, also increased the risk of a person developing rheumatoid arthritis, asthma, coeliac disease and type 1 diabetes.

In the second paper, researchers collaborated with scientists at the University of Cambridge, McGill University in Canada and several UK and European institutions to explore the role that epigenetics plays in the development and function of three major human immune cell types: CD14+ monocytes, CD16+ neutrophils and naïve CD4+ T cells, from the genomes of 197 individuals. They studied the contributions of various genetic control mechanisms, including epigenetic changes such as methyl tags on promoter regions in the DNA and histone modifications, to understand how these different levels of regulation interacted with genetic differences to change the expression of genes, immune function and, ultimately, human disease.

The team identified 345 regions of the genome where they could pinpoint the likely molecular causes underlying a person’s predisposition to immune-related diseases such as inflammatory bowel disease, type 1 diabetes and multiple sclerosis.

“We have created an expansive, high-resolution atlas of variations that deepens our understanding of the interplay between the genetic and epigenetic machinery that drives the three primary cells of the human immune system. We have identified hundreds of genetic variations associated with autoimmune diseases that appear to affect the activity of genes in specific regions of the genome, pointing to biological pathways that may be involved in disease and which, ultimately, may be treatable with medication.”

Sanger Institute www.sanger.ac.uk/news/view/landmark-project-shows-heart-disease-and-rheumatoid-arthritis-risk-raised-genetic-changes