New research shows that migraine and depression may share a strong genetic component. The research is published in the January 13, 2010, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Understanding the genetic factors that contribute to these disabling disorders could one day lead to better strategies to manage the course of these diseases when they occur together,” said Andrew Ahn, MD, PhD, of the University of Florida in Gainesville, who wrote an editorial accompanying the study and is a member of the American Academy of Neurology. “In the meantime, people with migraine or depression should tell their doctors about any family history of either disease to help us better understand the link between the two.”

The study involved 2,652 people who took part in the larger Erasmus Rucphen Family study. All of the participants are descendants of 22 couples who lived in Rucphen in the 1850s to 1900s.

“Genealogical information has shown them all to be part of a large extended family, which makes this type of genetic study possible,” said study author Gisela M. Terwindt, MD, PhD, of Leiden University Medical Center in the Netherlands.

Of the participants, 360 had migraine. Of those, 151 had migraine with aura, which is when headaches are preceded by sensations that affect vision, such as seeing flashing lights, and 209 had migraine with no aura. A total of 977 people had depression, with 25 percent of those with migraine also having depression, compared to 13 percent of those without migraine.

The researchers then estimated the relative contribution of genetic factors for both of the disorders. They found that for both types of migraine, the heritability was estimated at 56 percent, i.e., 56 percent of the trait is explained by genetic effects. For migraine with aura, the estimate was 96 percent. “This finding shows that migraine with aura may be a promising avenue to search for migraine genes,” Terwindt said.

Comparing the heritability scores for depression between those with migraine and those without showed a shared genetic component in the two disorders, particularly with migraine with aura. “This suggests that common genetic pathways may, at least partly, underlie both of these disorders, rather than that one is the consequence of the other,” Terwindt said.

Older patients with acute myeloid leukemia (AML) might benefit from a drug that reactivates genes that cancer cells turn off, according to research at Washington University School of Medicine in St. Louis and collaborating institutions. The researchers say the findings support further investigation of the drug, decitabine, as a first-line treatment for these patients, who have limited treatment options.

Almost two-thirds of AML patients over age 65 do not receive treatment for the disease because standard therapy can be risky and often is ineffective. On average, such patients survive only 1.7 months after diagnosis.

“Older leukemia patients don’t have good treatment options because the chemotherapy and stem cell transplants that we commonly use for younger patients are often too toxic for them,” says lead author Amanda F. Cashen, M.D., assistant professor of medicine in the Division of Oncology and a bone marrow transplant specialist with the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

“Furthermore, the biology of acute leukemia in the older patient population is different, making their response rate lower, their risk of relapse higher and their cure rates lower,” she says. “So we definitely need new therapies in that patient population – treatments that are going to be both better tolerated and more effective.”

The study, to be published in an upcoming issue of the Journal of Clinical Oncology and now available on-line, was conducted at three sites: Washington University School of Medicine; the University of California, Los Angeles; and the City of Hope National Medical Center in Duarte, Calif. The researchers tested decitabine in 55 AML patients with an average age of 74 years.

Decitabine can increase the activity of genes that have been silenced in cancer cells. It works by reducing the amount of DNA that is marked with a chemical tag called a methyl group. Scientists think that the excess methylation found in cancer cells inactivates genes that normally suppress tumor development.

All patients received the same decitabine dose for five consecutive days every four weeks until their disease stopped responding to the drug and began progressing or until an adverse event occurred to prevent further participation. By comparison to standard chemotherapy and stem cell transplantation, the treatment was considered a low-intensity treatment and was more tolerable for elderly patients, especially those with accompanying medical problems.

In 24 percent of the study participants, blood counts and bone marrow returned to normal, which is considered a complete response. It took 4.5 cycles of decitabine treatment on average to achieve a complete response. In those with a complete response, average survival time was 14 months. For all study participants, average survival time was 7.7 months.

Treatment-related adverse events included low blood counts (red cells, white cells and platelets), infection, fever and fatigue. Almost half of the study participants had at least one serious adverse event. Seven patients discontinued treatment, and three patients died as the result of adverse events.

“We have to wait for the results of further trials of decitabine to have a better estimate of the response rate and survival outcome compared to other low intensity options for older adults,” Cashen says. “This study can’t definitively establish decitabine’s role for treating older adults with AML, but it certainly excites us to study it more.”

Two new studies showing that protein bits produced by unusual “reading” of the HIV genome can induce immune responses appeared online in the Journal of Experimental Medicine on Jan. 11.

Small, compact RNA viruses like HIV make the most of their limited genomes by stuffing genes that direct protein production into several different reading frames and orientations. When teams – led by Berger et al. at the Ragon Institute of MGH, MIT, and Harvard; and Bansal et al. at the University of Alabama – examined viral genomes in groups of HIV-infected individuals, they found an accumulation of genetic variations specifically in unusual reading frames and orientations. This finding suggested that mutations in these reading frames may have been caused by pressure from the hosts’ immune systems.

The notion was supported by their finding that HIV-infected individuals exhibited killer immune cell responses specific for protein fragments generated by unconventional reading of the HIV genome. In some cases, mutations in these reading frames allowed HIV-infected cells to escape immune cell killing.

The information provided by these findings may prove useful during future HIV vaccine design efforts.

Neuroscientists have forged an unlikely molecular union as part of their fight against diseases of the brain and nervous system.

The team has brought together the herpes virus and a molecule known as Sleeping Beauty to improve a technology known as gene therapy, which aims to manipulate genes to correct for molecular flaws that cause disease.

The work, detailed in a paper published online in Gene Therapy, has allowed scientists at the University of Rochester Medical Center to reach a long-sought goal: Shuttling into brain cells a relatively large gene that can remain on for an extended period of time.

“We’ve broken what is in effect a size barrier – a limit to how much genetic material we can put into the nucleus of a cell and keep functioning for a long period of time,” said neuroscientist William Bowers, Ph.D., a scientist in the Center for Neural Development and Disease and the leader of the team. “That opens up more diseases to possible treatment with gene therapy.”

The first author of the paper is Biochemistry graduate student Suresh de Silva, who defends his doctoral thesis later this month.

The molecular rendezvous of Sleeping Beauty and herpes in human brain cells could spell good news in the search for treatments for horrific brain diseases known as pediatric leukodystrophies, or a group of diseases known as lysosomal storage disorders. In many of these diseases, even though just a single gene or protein is defective, the effects are devastating – the diseases slowly rob children of their brain cells and are often fatal after years of severe symptoms.

The findings bolster the tools that researchers have when approaching certain diseases, said Bowers, including Usher syndrome, which results in deafness and vision loss; Niemann-Pick disease Type C, a fatal childhood lysosomal storage disorder; and von Willebrand disease, an inherited disease that causes extensive, chronic bleeding.

“The field of gene therapy is just beginning to yield some successes for patients. Improvements like this are crucial for increasing the number of patients who might benefit from such an approach,” said Bowers, who is an associate professor of Neurology, Microbiology and Immunology, and of Pharmacology and Physiology.

The research is part of a decades-long endeavor by scientists trying to get the right genes into the right cells at the right time to improve human health.

In the new work, scientists dramatically increased the size of the “genetic payload” they can deliver to brain cells compared to some conventional techniques, nearly tripling the amount of genetic material by some measures. They hope to deliver even bigger genes in the future.

The team did this by bringing together in a new way two molecular players, herpes and Sleeping Beauty, which are commonly used in molecular technology.

For years Bowers’ team has been using the herpes virus – HSV-1, the type that causes cold sores – to shuttle genes into cells. Viruses like herpes are adept at infecting human cells, and scientists like Bowers use such viruses to carry into cells genes that would help people who are sick. Bowers and colleagues modify the viruses extensively, removing the portions that could make a person sick and using the portions that the virus uses to gain access to human cells.

Many scientists use other viruses, such as lentiviruses or a cold-related virus known as adeno-associated virus (AAV), to do a similar job. Each virus has its strengths and weaknesses when it comes to gene therapy. Herpes, for instance, readily infects cells, and it can carry a huge amount of genetic material, typically 15 to 30 times the amount of DNA that other viruses can carry into a cell.

But herpes as a genetic tool has a couple of big weaknesses. While the virus can deliver DNA into the nucleus of a cell, the genetic payload it carries does not become part of the package of genes that cells pass from one to another. Simply put, herpes cannot integrate the new DNA into the host genome. Instead, the DNA is adrift in the nucleus, where it’s silenced within a few weeks. The short time span spells trouble when scientists are trying to treat a disease that requires the genes to be active for months or years.

That’s where Sleeping Beauty comes in.

In molecular biology, Sleeping Beauty is a mobile genetic element that jumps into and out of longer segments of DNA. It’s normally silent, but years ago a team of scientists was able to activate or “awaken” the snippet – hence, Sleeping Beauty. Since Sleeping Beauty actually integrates segments of DNA into mammalian genomes, it sidesteps the main difficulties that herpes encounters inside a cell: Genes integrated within the cell’s chromosomes by Sleeping Beauty operate for much longer periods of time. The drawback: The molecule can insert only small snippets of DNA.

So the Rochester team brought herpes and Sleeping Beauty together in an attempt to get the best of both worlds: Delivery of the bigger genetic package made possible by herpes, and the integration of the DNA into the host genome made possible by Sleeping Beauty.

And that’s exactly what happened. In the tag-team approach funded by the National Institute of Neurological Disorders and Stroke, herpes gets the genetic package into the right neighborhood, the cell’s nucleus, and then Sleeping Beauty delivers the package precisely where it needs to go to be most effective – into the cellular genome.

In the current experiments, the herpes virus carried into cell nuclei the gene for green fluorescent protein, which allows scientists to track where the gene is active. The team also outfitted the herpes package with special molecular signals that Sleeping Beauty would recognize. Separately, the team introduced Sleeping Beauty into the cells. When the two met, Sleeping Beauty transferred the gene for GFP from the herpes package to the genome of the human cells, where the gene was stably expressed.

Scientists have found four new regions of the genome that increase the risk of a common blood cancer, according to results published in the journal Nature Genetics.

Professor Richard Houlston and his team at The Institute of Cancer Research (ICR) have now found the location of 10 genetic variants, common in the European population, that are associated with an increased risk of chronic lymphocytic leukaemia (CLL).

Professor Houlston’s team last year proved that people’s genes could make them more susceptible to CLL, identifying six regions of the genome more common among sufferers. In the latest paper, also funded by the charity Leukaemia Research, his team have identified another four regions that influence an individual’s risk of CLL.

CLL is the most common form of leukaemia in western countries, with around 2,700 people in the UK diagnosed each year with the disease, most after age 55.

The genetic factors identified in the latest study are all common in the population, and each increases the risk of CLL by between 1.2 and 1.4-fold. Each person may carry from a few of the identified risk factors to all the risk factors. Importantly, the more genetic factors carried, the higher their risk of developing CLL.

“People who have more than 13 risk factors are seven times more likely than the general population to develop CLL,” Professor Houlston says.

The risk factors were identified using a genome wide association study, a technique that ICR scientists have used previously to find risk genes in breast, prostate, testis, brain and colon cancer and childhood leukaemia. They scanned the genome of 2,503 CLL patients and compared them to 5,789 healthy individuals, looking for single letter differences in DNA between the two groups.

The study confirmed that the inherited risk of CLL is not due to a single gene, but often as a result of the cumulative effect of many genetic changes with small effects. The study found that 87 per cent of people with CLL would have at least one of these genetic factors.

The locations of these factors also provides new insights into the mechanism by which leukaemia develops.

Dr David Grant, Scientific Director of Leukaemia Research, says, “The possibility that this form of leukaemia may run in families has been suspected for sometime. So it is pleasing that this research is providing the genetic evidence that an increased risk of developing CLL can be inherited. However it is clearly a complex picture and we need to study more families before we can be certain of the particular genetic traits that are most important.”

Fossils may provide tantalizing clues to human history but they also lack some vital information, such as revealing which pieces of human DNA have been favored by evolution because they confer beneficial traits – resistance to infection or the ability to digest milk, for example. These signs can only be revealed through genetic studies of modern humans and other related species, though the task has proven difficult. Now, in a paper appearing in the January 7 edition of Science Express, researchers describe a method for pinpointing these preferred regions within the human genome that offers greater precision and resolution than ever before, and the possibility of deeply understanding both our genetic past and present.

“It’s clear that positive natural selection has been a critical force in shaping the human genome, but there are remarkably few examples that have been clearly identified,” said senior author Pardis Sabeti, an associate member of the Broad Institute of Harvard and MIT and an assistant professor of organismic and evolutionary biology at Harvard University. “The method we’ve developed makes it possible to zero in on individual genes as well as the specific changes within them that are driving important evolutionary changes.”

Positive natural selection is a process in which advantageous traits become more common in a population. That is because these traits boost an individual’s chances of survival and reproduction, so they are readily passed on to future generations. Identifying such traits – and the genes underlying them – is a cornerstone of current efforts to dissect the biological history of the human species as well as the diseases that threaten human health today.

“In the human genome, positive natural selection leaves behind very distinctive signals,” said co-first author Sharon Grossman, a research assistant at Harvard University and the Broad Institute. Yet earlier methods for detecting these signals are limited, highlighting relatively large chunks of the genome that are hundreds of thousands to millions of genetic letters or “bases” in length, and that can contain many genes.

Of the hundreds of these large genomic regions thought to be under positive natural selection in humans, only a handful have so far been winnowed to a precise genetic change. “Finding the specific genetic changes that are under selection can be like looking for a needle in a haystack,” said Grossman.

Sabeti, Grossman and their colleagues wondered if there might be a way to enhance this genomic search. Because existing methods for detecting natural selection each measure distinct genomic features, the researchers predicted that an approach that combines them together could yield even better results.

After some initial simulations to test their new method, the research team applied it to more than 180 regions of the human genome that are thought to be under recent positive selection, yet in most cases, the specific gene or genetic variant under selection is unknown.

The researchers’ method, called “Composite of Multiple Signals” or CMS, enabled them to dramatically narrow the size of the candidate regions, reducing them from an average of eight genes per region to one. Moreover the number of candidate genetic changes was reduced from thousands to just a handful, helping the researchers tease out the needles from the haystack.

“The list of genes and genetic loci we identified includes many intriguing candidates to follow up,” said co-first author Ilya Shylakhter, a computational biologist at the Broad Institute and Harvard University. “For example, a number of genes identified are involved in metabolism, skin pigmentation and the immune system.”

In some cases, the researchers were able to identify a specific genetic change that is the likely focal point of natural selection. For example, a variation in a gene called protocadherin 15, which functions in sensory perception, including hearing and vision, appears to be under selection in some East Asian populations. Several other genes involved in sensory perception also appear to be under selection in Asia. In addition, the team uncovered strong evidence of selection in East Asians at a specific point within the leptin receptor gene, which is linked to blood pressure, body mass index and other important metabolic functions.

Interestingly, the researchers also localized signals to regions outside of genes, suggesting that they function not by altering gene structure per se, but by changing how certain genes are turned on and off.

While the findings in the Science paper offer a deep glimpse of evolution’s handiwork, the researchers emphasize that further studies of individual genetic variations, involving experiments that explore how certain genetic changes influence biological function, are necessary to fully dissect the role of natural selection and its impact on human biology.

“This method allows us to trace evolution’s footprints with a much finer level of granularity than before, but it’s one piece of a much larger puzzle,” said Sabeti. “As more data on human genetic variation becomes available in the coming years, an even more detailed evolutionary picture should emerge.”

German Researchers have discovered a Novel Mechanism for Gene Regulation Publication in CELL

RNA molecules are the mobile messengers of genes. They carry information on the production of proteins from the DNA to the ribosomes. In addition to these messenger RNAs all living beings have micro RNAs that can hinder the messenger RNAs and thus the production of proteins. Biologists at the University of Freiburg, Germany, around Lecturer Dr. Wolfgang Frank und Professor Dr. Ralf Reski from the Chair Plant Biotechnology have discovered that such micro RNAs also come into direct contact with genes, effectively turning off the genes in the process. Their findings have now been published in the current issue of the scientific journal CELL.

With the exception of some viruses all living beings store their hereditary information, the sum of all their genes, as DNA. Active genes are transcribed into messenger RNAs (mRNAs) that function as blueprints for the production of proteins on ribosomes. Inactive genes are not transcribed into mRNAs. The fine balance between switched-on and switched-off genes differs between organs and changes during development and under varying environmental conditions. When this balance is disturbed disfiguration and illnesses such as cancer occur. In 2006 the American biologists Mello & Fire were awarded the Nobel Prize for their discovery that minute RNA molecules in the worm C. elegans can attach themselves to mRNAs und thus hinder their translation into proteins.

The biologists in Freiburg together with researchers from the Max-Planck-Institute for Developmental Biology in Tuebingen have now described how microRNAs not only indirectly turn off genes by obstructing mRNAs, but can also turn off genes directly. In the process the genes are silenced chemically by adding methyl groups. In the world of Biology such changes are termed as Epigenetics.

The researchers at the Freiburg Chair Plant Biotechnology have found this novel mechanism for gene regulation in their favoured object of research, the moss Physcomitrella patens.

When the biologists in Freiburg created so called knockout-mosses, they were surprised by the effect because it contradicted all existing expectations. Now they suspect that their newly discovered mechanism for gene regulation occurs not only in moss, but also in many other life forms, including us humans.

An international team of scientists has found that cells that protect nerves are likely to be the origins of a fatal cancer known as Devil Facial Tumour Disease (DFTD) that is spreading rapidly through populations of Tasmanian devils in Australia: if unchecked, scientists estimate the cancer, which is spread through biting, could wipe out the wild devil population within the next 30 years or so.

The findings are the subject of a collaborative study led by Australian scientists that was published in the international journal Science on 1 January.

Devil Facial Tumour Disease (DFTD) is a transmissible cancer that affects only the Tasmanian devil, a carnivorous marsupial about the size of a small dog that is found in Australia and Tasmania. The disease causes large tumours that occur mostly on the face and mouth but also spreads to internal organs.

First reported in 1996, DFTD spreads by biting and quickly kills infected animals; so much so, they are now considered an endangered species facing extinction.

In this study, the researchers traced the origins of DFTD to a type of cell that protects peripheral nerve fibres, the Schwann cell. They extracted genetic data from biopsies of Tasmanian devil tumours and identified a genetic marker that could be used to diagnose DFTD.

Dr Elizabeth Murchison led the study when she was at the Cold Spring Harbor Laboratory, New York, and at the Australian National University in Canberra. She told the media that pinpointing the Schwann cell as the origin of the disease was an important discovery because there are no diagnostic tests, treatments or vaccines for DFTD.

Dr Tony Papenfuss, a geneticist at Melbourne’s Walter and Eliza Hall Institute, led the part of the study that discovered which genes were switched on in the tumours and identified their genetic signature:

“When we compared the signature of the tumours to other normal tissues we found the tumours were most like Schwann cells,” he told the press.

Murchison, Papenfuss and colleagues pinpointed networks of genes that may be important in the development and transmission of tumours. They also found that the tumours strongly express a gene for myelin basic protein, which is an important constituent of the sheaths that protect nerve fibres.

Out of the 20 tumour-specific genes they identified, they found that 9 played a role in myelination. They also discovered that DFTD tumours, and cells that had spread to other organs, tested positive for periaxin, a Schwann-cell protein, and other types of tumour did not test positive for this protein, suggesting it would make a reliable diagnostic marker for DFTD.

“Devils develop tumours of all different types and the genetic markers we have identified are useful for telling apart the tumours that occur in DFTD from other kinds of tumours,” said co-author Dr Greg Woods, Associate Professor at the University of Tasmania’s Menzies Research Institute.

Papenfuss explained that:

“Differentiating between the devil facial tumour disease and some other tumour is particularly important, especially when it comes to the insurance population programme.”

The insurance programme is a captive population of less than 200 uninfected Tasmanian devils held at zoos and parks in Tasmania and mainland Australia; conservationists aim to increase that population to at least 500.

Tamara Keeley, a reproductive biologist at the Taronga Western Plains Zoo in Dubbo in New South Wales, Australia, and not a co-author of the study, said that the biggest problem for conservationists was the absence of a test for DFTD. Currently, to prevent spread in the wild, conservation workers kill devils that show signs of the disease, but many infected animals can go undetected.

“If we had a blood test, we could remove disease carriers in the hopes of managing the wild population,” said Keeley.

Although the insurance programme has not captured wild Tasmanian devils since 2008, a diagnostic test would help with future efforts, she explained.

The study also suggested clues for how DFTD may dodge the immune system. Co-author Dr Alexandre Kreiss, from the University of Tasmania’s Menzies Research Institute in Hobart, where he is working on a vaccination programme, said Tasmanian devils are genetically very similar to each other, and it could be that the cancer cells from another devil are not recognized as foreign when they enter a new host.

On the other hand, it could be because the origin is in the peripheral nervous system, which is rarely targeted by the immune system, said Kreiss, and it might explain why experiments with irradiated cancer cells at the Menzies Research Institute have been disappointing. He explained to Nature News that only one out of six devils mounted an immune response in a recent vaccination trial.

Papenfuss said that although a vaccine against DFTD was still a long way off, we now have “a good start on a set of genomic tools we can move forward with”.

Facing the increasing prevalence of type 2 diabetes worldwide in the past few decades, one may ask what is wrong with humans. Geneticists tell us that the human genome has not changed markedly in such a short time. Therefore, something must be happening in our environment or diet. As a matter of fact, dietary pattern is known to be closely linked to the development of type 2 diabetes. The increasing prevalence of type 2 diabetes following worldwide food fortification with niacin suggests that type 2 diabetes may involve excessive niacin intake.

A research article published in the World Journal of Gastroenterology addresses the association between nicotinamide overload and type 2 diabetes. The study revealed that diabetic patients have a slow nicotinamide metabolism and thus require a longer time to clear up excess nicotinamide metabolites within the body. High nicotinamide intake may lead to an increase the generation of reactive oxygen species, and subsequent oxidative stress and insulin resistance, both being the major features of type 2 diabetes. The liver is the main organ responsible for nicotinamide detoxification. This study found that liver-injury-inducing drugs may reduce nicotinamide detoxification and thus impair glucose tolerance. Most interestingly and importantly, this study demonstrates that sweating is an effective way for expelling excess nicotinamide from the body. The findings from this study may help explain a wide variety of well-documented but poorly understood phenomena in diabetes, such as lifestyle-triggered diabetes, liver-disease-related abnormal glucose metabolism, post-burn insulin resistance, and seasonal diabetes.

Nowadays, the high prevalence of type 2 diabetes may be due to both too much niacin in our foods and too little excretion through our sweat glands. The so-called gene-environment interaction in type 2 diabetes may actually be the outcome of the association of excess niacin intake and relatively low detoxification and excretion from the body, says lead author Dr. Shi-Sheng Zhou, Professor of the Institute of Basic Medical Sciences of Dalian University.

Historically, niacin deficiency was restricted mainly to those with poor nutrition who performed heavy industrial labor. Hence, this study gives rise to an important social and public health issue whether foods need to be fortified with niacin any more, when the people in developed countries have already been living in an age of over-nutrition. The authors found that reducing nicotinamide intake and facilitating the excretion of nicotinamide metabolites may be a useful preventive and therapeutic intervention in type 2 diabetes.

A group of Norwegian and American researchers have shown that common variations in genes associated with microcephaly – a neuro-developmental disorder in which brain size is dramatically reduced – may explain differences in brain size in healthy individuals as well as in patients with neurological and psychiatric disorders.

The study, which involved collaboration between researchers from the University of Oslo, the University of California, San Diego and Scripps Translational Science Institute in La Jolla, California, was published on line in the Proceedings of the National Academy of Science.

In relation to body size, brain size has expanded dramatically throughout primate and human evolution. In fact, in proportion to body size, the brain of modern humans is three times larger than that of non-human primates. The cerebral cortex in particular has undergone a dramatic increase in surface area during the course of primate evolution.

The microcephaly genes have been hot candidates for a role in the evolutionary expansion of the human brain because mutations in these genes can reduce brain size by about two-thirds, to a size roughly comparable to our early hominid ancestors. There is also evidence that four of the genes – MCPH1, ASPM, CDK5RAP2 and CENPJ – have evolved rapidly and have been subject to strong selective pressure in recent human evolution.

“It is obvious that such anatomical changes must have a basis in genetic alterations, said Lars M. Rimol, a research fellow at the University of Oslo. “Until now, little has been known about the molecular processes involved in this evolution and their genetic underpinnings. Now we have a piece of that genetic puzzle.”

Several previous MRI studies have attempted to demonstrate a link between single polymorphisms (an inherited genetic variation that is found in more than one percent of the population) in these genes and brain size in healthy human adults, all of them unsuccessful. According to the research team, the success of the current study is likely due to two unique characteristics: first, by using a whole genome scan, the scientists could access an unprecedented number of polymorphisms, including non-coding regions outside of the gene itself; second, they were able to estimate cortical surface area, using software that reconstructs the cortical surface, based on volumetric MR scans, allowing for highly precise measurements of cortical thickness and areal expansion.

The software was developed by Anders Dale, PhD, professor of Radiology and Neurosciences at the UC San Diego School of Medicine, who headed the American branch of the research team. “The most statistically significant associations were consistently found with the areal expansion measure, which has implications also for future studies,” said Dale.

The initial discovery was made in a sample of 289 psychiatric patients and controls from the Norwegian Thematically Organized Psychosis research project (TOP), led by Ole Andreassen from the University of Oslo, principal investigator of the Norwegian branch of the international research team. The most significant findings were then replicated in a sample of 655 healthy and demented patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the largest Alzheimer’s disease study ever funded by the National Institutes of Health. The Norwegian sample was ethnically homogenous; the ADNI sample was ethnically diverse. According to the researchers, the fact that reported associations were found across two independent studies, including healthy controls and various patient groups, shows that these effects are likely to be independent of population or disease.

Highly significant associations were found between cortical surface area and polymorphisms in possible regulatory regions near the gene CDK5RAP2. This gene codes for a protein involved in cell-cycle regulation in neuronal progenitor cells – cells that migrate to the cerebral cortex during the second trimester of gestation and eventually become fully functioning neurons. The cerebral cortex is the outer layer of the brain, often referred to as “gray matter.” The most highly developed part of the human brain, the cerebral cortex is responsible for higher cognitive functions, such as thinking, perceiving, producing and understanding language, some of which is considered uniquely human.

Similar but less significant findings were made for polymorphisms in two other microcephaly genes, known as MCPH1 and ASPM. All findings were exclusive to either males or females but the functional significance of this sex-segregated effect is unclear.

“One particularly interesting feature of this new discovery is that the strongest links with cortical area were found in regulatory regions, rather than coding regions of the genes,” said Andreassen. “One upshot of this may be that in order to further understand the molecular and evolutionary processes that have determined human brain size, we need to focus on regulatory processes rather than further functional characterization of the proteins of these genes. This has huge implications for future research on the link between genetics and brain morphology.”