The same gene family that may have helped the human brain become larger and more complex than in any other animal also is linked to the severity of autism, according to new research from the University of Colorado Anschutz Medical Campus.
The gene family is made up of over 270 copies of a segment of DNA called DUF1220. DUF1220 codes for a protein domain – a specific functionally important segment within a protein. The more copies of a specific DUF1220 subtype a person with autism has, the more severe the symptoms, according to a paper.
This association of increasing copy number (dosage) of a gene-coding segment of DNA with increasing severity of autism is a first and suggests a focus for future research into the condition Autism Spectrum Disorder (ASD). ASD is a common behaviourally defined condition whose symptoms can vary widely – that is why the word ‘spectrum’ is part of the name. One federal study showed that ASD affects one in 88 children.
‘Previously, we linked increasing DUF1220 dosage with the evolutionary expansion of the human brain,’ says James Sikela, PhD, a professor in the Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine. Sikela led the autism study which also involved other members of his laboratory.

‘One of the most well-established characteristics of autism is an abnormally rapid brain growth that occurs over the first few years of life. That feature fits very well with our previous work linking more copies of DUF1220 with increasing brain size. This suggests that more copies of DUF1220 may be helpful in certain situations but harmful in others.’

The research team found that not only was DUF1220 linked to severity of autism overall, they found that as DUF1220 copy number increased, the severity of each of three main symptoms of the disorder — social deficits, communicative impairments and repetitive behaviours – became progressively worse.
In 2012, Sikela was the lead scientist of a multi-university team whose research established the link between DUF1220 and the rapid evolutionary expansion of the human brain. The work also implicated DUF1220 copy number in brain size both in normal populations as well as in microcephaly and macrocephaly (diseases involving brain size abnormalities).

Jack Davis, PhD, who contributed to the project while a postdoctoral fellow in the Sikela lab, has a son with autism and thus had a very personal motivation to seek out the genetic factors that cause autism.

The research by Sikela, Davis and colleagues at the Anschutz campus in Aurora, Colo., focused on the presence of DUF1220 in 170 people with autism.
Strikingly, Davis says, DUF1220 is as common in people who do not have ASD as in people who do. So the link with severity is only in people who have the disorder.

‘Something else is at work here, a contributing factor that is needed for ASD to manifest itself,’ Davis says. ‘We were only able to look at one of the six different subtypes of DUF1220 in this study, so we are eager to look at whether the other subtypes are playing a role in ASD.’
Because of the high number of copies of DUF1220 in the human genome, the domain has been difficult to measure. As Sikela says, ‘To our knowledge DUF1220 copy number has not been directly examined in previous studies of the genetics of autism and other complex human diseases .So the linking of DUF1220 with ASD is also confirmation that there are key parts of the human genome that are still unexamined but are important to human disease.’ University of Colorado Denver

In a new study, researchers from North Carolina State University, UNC-Chapel Hill and other institutions have taken the first steps toward creating a roadmap that may help scientists narrow down the genetic cause of numerous diseases. Their work also sheds new light on how heredity and environment can affect gene expression.
Pinpointing the genetic causes of common diseases is not easy, as multiple genes may be involved with a disease. Moreover, disease-causing variants in DNA often do not act directly, but by activating nearby genes. To add to the complexity, genetic activation is not like a simple on/off switch on a light, but behaves more like a ‘dimmer switch’ – some people may have a particular gene turned all the way up, while others have it only turned halfway on, completely off, or somewhere in between. And different factors, like DNA or the environment, play a role in the dimmer switch’s setting.
According to Fred Wright, NC State professor of statistics and biological sciences, director of NC State’s Bioinformatics Center and co-first author of the study, ‘Everyone has the same set of genes. It’s difficult to determine which genes are heritable, or controlled by your DNA, versus those that may be affected by the environment. Teasing out the difference between heredity and environment is key to narrowing the field when you’re looking for a genetic relationship to a particular disease.’
Wright, with co-first author Patrick Sullivan, Distinguished Professor of Genetics and Psychiatry at UNC-Chapel Hill and director of the Center for Psychiatric Genomics, and national and international colleagues, analyzed blood sample data from 2,752 adult twins (both identical and fraternal) from the Netherlands Twin Register and an additional 1,895 participants from the Netherlands Study of Depression and Anxiety. For all 20,000 individual genes, they determined whether those genes were heritable – controlled by the DNA ‘dimmer switch’ – or largely affected by environment.
‘Identical twins have identical DNA,’ Wright explains, ‘so if a gene is heritable, its expression will be more similar in identical twins than in fraternal twins. This process allowed us to create a database of heritable genes, which we could then compare with genes that have been implicated in disease risk. We saw that heritable genes are more likely to be associated with disease – something that can help other researchers determine which genes to focus on in future studies.’
‘This is by far the largest twin study of gene expression ever published, enabling us to make a roadmap of genes versus environment,’ Sullivan says, adding that the study measured relationships with disease more precisely than had been previously possible, and uncovered important connections to recent human evolution and genetic influence in disease.
The Netherlands Twin Register has followed twin pairs for over 25 years and in collaboration with the longitudinal Netherlands Study of Depression and Anxiety established a resource for genetic and expression studies. Professor Dorret Boomsma, who started the twin register, says, ‘in addition to the fundamental insights into genetic regulation and disease, the results provide valuable information on causal pathways. The study shows that the twin design remains a key tool for genetic discovery.’ EurekAlert

Researchers have explored the role of a master gene that controls the functioning of other genes involved in heart development. Variations in this gene – NR2F2 – are responsible for the development of severe forms of congenital heart disease.
Approximately one per cent of all babies are born with congenital heart disease, where the normal workings of the heart are affected. Because the damage to the heart is structural, most babies will need surgery to correct the problem. Although genetic causes are known to underlie the disease, these causes are not very well understood.
Scientists have previously shown that mice with a less active NR2F2 gene had abnormal heart development. To see if the gene was involved in severe forms of human congenital heart disease, the team looked at DNA sequences of parents and affected children and found that variation on the NR2F2 caused the structural damage that underlies these conditions.
The team found that these genetic variants were typically only present in the child and not the parents, revealing that congenital heart disease producing variants occur in the womb.
‘What we see is that these rare variants in the NR2F2 gene interfere with the normal heart development and cause severe forms of congenital heart disease during human development,’ says Saeed Al Turki, first author from the Wellcome Trust Sanger Institute.
NR2F2 is a master regulator for other genes involved in the development of a healthy functioning heart – once the activity of NR2F2 is affected it has a knock-on effect on these other genes affecting the healthy development of the heart.
The team found that different types of damage in the NR2F2 gene cause different types of heart defects. Genetic variants that completely deactivate the NR2F2 gene tended to cause damage to the left side of the heart. In contrast, genetic variants that alter activity of the gene but do not deactivate it more commonly caused a specific sub-type of holes in the hearts of patients. Wellcome Trust Sanger Institute

Extreme and traumatic events can change a person – and often, years later, even affect their children. Researchers of the University of Zurich and ETH Zurich have now unmasked a piece in the puzzle of how the inheritance of traumas may be mediated.
The phenomenon has long been known in psychology: traumatic experiences can induce behavioural disorders that are passed down from one generation to the next. It is only recently that scientists have begun to understand the physiological processes underlying hereditary trauma. ‘There are diseases such as bipolar disorder, that run in families but can’t be traced back to a particular gene’, explains Isabelle Mansuy, professor at ETH Zurich and the University of Zurich. With her research group at the Brain Research Institute of the University of Zurich, she has been studying the molecular processes involved in non-genetic inheritance of behavioural symptoms induced by traumatic experiences in early life.

Mansuy and her team have succeeded in identifying a key component of these processes: short RNA molecules. These RNAs are synthesised from genetic information (DNA) by enzymes that read specific sections of the DNA (genes) and use them as template to produce corresponding RNAs. Other enzymes then trim these RNAs into mature forms. Cells naturally contain a large number of different short RNA molecules called microRNAs. They have regulatory functions, such as controlling how many copies of a particular protein are made.

The researchers studied the number and kind of microRNAs expressed by adult mice exposed to traumatic conditions in early life and compared them with non-traumatised mice. They discovered that traumatic stress alters the amount of several microRNAs in the blood, brain and sperm – while some microRNAs were produced in excess, others were lower than in the corresponding tissues or cells of control animals. These alterations resulted in misregulation of cellular processes normally controlled by these microRNAs.

After traumatic experiences, the mice behaved markedly differently: they partly lost their natural aversion to open spaces and bright light and had depressive-like behaviours. These behavioural symptoms were also transferred to the next generation via sperm, even though the offspring were not exposed to any traumatic stress themselves.

The metabolism of the offspring of stressed mice was also impaired: their insulin and blood-sugar levels were lower than in the offspring of non-traumatised parents. ‘We were able to demonstrate for the first time that traumatic experiences affect metabolism in the long-term and that these changes are hereditary’, says Mansuy. The effects on metabolism and behaviour even persisted in the third generation.

‘With the imbalance in microRNAs in sperm, we have discovered a key factor through which trauma can be passed on,’ explains Mansuy. However, certain questions remain open, such as how the dysregulation in short RNAs comes about. ‘Most likely, it is part of a chain of events that begins with the body producing too much stress hormones.’

Importantly, acquired traits other than those induced by trauma could also be inherited through similar mechanisms, the researcher suspects. ‘The environment leaves traces on the brain, on organs and also on gametes. Through gametes, these traces can be passed to the next generation.’

Mansuy and her team are currently studying the role of short RNAs in trauma inheritance in humans. As they were also able to demonstrate the microRNAs imbalance in the blood of traumatized mice and their offspring, the scientists hope that their results may be useful to develop a blood test for diagnostics. ETH Zurich

Johns Hopkins Kimmel Cancer Center investigators report they have designed a blood test that accurately detects the presence of advanced breast cancer and also holds promise for precisely monitoring response to cancer treatment.
The test, called the cMethDNA assay, accurately detected the presence of cancer DNA in the blood of patients with metastatic breast cancers up to 95 percent of the time in laboratory studies.
Currently, there is no useful laboratory test to monitor patients with early stage breast cancer who are doing well, but could have an asymptomatic recurrence, says Saraswati Sukumar, Ph.D., who is the Barbara B. Rubenstein Professor of Oncology and co-director of the Breast Cancer Program at the Johns Hopkins Kimmel Cancer Center. Generally, radiologic scans and standard blood tests are indicated only if a woman complains of symptoms, such as bone aches, shortness of breath, pain, or worrisome clinical exam findings. Otherwise, routine blood tests or scans in asymptomatic patients often produce false positives, leading to additional unnecessary tests and biopsies, and have not been shown to improve survival outcomes in patients with early stage breast cancer who develop a recurrence.
Sukumar, also a professor of pathology at Johns Hopkins, says that the current approach to monitoring for recurrence is not ideal, and that ‘the goal is to develop a test that could be administered routinely to alert the physician and patient as soon as possible of a return of the original cancer in a distant spot. With the development of cMethDNA, we’ve taken a first big step toward achieving this goal.’
To design the test, Sukumar and her team scanned the genomes of primary breast cancer patients, as well as DNA from the blood of metastatic cancer patients. They selected 10 genes specifically altered in breast cancers, including newly identified genetic markers AKR1B1, COL6A2, GPX7, HIST1H3C, HOX B4, RASGRF2, as well as TM6SF1, RASSF1, ARHGEF7, and TMEFF2, which Sukumar’s team had previously linked to primary breast cancer.
The test, developed by Sukumar, collaborator Mary Jo Fackler, Ph.D., and other scientists, detects so-called hypermethyation, a type of chemical tag in one or more of the breast cancer-specific genes present in tumour DNA and detectable in cancer patients’ blood samples. Hypermethylation often silences genes that keep runaway cell growth in check, and its appearance in the DNA of breast cancer-related genes shed into the blood indicates that cancer has returned or spread.
In one set of experiments, the researchers tested the assay’s ability to detect methylated tumor DNA in 52 blood samples – 24 from patients with recurrent stage IV breast cancer and 28 from healthy women without breast cancer, and again in blood samples from 60 individuals – 33 from women with all stages of breast cancer and 27 from healthy women. In each case, the blood test was up to 95 percent accurate in distinguishing patients with metastatic breast cancer from healthy women.
The investigators also studied the assay’s potential to monitor response to chemotherapy. They evaluated 58 blood samples from 29 patients with metastatic breast cancer, some taken before the initiation of therapy and some taken 18 to 49 days after starting a new chemotherapy regimen. In as little as two weeks, they report, the test detected a significant decrease in DNA methylation in patients with stable disease or in those who responded to treatment; this decrease was not found in patients whose disease progressed or who did not respond to treatment.
‘Our assay shows great potential for development as a clinical laboratory test for monitoring therapy and disease progression and recurrence,’ Sukumar says. If it’s determined early that a treatment is not working, clinicians can save time and switch to a different therapy, she says.
In addition, the researchers tested the gene panel used in the cMethDNA assay against samples from The Cancer Genome Atlas, a catalog of genes in various cancer types, finding that the gene panel may also be useful in detecting recurrent lung or colorectal cancers but not as accurate in detecting recurrent ovarian, kidney or stomach cancers. Johns Hopkins Kimmel Cancer Center