A suspected case of sexual transmission of Ebola virus disease (EVD) in Liberia was confirmed using genomic analysis, thanks to in-country laboratory capabilities established by U.S. Army scientists in collaboration with the Liberian Institute for Biomedical Research (LIBR).
The work provides molecular evidence of Ebola virus (EBOV) transmission between an EVD survivor and his female partner. It also demonstrates the value of real-time genomic surveillance during an outbreak, according to senior author Gustavo Palacios, Ph.D., of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).

CPT Suzanne Mate, Ph.D., of USAMRIID, said scientists working at the LIBR earlier this year analysed blood samples from a female patient who tested positive for EBOV in March 2015 when there had been no new documented cases for 30 days. The patient was reported have had recent sexual intercourse with a male partner who had survived EVD and had been declared EBOV negative in early October 2014.

Following the patient’s death on March 27, Mate said, public health officials were able to secure the consent of the male survivor to obtain and test a semen sample from him. The semen sample tested EBOV positive by quantitative RT-PCR, but the assay indicated that the level of viral RNA was low and required a different sample preparation method than the one originally deployed to sequence EBOV RNA from acute samples.

“We implemented a new enrichment strategy in collaboration with scientists from Illumina, Inc. that was pivotal in obtaining the required coverage to complete downstream genomic analysis,” said Michael Wiley, Ph.D, of USAMRIID. Next-generation sequencing of the enriched EBOV RNA extracted from the male survivor’s semen was used to compare the genome for similarity to the virus RNA extracted from the female patient’s blood sample.

“Ebola virus genomes assembled from the patient’s blood and the survivor’s semen were consistent with direct transmission,” commented Jason Ladner, Ph.D., of USAMRIID. “The samples shared three genetic substitutions that have not been found in any other Ebola virus sequences in Western Africa.”

In addition, said Ladner, these three genetic changes were distinct from the last
documented transmission chain in Liberia prior to this case. Combined with epidemiologic data, the genomic analysis provides support for sexual transmission of Ebola virus and for the persistence of infective EBOV in semen for more than 179 days after disease onset. This caused both the Centers for Disease Control and Prevention and the World Health Organization to change their recommendations for convalescent patients regarding sexual contact until more definitive information is obtained about how long Ebola virus can persist in semen. Research Institute of Infectious Diseases

Scientists at the University of Warwick have discovered that a lack of stem cells in the womb lining is causing thousands of women to suffer from recurrent miscarriages.

The academics behind the breakthrough are now to start research into a treatment which they believe could bring hope to those who have suffered failed pregnancies.

Professor Jan Brosens, Professor of Obstetrics & Gynaecology at Warwick Medical School at the University of Warwick, and Consultant in Reproductive Health atUniversity Hospitals Coventry and Warwickshire NHS Trust , led the team who unearthed the link between stem cells and miscarriage. He said: “We have discovered that the lining of the womb in the recurrent miscarriage patients we studied is already defective before pregnancy.
“I can envisage that we will be able to correct these defects before the patient tries to achieve another pregnancy. In fact, this may be the only way to really prevent miscarriages in these cases.”

The team found a shortfall of stem cells is the likely cause of accelerated ageing of the lining of the womb which results in the failure of some pregnancies.

Miscarriage is the most common cause of loss; between 15-25% of pregnancies end in miscarriage and one in 100 women trying to conceive suffer recurrent miscarriages, defined as the loss of three or more consecutive pregnancies.

The researchers examined tissue samples from the womb lining, donated by 183 women who were being treated at the Implantation Research Clinic, University Hospitals Coventry and Warwickshire NHS Trust.

The team found that an epigenetic signature – which is typical of stem cells – was absent in cultures established from womb biopsies taken from women suffering recurrent miscarriages. Indeed, fewer stem cells could be isolated from the lining of the womb from recurrent miscarriage patients when compared to women in the study’s control group.

The researchers further found that a stem cell shortage accelerates cellular ageing in the womb. The lining has to renew itself each cycle, each miscarriage and successful birth. This renewal capacity is dependent on resident stem cell population. A shortage of these stem cells in patients suffering recurrent loss is associated with accelerated ageing of the tissue. Ageing cells mount an inflammatory response, which may facilitate implantation of an embryo but is detrimental for its further development.

Professor Brosens added: “After an embryo has implanted, the lining of the uterus develops into a specialised structure called the decidua, and this process can be replicated when cells from the uterus are cultured in the lab.

“Cultured cells from women who had had three or more consecutive miscarriages showed that ageing cells in the lining of the womb don’t have the ability to prepare adequately for pregnancy.” University of Warwick

The UK10K study explored the contribution of these rare genetic variants to human disease and its risk factors.

Rare genetic variants are changes in DNA that are carried only by relatively few people in a population. The UK10K study was designed to explore the contribution of these rare genetic variants to human disease and its risk factors.

‘The project has made important new contributions towards describing the role of rare genetic variants in a broad range of disease scenarios and human traits.’ says Dr Nicole Soranzo, corresponding author from the Wellcome Trust Sanger Institute. ‘It has shown that the value of sequencing a few thousand individuals is high for highly penetrant, rare diseases, but that for complex traits and diseases much larger sample sizes will be required in future studies. The data and results produced by this project will be instrumental for these future efforts.’

The project studied nearly 10,000 individuals, both healthy and affected by disease. The conditions included very rare disorders inherited in families, and more common diseases such as autism, schizophrenia and obesity. In healthy people, 64 different biomedical risk factors such as blood pressure or cholesterol levels were studied. By characterising the DNA sequence of these individuals, the project gained insight into the contribution of rare variants to a broad range of disease scenarios, and discovered new genetic variants and genes underpinning disease risk.

‘The UK10K project has increased the resolution of genetic discoveries. It has enabled access to a much denser set of variants within the genome in the UK population, which can be used to refine our understanding of genetic effect on phenotypic traits,’ explains Richard Durbin, senior UK10K researcher at the Sanger Institute. ‘In earlier studies either very rare variants with big effects or common variants, which usually only have small effects, could be analysed. Now we have been able to explore an increased part of the spectrum of variation in between the very rare and the common ones.’

A series of papers published today in Nature and Nature Genetics in collaboration with other investigators demonstrates the value of these data for genetic discoveries.

As efforts continue to characterise the genetic underpinnings of complex diseases, the data and results of this study are expected to enable the next wave of discoveries. The UK10K sequence reference panel, described in greater detail in a companion paper published in Nature Communications, has been shown to greatly increase the ability to characterise rare variants in large population samples available to the worldwide research community. This resource will enable researchers to ‘fill in’ missing data from lower resolution genotype studies, allowing them to explore full genotypes more quickly and cheaply. Sanger Institute

The largest genetic study of atopic dermatitis ever performed permitted a team of international researchers to identify ten previously unknown genetic variations that contribute to the development of the condition. The researchers also found evidence of genetic overlap between atopic dermatitis and other illnesses, including inflammatory bowel disease.

Atopic dermatitis, a type of eczema, afflicts approximately one out of every five children and one out of every twelve adults. Though knowledge of the genome is crucial to assessing the likelihood that an individual will develop atopic dermatitis, most genes responsible for the condition have not yet been discovered.

The team of international researchers that conducted the largest genetic study of atopic dermatitis to this point pooled data obtained from 377,000 subjects in 40 different projects around the world.

 “We identified ten new genetic variations, making a total of 31 that are currently known to be associated with atopic dermatitis,” says Bo Jacobsson, a professor at Sahlgrenska Academy who was a member of the team. “Of particular interest is that each of the new ones has a role to play in regulation of the immune system.”
The researchers found evidence of genetic overlap between atopic dermatitis and other illnesses, including inflammatory bowel disease.

 “While the new variations contribute in only a small way to the risk of developing atopic dermatitis, knowing about them will raise our awareness about the mechanisms of the various diseases,” Professor Jacobsson says. “Our ultimate hope is that additional treatment methods will emerge as a result.”
Although the importance of genetic factors in the pathogenesis of atopic dermatitis had already been established, the sheer size of this study allowed researchers to fine tune their understanding and obtain more information about the ways that autoimmune mechanisms run amok as the disease develops.

A total of 21,399 cases of European, African, Japanese and Latino ancestry were first compared in 22 different studies with 95,464 controls. The findings were then replicated in 18 studies of 32,059 cases and 228,628 controls.

“Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis” was published in Nature Genetics online on October 19. University of Gothenburg

A global study involving 50 different research centres has found hundreds of genes which cause five common, hard-to-treat and debilitating inflammatory diseases, paving the way to new treatments for these conditions.
Led by Brisbane’s QUT and Christian-Albrechts-University, Kiel, Germany, the results of the world-first study have been published.

Co-senior author Professor Matthew Brown, from QUT’s Institute of Health and Biomedical Innovation, said they investigated ankylosing spondylitis, Crohn’s Disease and ulcerative colitis (collectively known as inflammatory bowel disease), psoriasis, and primary sclerosing cholangitis.
“These diseases affect about three per cent of the world’s population, and commonly occur together in families and in individuals. The big question has been whether this is due to shared environmental risk factors, or due to shared genes and now we believe we have the answer,” Professor Brown said.
“The research has conclusively demonstrated these conditions occur together mostly because they share similar genetic backgrounds.

“Studying nearly 86,000 subjects from 26 countries, our researchers identified 244 genetic variants which control whether or not people develop these conditions, a large proportion of which were completely new findings.
“They found that for nearly all of these diseases the reason they frequently occur together in individuals is due to the different diseases sharing genetic risk factors, rather than one disease causing the other.

“For some diseases such as the common form of spinal arthritis, ankylosing spondylitis, the study roughly trebled the number of genes known to be involved.”

Professor Brown said the new gene discoveries pointed to some potential new therapies, including agents already in use for other diseases which can now be trialled in these conditions very promptly.
“The discoveries have shed new light onto the causes of these diseases, such as identifying genetic risk variants which most likely work by affecting the bacteria present in the gut, in turn causing inflammation in joints, the liver or the gut itself,” Professor Brown said. Queensland University of Technology