Monthly Archives: February 2017

Scientists have long observed important differences in the rate of disease progression among individuals infected with HIV. It is now well established that the disease progresses faster in people with a higher viral load the amount of genetic material from the virus found in their blood.

[This study]is the first to investigate the relative impacts of human and viral genetics on viral load, within one group of patients.

[The researchers]found that genetic differences between HIV strains accounted for 29% of the contrasts in viral load between patients. Human genetic variation on the other hand, explains 8.4%. Together, human and viral genetics explained a third of viral load variation.

These findings suggest that the patients genetics trigger genetic mutations in the HIV virus as it multiplies inside them, thus influencing the clinical course of HIV infection.

Our study improves our understanding of HIV pathogenesis. This is an important step the better you know your enemy, the more equipped you are to fight it and fight against the disease, said [Jacques Fellay, director of the study bycole Polytechnique Fdrale de Lausanne in Switzerland.]

[The study can be found here.]

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Patients and virus genetics account for a third of HIV viral load

Here is the original post:
Progression of HIV triggered by each patient's genes - Genetic Literacy Project

Genetic analysis suggests that humans have continuously inhabited the Tibetan Plateau as far back as the last ice age.

The first humans who ventured onto the Tibetan Plateau, often called the roof of the world, faced one of the most brutal environments our species has ever confronted. At an average elevation of more than 4,500 meters, it is a cold and arid place with half the oxygen present at sea level. Although scientists had long thought no one set foot on the plateau until 15,000 years ago, new genetic and archaeological data indicate that this event may have taken place much earlierpossibly as far back as 62,000 years ago, in the middle of the last ice age. A better understanding of the history of migration and population growth in the region could help unravel the mysteries of Tibetans' origin and offer clues as to how humans have adapted to low-oxygen conditions at high altitudes.

As reported in a recent study in the American Journal of Human Genetics, researchers got a better grasp of the plateau's settlement history by sequencing the entire genomes of 38 ethnic Tibetans and comparing the results with the genomic sequences of other ethnic groups. It has revealed a complex patchwork of prehistoric migration, says Shuhua Xu, a population geneticist at the Chinese Academy of Sciences' Shanghai Institutes for Biological Sciences. A big surprise was the antiquity of Tibetan-specific DNA sequences, Xu says. They can be traced back to ancestors 62,000 to 38,000 years ago, possibly representing the earliest colonization of the plateau.

As an ice age tightened its grip after that first migration, genetic mixing between Tibetans and non-Tibetans ground to a halt for tens of thousands of yearssuggesting that movement into Tibet dropped to a minimum. The migration routes were probably cut off by ice sheets, Xu says. It was simply too harsh even for the toughest hunter-gatherers. But about 15,000 to 9,000 years agoafter the so-called last glacial maximum (LGM), when the ice age was at its harshest and Earth's ice cover had reached its peakthousands flocked to Tibet en masse. It's the most significant wave of migration that shaped the modern Tibetan gene pool, Xu says. This meshes well with several independent lines of evidence showing that Tibetans began to acquire genetic mutations that protected them from hypoxia 12,800 to 8,000 years ago.

Xu's team was the first to sequence the entire Tibetan genome, and the resolution is really impressive, says archaeologist Mark Aldenderfer of the University of California, Merced, who was not involved in the research. The study, he adds, provides fine details of how different populations from various directions may have combined their genes to ultimately create the people that we call Tibetans. It shows that 94 percent of the present-day Tibetan genetic makeup came from modern humanspossibly those who ventured into Tibet in the second wave of migrationand the rest came from extinct hominins. The modern part of the Tibetan genome reflects a mixed genetic heritage, sharing 82 percent similarity with East Asians, 11 percent with Central Asians and 6 percent with South Asians.

In addition, Xu's team identified a Tibetan-specific DNA segment that is highly homologous to the genome of the Ust'-lshim Man (modern humans living in Siberia 45,000 years ago) and several extinct human species, including Neandertals, Denisovans and unknown groups. The segment contains eight genes, one of which is known to be crucial for high-altitude adaptation. Xu suspects that a hybrid of all these species may have been the common ancestor of the pre-LGM population on the plateau.

The study also reveals a startling genetic continuity since the plateau was first colonized. This suggests that Tibet has always been populatedeven during the toughest times as far as climate was concerned, Xu says. That idea contradicts the commonly held notion that early plateau dwellers would have been eliminated during harsh climate intervals, including the LGM, says David Zhang, a geographer at the University of Hong Kong, who was not involved in Xu's work. Aldenderfer and others contend that parts of the plateau could have provided a refuge for people to survive the ice age. There were plenty of places for [those early populations] to live where local conditions weren't that bad, such as the big river valleys on the plateau, he says.

Also supporting the antiquity of the peopling of Tibet is a study presented at the 33rd International Geographical Congress last summer in Beijing, where a team unveiled the plateau's earliest archaeological evidence of human presencedating to 39,000 to 31,000 years ago. The site, rich with stone tools and animal remains, lies on the bank of the Salween River in the southeastern Tibetan Plateau.

Different lines of evidence are now converging to point to much earlier and much more persistent human occupation of the plateau than previously thought, Aldenderfer says. But he notes that pieces are still missing from the puzzle: More excavations are required to close those gaps.

Read the original here:
The Surprisingly Early Settlement of the Tibetan Plateau - Scientific American

Although not widely known, RASopathies are among the most common genetic disorders, affecting approximately one child out of 1,000. RASopathies are caused by mutations within the RAS pathway, a biochemical system cells use to transmit information from their exterior to their interior.

Two Princeton University studies are opening important new windows into understanding an untreatable group of common genetic disorders known as RASopathies that affect approximately one child out of 1,000 and are characterized by distinct facial features, developmental delays, cognitive impairment and heart problems. The researchers observed in zebrafish and fruit fly embryos how cancer-related mutations in the RAS pathway a biochemical system cells use to transmit information from their exterior to their interior caused severe deformations. Fruit-fly embryos (above) showed how signals at the early stage of development (red in top photo) activate genes (purple in middle photo) and pattern structures in the fly larva (bottom photo.) (Photo courtesy of Stanislav Shvartsman, Department of Chemical and Biological Engineering)

Human development is very complex and its amazing that it goes right so often. However, there are certain cases where it does not, as with RASopathies, said Granton Jindal, co-lead author of the two studies. Both Jindal and the other co-lead author, Yogesh Goyal, are graduate students in theDepartment of Chemical and Biological Engineeringand theLewis-Sigler Institute for Integrative Genomics (LSI). Jindal and Goyal do their thesis research in the lab ofStanislav Shvartsman, professor of chemical and biological engineering and LSI.

Our new studies are helping to explain the mechanisms underlying these disorders, Jindal said.

These studies were published this year, one in the Proceedings of the National Academy of Sciences (PNAS) and the other in Nature Genetics online. The researchers made the discoveries in zebrafish and fruit flies animals commonly used as simplified models of human genetics and Jindal and Goyals specialties, respectively. Due to the evolutionary similarities in the RAS pathway across diverse species, changes in this pathway would also be similar. Thus, it is likely that significant parts of findings in animals would apply to humans as well, although further research is needed to confirm this.

The first paper published Jan. 3in PNAS presented a way to rank the severity of different mutations involved in RASopathies. The researchers introduced 16 mutations one at a time in developing zebrafish embryos. As each organism developed, clear differences in the embryos shapes became evident, revealing the strength of each mutation. The same mutant proteins produced similarly varying degrees of defects in fruit flies. Some of the mutations the researchers tested were already known to be involved in human cancers. The researchers noted that these cancer-related mutations caused more severe deformations in the embryos, aligning with the medical communitys ongoing efforts to adapt anti-cancer compounds to treat RASopathies.

Until now, there was no systematic way of comparing different mutation severities for RASopathies effectively, Goyal said.

Jindal added, This study is an important step for personalized medicine in determining a diagnosis to a first approximation. The study therefore suggested a path forward to human diagnostic advances, potentially enabling health care professionals to offer better diagnoses and inform caretakers about patients disease progression.

The study went further and examined the use of an experimental cancer-fighting drug being investigated as a possible way to treat RASopathies. The researchers demonstrated that the amount of medication necessary to correct the developmental defects in the zebrafish embryos corresponded with the mutations severity more severe mutations required higher dosages.

The more recent paper, published online by Nature Genetics Feb. 6, reports an unexpected twist in treatment approach to some RASopathies. Like all cellular pathways, the RAS pathway is a series of molecular interactions that changes a cells condition. Conventional wisdom has held that RASopathies are triggered by overactive RAS pathways, which a biologist would call excessive signaling.

The Nature Genetics study, however, found that some RASopathies could result from insufficient signaling along the RAS pathway in certain regions of the body. This means that drugs intended to treat RASopathies by tamping down RAS pathway signaling might actually make certain defects worse.

To our knowledge, our study is the first to find lower signaling levels that correspond to a RASopathy disease, Goyal said. Drugs under development are primarily RAS-pathway inhibitors aimed at reducing the higher activity, so maybe we need to design drugs that only target specific affected tissues, or investigate alternative, novel treatment options.

The Nature Genetics study also found that RAS pathway mutations cause defects by changing the timing and specific locations of embryonic development. For example, in normal fruit fly cells, the RAS pathway only turns on when certain natural cues are received from outside the cell. In the mutant cells, however, the RAS pathway in certain parts of fly embryo abnormally activated before these cues were received. This early activation disturbed the delicate process of embryonic development. The researchers found similar behavior in zebrafish cells.

Our integrative approach has allowed us to make enormous progress in understanding RASopathies, some of which have just been identified in the last couple of decades, Shvartsman said. With continued steps forward in both basic and applied science, as weve shown with our new publications, we hope to develop new ideas for understanding and treatment of a large class of developmental defects.

Princeton co-authors of the two papers includeTrudi Schpbach, the Henry Fairfield Osborn Professor of Biology and professor ofmolecular biology, andRebecca Burdine, an associate professor of molecular biology, as well as co-advisers to Goyal and Jindal; Alan Futran, a former graduate student in the Department of Chemical and Biological Engineering and LSI; graduate student Eyan Yeung of the Department of Molecular Biology and LSI; Jos Pelliccia, a graduate student in the Department of Molecular Biology; seniors in molecular biology Iason Kountouridis and Kei Yamaya; and Courtney Balgobin Class of 2015.

Bruce Gelb, a pediatric cardiologist specializing in cardiovascular genetics and the director of the Mindich Child Health and Development Institute at the Mount Sinai School of Medicine in New York, described the two new studies as wonderful in advancing the understanding of altered biology in RASopathies and developing a framework for comparing mutation strengths, bringing effective treatments significantly closer.

At this time, most of the issues that arise from the RASopathies are either addressed symptomatically or cannot be addressed, Gelb said. The work [these researchers] are undertaking could lead to true therapies for the underlying problem.

The paper, In vivo severity ranking of Ras pathway mutations associated with developmental disorders, was published Jan. 3 in the Proceedings of the National Academy of Sciences. The paper, Divergent effects of intrinsically active MEK variants on developmental Ras signaling, was published on Feb. 6 in Nature Genetics online. The research for both papers was supported in part by the National Institutes of Health and the National Science Foundation.

Media contact: Steven Schultz, 609-258-3617, sschultz@princeton.edu

Read more here:
Studies point way to precision therapies for common class of genetic disorders - HealthCanal.com (press release) (blog)