In the first study to run a genome-wide analysis of Short Tandem Repeats (STRs) in gene expression, a large team of computational geneticists led by investigators from Columbia Engineering and the New York Genome Center have shown that STRs, thought to be just neutral, or ‘junk,’ actually play an important role in regulating gene expression.

“Our work expands the repertoire of functional genetic elements,” says the study’s leader Yaniv Erlich, who is an assistant professor of computer science at Columbia Engineering, a member of Columbia’s Data Science Institute, and a core member of the New York Genome Center. “We expect our findings will lead to a better understanding of disease mechanisms and perhaps eventually help to identify new drug targets.”

Genomic variants are what makes our DNA different from each other, and come,
Erlich explains, “like spelling errors in different flavours.” The most common
variants are SNPs (single nucleotide polymorphisms). Computational geneticists
have been focused mostly on SNPs that look like a single letter typo—mother vs.
muther—and their effect on complex human traits.

Erlich’s study looked at Short Tandem Repeats (STRs), variants that create what
look like typos: stutter vs. stututututututter. Most researchers, assuming that
STRs were neutral, dismissed them as not important. In addition, these variants
are extremely hard to study. “They look so different to analysis algorithms,” Erlich notes, “that they just usually classify them as noise and skip these positions.”

Erlich used a multitude of statistical genetic and integrative genomics analyses to
reveal that STRs have a function: they act like springs or knobs that can expand
and contract, and fine-tune the nearby gene expression. Different lengths
correspond to different tensions of the spring and can control gene expression and disease traits. He is calling these variants eSTRs, or expression STRs, to note that they regulate gene expression. He and his team also discovered that these eSTRs can be associated with a range of conditions including Crohn’s diseases, high blood pressure, and a range of metabolites. These eSTRs explain on average 10 to 15% the genetic differences of gene expression between individuals.
“We’ve known that STRs are known to play a role in these diseases, but no one has ever conducted a genome-wide scan to find their effect on complex traits,” Erlich adds. “If we want to do personalized medicine, we really need to understand every part of the genome, including repeat elements—there’s a lot of exciting biologyahead.” New York Genome Centre

Two proteins that share the ability to help cells deal with their trash appear to need each other to do their jobs and when they don’t connect, it appears to contribute to development of Parkinson’s disease, scientists report.

Much like a community’s network for garbage handling, cells also have garbage sites called lysosomes, where proteins, which are functioning badly because of age or other reasons, go for degradation and potential recycling, said Dr. Wen-Cheng Xiong, developmental neurobiologist and Weiss Research Professor at the Medical College of Georgia at Georgia Regents University.

Inside lysosomes, other proteins, called proteases, help cut up proteins that can no longer do their job and enable salvaging of things like precious amino acids. It’s a normal cell degradation process called autophagy that actually helps cells survive and is particularly important in cells such as neurons, which regenerate extremely slowly, said Xiong, corresponding author of the study.

Key to the process – and as scientists have shown, to each other – are two more proteins, VPS35 and Lamp2a. VPS35 is essential for retrieving membrane proteins vital to cell function. Levels naturally decrease with age, and mutations in the VPS35 gene have been found in patients with a rare form of Parkinson’s. VPS35 also is a critical part of a protein complex called a retromer, which has a major role in recycling inside cells. Lamp2a enables unfit proteins to be chewed up and degraded inside lysosomes.

If the two sound like a natural couple, scientists now have more evidence that they are. They have shown that without VPS35 to retrieve Lamp2a from the trash site for reuse, Lamp2a, or lysosomal-associated membrane protein 2, will be degraded and its vital function lost.

When the scientists generated VPS35-deficient mice, the mice exhibited Parkinson’s-like deficits, including impaired motor control. When they looked further, they found the lysosomes inside dopamine neurons, which are targets in Parkinson’s, didn’t function properly in the mice. In fact, without VPS35, the degradation of Lamp2a itself is accelerated. Consequently, yet another protein, alpha-synuclein, which is normally destroyed by Lamp2a, is increased. Alpha-synuclein is a major component of abnormal protein clumps, called Lewy bodies, found in the brains of patients with Parkinson’s.

“If alpha-synuclein is not degraded, it just accumulates. If VPS35 function is normal, we won’t see its accumulation,” Xiong said.

Conversely, when scientists increased expression of Lamp2a in the dopamine neurons of the VPS35-deficient mice, alpha-synuclein levels were reduced, a finding that further supports the linkage of the three proteins in the essential ability of the neurons to deal with undesirables in their lysosomes.

Without lamp2a, dopamine neurons essentially start producing more garbage rather than eliminating it. Recycling of valuables such as amino acids basically stops, and alpha-synuclein is free to roam to other places in the cell or other brain regions where it can damage still viable proteins.

The bottom line is dopamine neurons are lost instead of preserved. Brain scans document the empty spaces where neurons used to be in patients with neurodegenerative diseases such as Parkinson’s and Alzheimer’s. One of the many problems with treatment of these diseases is that by the time the empty spaces and sometimes the associated symptoms are apparent, much damage has occurred, Xiong said.

Putting these pieces together provides several new, early targets for disease intervention. “Everything is linked,” Xiong said. Medical College of Georgia at Georgia Regents University

Kidney disease is a major health concern worldwide. It’s estimated that 1 in 3 American adults are at risk of developing kidney disease, and 26 million adults already have kidney disease. Many are undiagnosed. Because kidney disease can go undetected until it’s too late, effective and consistent diagnosis is essential. Physicians on Mayo Clinic’s Rochester, Minn., campus – one of the world’s leading kidney disease centers – are at the forefront of an effort to standardize the diagnosis of kidney disease.

In a paper, Mayo Clinic researchers provide a detailed recommendation for standardizing the diagnosis of glomerulonephritis. This is a term used to describe various conditions involving inflammation of the glomeruli, which is the basic filtering unit in the kidneys. Inflammation prevents the kidneys from properly filtering toxins out of the blood and regulating fluid levels in the body, and, ultimately, can lead to permanent damage to the kidneys and potential kidney failure.

 “Earlier this year, we convened renal pathologists and nephrologists from around the world at Mayo Clinic to begin work on an effort that could transform the way kidney disease is diagnosed for patients everywhere,” says Sanjeev Sethi, M.D., Ph.D, professor, Department of Laboratory Medicine and Pathology, Mayo Clinic. “It was time to move the field toward diagnosing glomerulonephritis based on the underlying cause of the disease, which leads to a more personalized diagnosis and more targeted treatment for the patient.”

According to convention, glomerulonephritis historically has been classified by the pattern of inflammation in the glomerulus; however, this does not speak to the underlying cause of the disease. The recommendations published by Mayo Clinic provide a detailed approach to classifying and reporting glomerulonephritis that is based on pathology and etiology.

“The approach outlined in the consensus paper provides a detailed approach to diagnosing kidney disease that has many advantages for clinicians and patients,” says Fernando Fervenza, M.D., Ph.D., professor, Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic. “In addition to being focused on the individual patient’s pathology and potential cause of disease, this approach makes the data more adaptable should new diseases be identified by future research. It aligns with database reporting, and it focuses on information that is relevant to the patient and [his or her] potential treatment options.”

Drs. Sethi and Fervenza led the development of the consensus paper, which has been endorsed by the Renal Pathology Society with funding from the Fulk Foundation. The recommendations provided by the consensus report likely will form the basis of how glomerulonephritis is diagnosed and reported worldwide. Based on the recommendations, the kidney biopsy report will be disease and etiology based. This will provide the treating physician a clear pathway toward appropriate testing and evaluation of the underlying kidney disease, followed by correct and specific management of the underlying cause of the glomerulonephritis. The standardized reporting will make it easier for physicians to interpret the kidney biopsy report from various institutions. This is particularly true for Mayo physicians who see patients from different institutions. Thus, based on the etiology-driven kidney biopsy report, a patient visiting Mayo Clinic can be directed to the physician with expertise in the specific area, resulting in targeted, cost effective evaluation, and appropriate treatment of the underlying cause of kidney disease. Mayo Clinic

Chemicals used as flame retardants that are potentially harmful to humans are found in hair, toenails and fingernails, according to new research from Indiana University.

The discovery of an easily available biomarker should ease the way for further research to determine the human impact of chemicals commonly found in the environment, including in indoor dust, water and air.

Exposure to flame retardants in various forms has been linked to obesity, learning disabilities, neuro and reproductive toxicity, and endocrine disruption. Flame retardants are frequently added to plastic, foam, wood and textiles. They are used in both commercial and consumer products worldwide to delay ignition and to slow the spread of fire. Flame retardants persist in the environment and bio-accumulate in ecosystems and in human tissues.

“Little is known about the human exposure to flame retardants, especially new classes of the retardants,” said researcher Amina Salamova at the School of Public and Environmental Affairs at IU Bloomington. “The first step is to establish a relatively easy and reliable way of measuring chemical levels in people, especially children, and we’ve determined that hair and nails can provide exactly that.”

Until now, researchers depended on samples of human milk, blood and urine, and those samples are more difficult to obtain than hair and nails.

The researchers collected hair, fingernails and toenails from 50 students in Bloomington and compared the levels of chemicals found in those samples with what was found in blood from the same people.

Salamova and colleagues found that there was a strong relationship between the levels of a large group of flame retardants, the polybrominated diphenyl ethers or PBDEs, in hair and nails, on the one hand, and those in serum, on the other. In some cases, women had higher concentrations of common flame retardants, and the researchers speculate that was a result of nail polishes that contain these chemicals. Indiana University