TAG: "Genetics"

Researchers seek middle-aged and older men for aging study


UC Davis study will follow groups of men with and without the fragile X premutation.

David Hessl, UC Davis

How alterations in a single gene on the X chromosome affects neurological and psychological functioning in men as they age is the subject of a new study by UC Davis MIND Institute researchers.

The gene is FMR1 (fragile X mental retardation 1), and those with an alteration in this gene, known as a “premutation,” are at risk for a range of psychological and medical conditions including decreased cognitive capacity and anxiety. In older adults with the premutation it can cause fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder that has motor symptoms that are similar to Parkinson’s disease and dementia and psychiatric symptoms that are similar to Alzheimer’s disease.

Researchers with the MIND Institute’s Fragile X Research and Treatment Center are seeking individuals the fragile X premutation who will participate in the study over five years, allowing researchers to track their brain changes, motor functioning, thinking and memory skills, as well as their emotional well‐being. They also are seeking healthy men of the same age, who will act as controls.

The study is co‐led by David Hessl, professor of psychiatry and behavioral sciences, and Susan Rivera, professor in the Department of Psychology.

“This study will follow groups of men with and without the fragile X premutation. It will examine the trajectory of change in their cognitive and emotional functioning, and the structure and function of their brains, in an effort to determine which factors are important for predicting the disease process that will occur in some of these men,” Hessl said.

Healthy male control participants must be between 40 and 75 and live in Northern California. Fragile X premutation carriers of the same age may travel to the MIND Institute from their homes anywhere in North America. Participation involves three two‐day study visits over five years. Compensation of $200, as well as travel reimbursement, will be provided for each two-day visit.

Once enrolled, individuals will receive tests to assess their ability to think and their memory skills. They will be interviewed and fill out questionnaires about their health history. They also will be asked to provide blood samples and will have brain scans taken while engaged in a variety of tasks.

For further information, please contact Jessica Famula, recruitment coordinator, (916) 703‐0470 or email jessica.famula@ucdmc.ucdavis.edu.

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Better education about prenatal testing leads to fewer tests


UCSF study shows importance of clear information on all prenatal testing options.

Miriam Kuppermann, UC San Francisco

A clinical trial led by UC San Francisco has found that when pregnant women are educated about their choices on prenatal genetic testing, the number of tests actually drops, even when the tests are offered with no out-of-pocket costs.

The findings underscore the need for clear information on all prenatal testing options and their possible outcomes, including the option of no testing, before pregnant women decide whether or not to have genetic testing, the authors said.

The study also suggests that some women may have undergone prenatal screening for Down syndrome without having full information about the implications of testing, the authors said.

The article is published in today’s (Sept. 24) issue of JAMA.

“Our findings show that prenatal testing is not appropriate for everyone, and that all women need information that is readily understood and unbiased to enable them to make informed choices reflecting their own preferences and values,” said lead author Miriam Kuppermann, Ph.D., M.P.H., professor and vice chair for clinical research at the UCSF Department of Obstetrics, Gynecology and Reproductive Sciences.

“Decisions about prenatal testing are personal and should be reflective of the patient’s own values and preferences, not those of her health care providers,” said Kuppermann.

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How to delay the aging process by ‘remote control’


UCLA biologists ID gene that can slow the aging process.

David Walker, UCLA

UCLA biologists have identified a gene that can slow the aging process throughout the entire body when activated remotely in key organ systems.

Working with fruit flies, the life scientists activated a gene called AMPK that is a key energy sensor in cells; it gets activated when cellular energy levels are low.

Increasing the amount of AMPK in fruit flies’ intestines increased their lifespans by about 30 percent — to roughly eight weeks from the typical six — and the flies stayed healthier longer as well.

The research, published Sept. 4 in the open-source journal Cell Reports, could have important implications for delaying aging and disease in humans, said David Walker, an associate professor of integrative biology and physiology at UCLA and senior author of the research.

“We have shown that when we activate the gene in the intestine or the nervous system, we see the aging process is slowed beyond the organ system in which the gene is activated,” Walker said.

Walker said that the findings are important because extending the healthy life of humans would presumably require protecting many of the body’s organ systems from the ravages of aging — but delivering anti-aging treatments to the brain or other key organs could prove technically difficult. The study suggests that activating AMPK in a more accessible organ such as the intestine, for example, could ultimately slow the aging process throughout the entire body, including the brain.

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Study IDs genetic factors involved in pediatric ulcerative colitis


Findings point to novel approaches for prevention, treatment.

Microscope images of a normal mouse colon (left) and one with colitis (right).

UCLA researchers were part of a team that has discovered the interplay of several genetic factors that may be involved in the development of early-onset ulcerative colitis, a severe type of inflammatory bowel disease.

The early research findings may offer new targets for prevention and treatment strategies to address the inflammation generated by early-onset ulcerative colitis.

The rare disease affects infants and young children and can lead to early development of colon cancer and an increased risk of liver damage.

Scientists from the David Geffen School of Medicine at UCLA and Pusan National University in South Korea also created a first-of-its-kind animal model that mimics early-onset ulcerative colitis and can be used to help test new drug candidates to treat the disease. Their findings are published in the current issue of the peer-reviewed journal Gastroenterology.

“We hope that identifying these key genetic factors and providing a unique research model will help lead to new approaches to treat early-onset ulcerative colitis, a devastating disease that currently has no cure,” said Dr. Sang Hoon Rhee, the study’s senior author and an associate adjunct professor of medicine in the Division of Digestive Diseases at the David Geffen School of Medicine at UCLA.

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Chicken gene provides insight on craniofacial birth defects


UC Davis findings significant for humans as well as poultry and livestock.

These chicks are part of UC Davis' living library of poultry and avian genetics, which includes the talpid lines examined in this study. (Photo by Mary Delany, UC Davis)

Each year, thousands of babies are born in the U.S. with craniofacial defects, from cleft lips and palates to more severe abnormalities of the face or head. Now new discoveries in chicken genetics and biology are shedding light on the basis of these abnormalities in both birds and humans.

The work, by a team including UC Davis animal science professor Mary Delany, was made possible by information from the chicken genome sequence and a stock of rare chicken lines kept at UC Davis. The findings appear in the August issue of the journal Development.

The researchers focused on a mutation of the gene named talpid2, known to be associated with a number of congenital abnormalities, including limb malformations and cleft lip or palate.

They found that talpid2 — like other limb and craniofacial mutations found in both humans and chickens — is related to the malfunction of “cilia,” tiny, hairlike structures on the surface of cells of the body.

Cilia play a vital role in passing along signals during development. When a gene mutation interferes with the normal structure and function of the cilia, it sets off a chain reaction of molecular miscues that result in physical abnormalities, in chickens or in people.

“Now that this new information is available, the talpid2 mutation can be expanded as a model for studying similar congenital abnormalities in humans including oral-facial defects, which affect many people around the world,” said Delany, who also serves as executive associate dean of the College of Agricultural and Environmental Sciences.

Delany said that the findings also are significant for production of poultry and livestock, which are likewise vulnerable to genetic mutations that cause similar physical abnormalities.

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Tackling rare diseases


UC Irvine researchers’ search for genetic clues is giving new hope to families.

“In our lab, we don’t give up,” says Virginia Kimonis, a UC Irvince specialist in rare genetic diseases. “If people are reaching out, you have to do all you can about rare diseases.” (Photo by Steve Zylius, UC Irvine)

By the time families meet with Dr. Virginia Kimonis, hope is about all they have left.

Her pediatric patients are afflicted with debilitating diseases caused by mutations in an alphabet soup of genes – VCP and NUBPL among them. Prader-Willi, Rett, Paget’s and the like are difficult to diagnose and even harder to treat. But with cutting-edge genomic sequencing and old-fashioned scientific sleuthing, physician-researchers such as Kimonis are on the vanguard of modern medicine, finding therapies where none seemed possible.

Kimonis specializes in one of the most challenging areas: rare genetic diseases. What she and others in her field are learning about disorders that impact only a few is paving the way to a greater understanding of diseases that impact millions.

“It’s wonderful to show in the lab and in the clinic that we can offer these patients some hope,” says Kimonis, a UC Irvine pediatrician and clinical geneticist.

A rare disease is defined as one diagnosed in no more than 200,000 people worldwide; 70 percent, though, affect fewer than 6,000. And of the nearly 7,000 known rare diseases, half involve children, and 80 percent are linked to genetic flaws. These are Kimonis’ focus.

According to UC Irvine’s Dr. J. Jay Gargus, an expert in genetic metabolic diseases, rare disease research can be a springboard to understanding and treating more common ailments.

“We have a special opportunity with rare genetic diseases to provide an insight into how common diseases arise,” says Gargus, who directs the campus’s Center for Autism Research & Translation. “This is an important venue for drug discovery. The National Institutes of Health and the Food & Drug Administration recognize this and have programs established for target diseases. UC Irvine has a great strength in diagnostics, and we should be very involved in this.”

Gargus himself is making a breakthrough on a rare genetic disease. He recently held the first U.S. clinical trial of a treatment for Wolman disease, a cholesterol storage disorder, at UC Irvine Medical Center – with promising results.

Kimonis is also helping the campus establish itself as a leader in the field. She manages a section of the NIH’s Rare Diseases Clinical Research Network dedicated to Prader-Willi, Rett and Angelman syndromes.

Children with Prader-Willi – which is caused by the loss of several genes on chromosome 15 – are characterized by obesity, low muscle tone and cognitive disabilities. In addition to treating Prader-Willi patients with novel approaches, Kimonis is building a national database of those with the disease and designing studies to identify promising therapies.

In one project, she plans to partner with Daniele Piomelli – UC Irvine’s Louise Turner Arnold Chair in the Neurosciences, who examines the endocannabinoid system – to see how marijuana-like chemicals called OEAs created in the body can help curb the insatiable appetites of Prader-Willi children. By creating mice models with Prader-Willi gene mutations, the two hope to learn if the hunger-curbing signal provided by OEA is missing and whether compounds that boost OEA can aid satiety.

“If successful, our experiments will achieve two important objectives,” Piomelli says. “First, they will help us understand why Prader-Willi causes hunger; second, and more importantly, they will suggest new possible therapies to reduce appetite.”

Another focus of Kimonis’ work centers on disorders triggered by mutations in the valosin-containing protein gene. VCP programs enzymes that help maintain cell health by breaking down and clearing away old and damaged proteins that are no longer necessary. Mutations in the VCP gene have been discovered in people who have a muscle-weakening disease called inclusion body myopathy, early-onset Paget’s disease of the bone or frontotemporal dementia.

Kimonis was the first scientist to map and identify mutations in the VCP gene in inclusion body myopathy, and in 2012, she developed the first genetically modified mouse model that exhibits many of the clinical features of diseases largely caused by VCP gene mutations.

“Mouse models like these are important because they let researchers study how these now-incurable, degenerative disorders progress in vivo and will provide a platform for translational studies that could lead to lifesaving treatments,” says Kimonis, who co-directs UC Irvine’s MitoMed laboratory, which offers testing for many rare diseases.

Her research breakthroughs are coinciding with greater public recognition of rare genetic diseases. The NIH has established an Office of Rare Diseases Research, and nonprofit groups such as the Orange County-based Global Genes Project are increasing awareness, advocating and soliciting philanthropic aid on behalf of this issue. (The GGP is hosting a patient advocacy summit Sept. 11 and 12 in Huntington Beach.)

Parents of children with rare genetic diseases are also speaking out. Cristy and Rick Spooner of Rancho Santa Margarita, who’ve endured a long quest to identify a disabling condition affecting two of their three daughters, have gone public with their story, hoping to raise the profile of such diseases.

After the Spooners spent years seeking help from doctors, Kimonis contacted them about a new technique, called exome sequencing, that examines the tens of thousands of genes in the human body for disease-causing mutations. Aliso Viejo-based Ambry Genetics, which partners with Kimonis’ research group, provided the sequencing services.

Test results showed that Cali and Ryann Spooner harbored mutations in the NUBPL gene. This defect prevents their mitochondria – the power generators in cells – from efficiently producing energy. Armed with this information, Kimonis developed dietary and drug treatments for the Spooner sisters.

“What’s even more satisfying about our work is that it has huge implications for other diseases,” she says.

Kimonis is seeking funding to determine whether mitochondrial defects caused by mutated NUBPL genes underlie the onset of Parkinson’s disease. She hopes to partner with UC Irvine neurologist Dr. Neal Hermanowicz, who manages the movement disorders program, to establish a clinical research network for this effort.

“In our lab, we don’t give up,” Kimonis says. “If people are reaching out, you have to do all you can about rare diseases.”

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Target ID’d for rare inherited neurological disease in men


Finding provides insight for Kennedy’s disease, other neurodegenerative diseases.

Researchers at the UC San Diego School of Medicine have identified the mechanism by which a rare, inherited neurodegenerative disease causes often crippling muscle weakness in men, in addition to reduced fertility.

The study, published today (Aug. 10) in the journal Nature Neuroscience, shows that a gene mutation long recognized as a key to the development of Kennedy’s disease impairs the body’s ability to degrade, remove and recycle clumps of “trash” proteins that may otherwise build up on neurons, progressively impairing their ability to control muscle contraction. This mechanism, called autophagy, is akin to a garbage disposal system and is the only way for the body to purge itself of non-working, misshapen trash proteins.

“We’ve known since the mid-1990s that Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are caused by the accumulation of misfolded proteins that should have been degraded, but cannot be turned over,” said senior author Albert La Spada, M.D., Ph.D. and professor of pediatrics, cellular and molecular medicine, and neurosciences. “The value of this study is that it identifies a target for halting the progression of protein build-up, not just in this rare disease, but in many other diseases that are associated with impaired autophagy pathway function.”

Of the 400 to 500 men in the U.S. with Kennedy’s disease, the slow but progressive loss of motor function results in about 15 to 20 percent of those with the disease becoming wheelchair bound during later stages of the disease.

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Researchers ID gene mutation for heart disease in Newfoundland dogs


Information could help gradually eliminate the disease from the breed.

Newfoundlands — those massive, furry, black dogs — have captured many a heart with their hallmark size, sweet nature and loyalty. Unfortunately these gentle giants’ own hearts are all too often afflicted with a potentially lethal congenital disease called subvalvular aortic stenosis, or SAS, which also affects children and other dog breeds including the golden retriever.

A team of researchers led by UC Davis veterinary cardiologist Joshua Stern has for the first time identified a gene mutation responsible for canine SAS, the most common inherited heart disease in dogs. The study appears online in the journal Human Genetics: www.ncbi.nlm.nih.gov/pubmed/24898977.

“Our hope now is that breeders will be able to make informed breeding decisions and avoid breeding dogs that harbor this mutation, thus gradually eliminating the disease from the Newfoundland breed,” Stern said. “In addition, now that we know one gene responsible for SAS and more about which proteins are involved, we can move forward to consider novel therapies that may help treat this devastating condition.”

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UC Irvine study offers new leads for liver disease treatments


Genomic partitioning by biological clock separates key metabolic functions.

Much of the liver’s metabolic function is governed by circadian rhythms – our own body clock – and UC Irvine researchers have now found two independent mechanisms by which this occurs.

The study, published online today (July 31) in Cell, reveals new information about the body clock’s sway over metabolism and points the way to more focused drug treatments for liver disease and such metabolic disorders as obesity and diabetes.

Paolo Sassone-Corsi, UCI’s Donald Bren Professor of Biological Chemistry, and postdoctoral scholar Selma Masri report that two of these circadian-linked proteins, SIRT1 and SIRT6, manage important liver processes – lipid storage and energy usage in liver cells – separately and distinctly from each other.

This surprising discovery of genomic partitioning, Masri noted, reveals how strictly regulated circadian control of metabolism can be.

“The ability of the genome and epigenome to cross-talk with metabolic pathways is critical for cellular and organismal functions. What’s remarkable is that the circadian clock is intimately involved in this dialogue,” she said.

Circadian rhythms of 24 hours govern fundamental physiological functions in virtually all organisms. The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Changes to these rhythms can profoundly influence human health. Up to 15 percent of people’s genes are regulated by the day-night pattern of circadian rhythms; nearly 50 percent of those involved with metabolic pathways in the liver are influenced by these rhythms.

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Gene behind rare birth abnormality provides a window on evolution


Fine-tuning genes shapes teeth as evolution did.

Ophir Klein, UC San Francisco

A UC San Francisco physician who treats birth defects affecting the face has teamed up with a European expert on animal evolution to create rodent teeth that harken back in evolutionary time.

By making a molar that mimics features found in an ancestral uber-rodent that roamed the earth 60 million years ago, the scientists successfully demonstrated a new way to explore how genetic changes affect mammalian development and how advantageous genetic mutations that spontaneously arise in new generations might take hold over time in an evolving population.

It’s not Jurassic Park, but the research team showed that real-time lab experiments are relevant to paleontologists, who typically are stuck working on mysteries of evolution equipped with little more than bits of fossilized bone or teeth. Especially for mammals, the fine features of teeth are used to determine how fossil species are related to each other and to modern animals.

A key gene manipulated by the researchers in their new study, published online today (July 30) in Nature, already had been a clinical research focus of study co-senior author Ophir Klein, M.D., Ph.D., Larry L. Hillblom Distinguished Professor in Craniofacial Anomalies at UCSF. The gene, Eda, encodes a developmental protein called ectodysplasin. It is defective in a rare human birth defect that results in a shortage or absence of sweat glands, misshapen and absent teeth, and loss of hair follicles – all appendages that develop from the same embryonic tissue. The syndrome was even described by Charles Darwin in “The Variation of Animals and Plants Under Domestication,” published in 1868.

Researchers in Switzerland had previously found that the syndrome in mice can be treated during the mother’s gestation by administering the missing ectodysplasin — the first demonstration that a structural birth defect could be prevented with a medical approach, Klein said.

Klein led the first phase I clinical trial to similarly treat the condition in humans, and this past November treated the first North American baby in an ongoing phase II study.

But Klein and collaborator Jukka Jernvall, Ph.D., Academy Professor of evolution and development at the University of Helsinki, Finland, had also been wondering if the same biochemical pathway also could be manipulated to study evolution.

In the past, biologists have studied fine features of teeth in mutant animals to try to help them reconstruct evolutionary history. However, the changes in the mutants are often too dramatic to be very informative. “We wanted to know if we could play with these biochemical pathways to recapitulate changes that are seen in the fossil record,” Klein said.

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Friends are the family you choose


Genome-wide analysis reveals genetic similarities among friends.

A genome-wide analysis by researchers and friends James Fowler (right) and Nicholas Christakis shows that pairs of friends share genetic similarities. (Photo by Liza Green)

If you consider your friends family, you may be on to something. A study from UC San Diego and Yale University finds that friends who are not biologically related still resemble each other genetically.

Published in the Proceedings of the National Academy of Sciences, the study is co-authored by James Fowler, professor of medical genetics and political science at UC San Diego, and Nicholas Christakis, professor of sociology, evolutionary biology and medicine at Yale.

“Looking across the whole genome,” Fowler said, “we find that, on average, we are genetically similar to our friends. We have more DNA in common with the people we pick as friends than we do with strangers in the same population.”

The study is a genome-wide analysis of nearly 1.5 million markers of gene variation, and relies on data from the Framingham Heart Study. The Framingham dataset is the largest the authors are aware of that contains both that level of genetic detail and information on who is friends with whom.

The researchers focused on 1,932 unique subjects and compared pairs of unrelated friends against pairs of unrelated strangers. The same people, who were neither kin nor spouses, were used in both types of samples. The only thing that differed between them was their social relationship.

The findings are not, the researchers say, an artifact of people’s tendency to befriend those of similar ethnic backgrounds. The Framingham data is dominated by people of European extraction. While this is a drawback for some research, it may be advantageous to the study here: because all the subjects, friends and not, were drawn from the same population. The researchers also controlled for ancestry, they say, by using the most conservative techniques currently available. The observed genetic go beyond what you would expect to find among people of shared heritage – these results are “net of ancestry,” Fowler said.

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Extinct human cousin gave Tibetans advantage at high elevation


First time a gene from another species of human shown to help modern humans adapt to environment.

Tibetan boy (Photo courtesy of BGI-Shenzen, China)

Tibetans were able to adapt to high altitudes thanks to a gene picked up when their ancestors mated with a species of human they helped push to extinction, according to a new report by University of California, Berkeley, scientists.

This is the first time a gene from another species of human has been shown unequivocally to have helped modern humans adapt to their environment, the researchers said.

An unusual variant of a gene involved in regulating the body’s production of hemoglobin – the molecule that carries oxygen in the blood – became widespread in Tibetans after they moved onto the high-altitude plateau several thousand years ago. This variant allowed them to survive despite low oxygen levels at elevations of 15,000 feet or more, whereas most people develop thick blood at high altitudes, leading to cardiovascular problems.

“We have very clear evidence that this version of the gene came from Denisovans,” a mysterious human relative that went extinct 40,000-50,000 years ago, around the same time as the more well-known Neanderthals, under pressure from modern humans, said principal author Rasmus Nielsen, UC Berkeley professor of integrative biology. “This shows very clearly and directly that humans evolved and adapted to new environments by getting their genes from another species.”

Nielsen and his colleagues at BGI-Shenzhen in China, the world’s largest genome sequencing center, will report their findings online today (July 2) in advance of publication in the journal Nature.

The gene, called EPAS1, is activated when oxygen levels in the blood drop, triggering production of more hemoglobin. The gene has been referred to as the “superathlete” gene because at low elevations, some variants of it help athletes quickly boost hemoglobin and thus the oxygen-carrying capacity of their blood, upping endurance. At high altitudes, however, the common variants of the gene boost hemoglobin and its carrier, red blood cells, too much, increasing the thickness of the blood and leading to hypertension and heart attacks as well as low birth weight babies and increased infant mortality. The variant, or allele, found in Tibetans raises hemoglobin and red blood cell levels only slightly at high elevations, avoiding the side effects seen in most people who relocate to elevations above 13,000 feet.

“We found that part of the EPAS1 gene in Tibetans is almost identical to the gene in Denisovans and very different from all other humans,” Nielsen said. “We can do a statistical analysis to show that this must have come from Denisovans. There is no other way of explaining the data.”

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