TAG: "Genetics"

Specific genetic mutation may increase risk for breast cancer

Study shows women with KRAS-variant also likelier to develop new cases of breast cancer.

Joanne Weidhaas, UCLA

By Reggie Kumar, UCLA

UCLA researchers have discovered that for women with a relatively common inherited genetic mutation, known as the KRAS-variant, an abrupt lowering of estrogen in the body may increase the risk for breast cancer and impact the biology of their breast cancer. Scientists also found that women with the KRAS-variant are more likely to develop a second primary breast cancer, independent of a first breast cancer.

The two-year study, led by Dr. Joanne Weidhaas, a professor of radiation oncology at the UCLA Jonsson Comprehensive Cancer Center and director of translational research at the David Geffen School of Medicine, analyzed data from more than 1,700 women with breast cancer who submitted DNA samples to be tested for the inherited KRAS-variant. The study also included a group of women with the KRAS-variant who were cancer-free, as well as biological models to scientifically confirm the clinical findings.

Weidhaas’ team found that acute estrogen withdrawal, as experienced after removal of the ovaries or when hormone replacement therapy was discontinued, and/or a low estrogen state were associated with breast cancer in women with the KRAS-variant. Acute estrogen withdrawal also triggered breast cancer formation in KRAS-variant biological models used in the study. In addition, up to 45 percent of breast cancer patients with the KRAS-variant eventually developed a second independent breast cancer — representing a 12-fold greater risk than women with breast cancer who did not have the KRAS-variant.

“Although we had evidence that the KRAS-variant was a stronger predictor of cancer risk for women than men, we did not previously have a scientific explanation for this observation,” Weidhaas said. “This study’s findings, showing that estrogen withdrawal can influence cancer risk for women with the KRAS-variant, begins to provide some answers.”

The findings are contrary to some past research suggesting that women on combination hormone replacement therapy are more likely to develop breast cancer, but the study is in agreement with follow-up studies which found that estrogen alone might actually protect women from breast cancer.

“The KRAS-variant may be a genetic difference that could actually help identify women who could benefit from continuing estrogen, or at a minimum, at least tapering it appropriately,” Weidhaas said. “We hope that there are real opportunities to personalize risk-reducing strategies for these women, through further defining the most protective estrogen management approaches, as well as by understanding the impact of different treatment alternatives at the time of a woman’s first breast cancer diagnosis.”

The study was published in the journal Cell Cycle.

The research, which was supported by the National Cancer Institute, was done in collaboration with MiraKind, a nonprofit organization.

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Biology students join undergrads across nation to co-author research paper

Students tackle investigation of ‘dot’ chromosome of Drosophila fruit flies.

Stephanie Mel, a teaching professor in the Division of Biological Sciences, designed and taught a new biology course called “Research Explorations in Genomics” to allow UC San Diego undergraduates to conduct original research in a classroom setting while becoming co-authors in a peer‐reviewed scientific journal.

By Kim McDonald, UC San Diego

An unusual genomics research paper published this month by 940 students at 63 universities around the nation provided 16 undergraduate biology students at UC San Diego with an opportunity to conduct original research in a classroom setting, while becoming co-authors in a peer‐reviewed scientific journal.

Published in the May issue of the journal G3: Genes|Genomes|Genetics, the study conducted by the undergraduate student researchers detailed the evolution of an unusual chromosome in fruit flies. It was made possible by the Genomics Education Partnership, a Howard Hughes Medical Institute-funded collaboration with the biology department and Genome Sequencing Center of Washington University in St. Louis, which coordinated the work.

“This collaboration provided a genuine research experience in our undergraduate biology classroom,” said Stephanie Mel, a teaching professor in the Division of Biological Sciences at UC San Diego who in 2010 designed and taught a new biology course called “Research Explorations in Genomics” to take part in this effort.

In that course, the 19 undergraduate biology students taught by Mel and helped by a master’s student teaching assistant, conducted the UC San Diego portion of the research study. It was an experiment for the instructors as well as the students. And both loved the new approach.

“I got extremely positive feedback from the students in the course,” Mel added. “Since so many of their other biology courses had several hundred people in them, it was an extraordinary opportunity for the students at UC San Diego to learn in a small, highly interactive environment, and to learn in the context of solving a real life research problem.”

Recent reports on undergraduate education have emphasized the crucial role of providing authentic research experiences, where students can learn more than from the traditional textbook lectures and canned experiments.

While faculty at the various universities that collaborated in the effort oversaw the project and drafted the paper, each of the 940 students listed as a co‐authors performed original research and read and approved the manuscript before submission. Many students also provided important comments that were incorporated into the final version.

The students tackled the investigation of the “dot” chromosome of Drosophila fruit flies. The dot chromosome gets its name from its tiny size; next to the other fruit fly chromosomes, it looks like a compact dot. Scientists are interested in the dot chromosome because its DNA is tightly packaged in a form called heterochromatin — a state normally linked with relatively inactive genome regions that contain only a few rarely expressed genes. But despite being packed into heterochromatin, a large region of the dot chromosome carries a similar density of actively expressed genes compared to other, non‐heterochromatic parts of the fruit fly genome. Non‐heterochromatic DNA is known as euchromatin.

How has this unusual state affected evolution of the dot chromosome genes? To investigate, the collaboration of students set out to compare the dot chromosome to a euchromatic region from a different chromosome. But this exploration required a high quality genome sequence from several different Drosophila species, not just Drosophila melanogaster, the species in which the dot chromosome has been most intensively studied. Draft genome sequences for other Drosophila species were already publicly available, but because the dot chromosome carries many repetitive sequences, the genome data was sometimes unreliable. That’s because repeat sequences cause trouble for the software that stitches together the fragments of raw sequence data — like a jigsaw puzzle with many pieces of the same color and shape, it’s hard to figure out which fragments belong where.

In this case, humans do a better job than computers. The collaboration was able to correct errors in the draft genome assembly by breaking the work up into chunks and distributing it among hundreds of students. The students carefully examined each region they were assigned and paid attention to small differences in repeated sequences that gave the students clues on how to put the puzzle together.

“From my perspective, it was a privilege to be able to involve undergraduates in a genuine research experience in a regular class setting,” said Mel. “And to have this result in student authorship on a scientific publication is tremendously exciting.”

Said one of the UC San Diego biology students, Jim Liu, “It was a unique educational and empowering experience that set itself FAR apart from and above the bulk of the ‘memorize-regurgitate-repeat’ undergraduate experience.”

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Breakthrough in understanding Canavan disease

UC Davis findings could help find a way to treat devastating genetic disorder.

David Pleasure, UC Davis

By Charles Casey, UC Davis

UC Davis investigators have settled a long-standing controversy surrounding the molecular basis of an inherited disorder that historically affected Ashkenazi Jews from Eastern Europe but now also arises in other populations of Semitic descent, particularly families from Saudi Arabia.

Through a series of elegant experiments, the researchers uncovered the biochemical underpinnings of Canavan disease, a type of leukodystrophy that is an incurable and progressively fatal neurological condition. The UC Davis team identified an abnormally high buildup of the second most common molecule in the brain, N-acetylaspartate (NAA), as the culprit that causes the syndrome’s destructive effect.

The findings, which are now available online, appear in the May issue of the journal Annals of Neurology in an article titled, “Ablating N-acetylaspartate prevents leukodystrophy in a Canavan disease model.”

“By finally identifying the biochemical basis for this terrible disorder, we are hopeful that it can lead to an effective treatment,” said David Pleasure, a UC Davis Distinguished Professor of neurology and pediatrics, and principal investigator of the study.

Leukodystrophies comprise a number of rare genetic disorders of the central nervous system that involve disrupted development of the myelin sheath that grows around neurons, which is essential for normal nerve conduction. Canavan disease usually becomes apparent in infancy with poor muscle tone and abnormal head enlargement, and rapidly progresses to mental retardation, paralysis, blindness, hearing loss and usually death by age 10. There is currently no treatment.

Canavan disease is inherited in an autosomal recessive pattern, meaning that if both parents carry the mutation, each child has a 1 in 4 chance of developing the condition. Although the disease occurs worldwide, the most frequent carriers of the mutation are Ashkenazi Jews from Eastern Europe. Because of widespread genetic counseling in that population, most cases of the disease now arise in families from other backgrounds, especially in Saudi Arabians.

It has been well understood for years that the critical mutation that leads to Canavan disease is of the gene that codes for an enzyme called aspartoacylase (ASPA), which breaks down NAA into acetate and aspartate. Without a working ASPA enzyme, NAA – which provides multiple important functions in the brain — builds up, resulting in a shortage of the two byproducts. Knowing this led to two hypotheses of what is responsible for the manifestation of Canavan disease – it might either be a problem of too much NAA or too little availability of the byproducts. Because acetate is an essential component of myelin synthesis, the “too little byproduct” hypothesis had a good theoretical basis and led to attempted treatments that stymied investigators because of their ineffectiveness.

Pleasure’s group used mice engineered with specific genetic mutations to prove that the “too much NAA” theory is the correct one. Mice that were genetically unable to produce NAA exhibited normal myelination, indicating that not having acetate available from this pathway cannot be responsible for poor myelin development. Furthermore, these same mice, if also given the ASPA mutation of Canavan disease, did not develop signs of the syndrome.

It has been suggested that one of NAA’s functions is to preserve the essential water and salt balance in the brain. It is this possible function that Pleasure believes is likely to be the primary problem in Canavan disease. Children with the disease have enlarged fluid-filled areas in the brain evident in magnetic resonance imaging studies, possible evidence of a water-salt imbalance. According to this theory, dysmyelination occurs secondarily to the problems caused by fluid imbalance.

Attempts to treat Canavan disease have taken several directions. Supplementing acetate has been unsuccessful, which according to the new findings is to be expected. Combating the mutation directly by implanting a working ASPA gene using a viral vector has worked well in mouse models of the disease but is technically unfeasible so far in humans.

This current research points to a new avenue of treatment: blocking the production of NAA. However, NAA, being such a common molecule in the brain, must have essential functions, according to Pleasure. Mice that are genetically engineered to be unable to synthesize NAA have been reported to have abnormal social interactions. One child has been identified in the literature who was unable to produce NAA because of a genetic mutation. The child had neurodevelopmental retardation.

“Reducing NAA without eliminating it completely may be the most promising direction of treatment,” said Pleasure, whose laboratory is based in Sacramento at Shriners Hospitals for Children Northern California. “Our goal is to find a method to reverse the process in children with the disease – that will be the most useful to families with this heartbreaking condition.”

Research for this study was funded by Shriners Hospitals for Children and the European Leukodystrophy Association.

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Rare mutation causes vitamin A deficiency, eye deformities

Altered protein highlights unique genetic inheritance.

Researchers at the University of Michigan and UC Davis have solved a genetic mystery that has afflicted three unrelated families, and possibly others, for generations. These families have been plagued by a variety of congenital eye malformations, including small eyes with poor vision and the complete absence of eyes. But until now, no one could figure out the genetic basis for these conditions.

By mapping and sequencing family DNA, the research team found mutations in a protein (RBP4) that transports a form of vitamin A called retinol, an essential nutrient for eye development. The mutations create a functional “double-whammy.”

First, the mutated proteins fail to transport retinol to the developing embryo. Then, to make matters worse, they also block the cell surface receptor for RBP4 (called STRA6), keeping healthy proteins from delivering their nutritional payload. The end result is a severe retinol deficiency and subsequent birth defects. The research appears online today (April 23) in the journal Cell.

“Instead of being inactive, the mutated proteins have altered function,” said senior author Tom Glaser, a professor in the Department of Cell Biology and Human Anatomy at UC Davis who began this project at the University of Michigan. “They fail to bind to retinol, but they also plug up the receptor, binding 40 times more tightly than the unmutated protein. The mutants act like goalies, keeping retinol away from the receptors.”

Family  tree ‘invaluable’ to the research

The paper also highlights a unique collaboration between families, clinicians and researchers, according to Christine Nelson, a senior clinical author of the study and professor in the Department of Ophthalmology and Visual Sciences at the University of Michigan’s Kellogg Eye Center. The study arose from Nelson’s discovery that two of her young patients with similar eye malformations were related. The project gained momentum when the team received an unexpected “gift” from the family patriarch — an invaluable family tree that, together with old photographs, revealed a new type of inheritance.

“Some family members only took pictures from one side, or tilted their heads a certain way so they could see better,” Nelson said. “This visual evidence helped us identify eye defects in earlier generations.”

Tracking the path of vitamin A transport and eye defects

RBP4 is secreted by the liver and plays a critical role in eye development. Because retinol is not water-soluble, it needs a vehicle to carry it in the bloodstream to the STRA6 receptor. The transaction becomes even more intricate in utero, as the nutrient must be passed through the placenta from mother to baby.

This complicated transfer process plays a crucial role in how the defect is inherited from one generation to the next. The largest family in the study had endured eye issues for five generations. However, though the mutated gene is dominant, it only causes problems when passed through the mother, often skipping generations. One child inherited the gene through the father and exhibited the trait, but experienced only mild symptoms. The research team had inadvertently discovered a unique form of maternal inheritance.

“When the trait is inherited from the mother, there’s a problem transporting retinol from the mother’s liver to the placenta and from the placenta to the fetus,” said Glaser. “It’s a two-part process and the retinol has to be handed off, like a relay race, to cross between maternal and fetal circulation. When inherited from the father, only one leg of the journey is defective, allowing enough vitamin A to get through to prevent the birth defect.”

This unusual maternal inheritance pattern may have implications for other families experiencing congenital diseases. However, the research is already having profound implications for these particular families. In some cases, mothers and babies have both carried the mutation but experienced no ocular birth defects, showing the defective pathway can be circumvented.

Hope for preventing eye defects in families at risk

“While further clinical research is needed, it appears that we might be able to save a child from blindness with a simple and inexpensive treatment – an extra vitamin A pill,” Nelson said. “This supplementation relies on an alternate pathway, independent of RBP, that delivers another form of vitamin A, called retinyl ester, bypassing the mutations altogether.

Nelson suggests that women with this family history of eye malformations or those who learn that they carry the mutation consult with their obstetricians about taking vitamin A supplements during pregnancy. The discussion should begin before pregnancy since major steps in eye development take place in the first two months of gestation. Thus, a woman might not know she is pregnant when treatment is optimal.

“We’re lucky that nature has created this parallel pathway because vitamin A is so important to a developing fetus,” said Christopher Chou, the study’s first author and a resident physician in emergency medicine at the University of Michigan. “It’s not often you have a genetic defect on which you can directly intervene. This study illustrates how understanding one’s genetic make-up can add a personal touch to medical care.”

Next steps

The researchers still have much work to do. Glaser notes the team would like to map the entire genetic pathway associated with eye malformations. In addition, the study could help researchers investigate other genetic conditions.

“We need to look at genes governing vitamin A transport, as well as transport genes that affect the development of other organs,” Nelson said. “Also, there may be additional diseases that result from defective placental transport.”

Other authors of the research paper, entitled “Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease,” include: Susan A. Tarlé and Jonathan T. Pribila  (Univ. of Michigan Medical School); Tanya Bardakjian and Adele Schneider (Einstein Medical Center); and Sean Woods (UC Davis). The study was funded by grants from the NIH (EY19497), NIH T32 grants (GM07544 and HD07505), the Midwest Eye Bank and Transplantation Center and the UM Centers for Rare Disease and Genetics in Health and Medicine.

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Childhood syndrome combining lung disease, arthritis is ID’d

Discovery suggests mechanism, possible therapies for severe disorder.

By Pete Farley, UC San Francisco

Using the latest genome sequencing techniques, a research team led by scientists from UC San Francisco, Baylor College of Medicine and Texas Children’s Hospital has identified a new autoimmune syndrome characterized by a combination of severe lung disease and arthritis that currently has no therapy.

The hereditary disorder, which appears in early childhood, had never been diagnosed as a single syndrome. The new research revealed that it is caused by mutations in a single gene that disrupt how proteins are shuttled around within cells. Patients with the newly discovered syndrome have a poor prognosis, and at present can only be treated with anti-inflammatory and immunosuppressant drugs. Many have lung disease so severe that they must receive lung transplants.

Thanks to biological mechanisms revealed in the research, patients could soon have access to a wider range of therapies, according to Anthony K. Shum, M.D., UCSF assistant professor of medicine and co-senior author of the new study. “We believe that there are small molecules in development that can help correctly traffic the proteins that are misdirected in this syndrome, so that’s something we really want to go after.”

Levi B. Watkin, Ph.D., a postdoctoral fellow at Baylor; former UCSF postdoctoral fellow Birthe Jessen, Ph.D.; and Wojciech Wiszniewski, M.D., assistant professor of molecular and human genetics at Baylor, led the research, which is reported in the April online edition of Nature Genetics.

For Shum, the project was sparked when a woman was admitted to the Emergency Department at a California medical center with pulmonary hemorrhage. In the course of treating the patient, Shum learned that she had arthritis as well, and that a sibling and aunt also had both lung disease and arthritis.

Some time later, when Shum encountered the patient’s mother in the hospital’s corridor, she mentioned that a distant cousin she had never met had posted on a social media site that her own 2 1/2-year-old daughter was being treated at another hospital for pulmonary hemorrhage. Shum went to that hospital and found that, in addition to dramatic hemorrhaging in the child’s lungs, she too had arthritis.

With the help of UCSF medical students, Shum began searching for other affected family members and ultimately identified a distant relative in another state with the same syndrome. The group then sequenced DNA samples from nine family members, some with the syndrome and some who are unaffected, to search for mutations that might underlie the disorder.

“We sort of took a flyer,” Shum said. “The likelihood of finding something was low.”

UCSF scientists quickly zeroed in on a region of the genome containing a gene known as COPA, a result in which they initially had little confidence.

COPA mutations were completely unexpected,” Shum said. “The COPA protein is expressed throughout the body, and no diseases associated with this gene had ever been reported.” But an independent genetic analysis produced the same result: using this second method, Shum said, “You’ll usually see peaks spread across the genome, but we only got a single peak. It was highly significant, and COPA was right under it.”

The COPA protein is essential in intracellular transport – the process by which newly made proteins are moved to their proper locations in the cell – and the scientists found that the COPA mutations seen in the patients “cripple the protein,” said Shum, preventing it from performing this vital function.

Encouraged by the consistency and clarity of these results, Shum reached out to physicians at other institutions to see if they had seen patients with the same cluster of symptoms.

“By pure serendipity,” Shum said, he was soon contacted by co-senior author Jordan S. Orange, M.D., Ph.D., director of the Texas Children’s Hospital Center for Human Immunobiology, who had seen similar cases. Moreover, Orange’s colleague, sequencing expert James R. Lupski, M.D., Ph.D., co-senior author and Cullen Professor of Molecular and Human Genetics at Baylor, had independently fingered COPA mutations in his own genomic analyses of these cases.

Ultimately the UCSF-Baylor-Texas Children’s team identified five families in which 30 family members carried deleterious COPA mutations. Only 21 of those carriers were affected by lung and joint problems, suggesting that, although the disease is inherited, it has “incomplete penetrance” – the presence of COPA mutations does not solely determine that an individual will develop the syndrome.

“The fact that we discovered five unrelated families and over 20 affected individuals in just over two and half years of investigating this leads me to believe that this is by no means ultra-rare,” said Orange.

Subsequent experiments with tissue from affected patients revealed that faulty protein trafficking by mutant COPA results in a condition known as “cellular stress,” which in turn sets off an autoimmune reaction mediated by immune-system cells known at Th17 cells.

Because Th17 cells have already implicated in autoimmune diseases, particularly in rheumatoid arthritis, Shum believes that targeting these cells with drugs may provide a new therapeutic avenue for those with the syndrome.

“In our current research we’re making sure that we have a clear mechanism, so we can come up with a potential drug target,” he said.

Orange added that the new research may have ramifications that extend beyond this particular syndrome, especially for arthritis therapies.

“We are excited to learn how variants of this disease might be more broadly applicable and might be instructive to our overall understanding of arthritis,” he said.

In the meantime, Shum said, patients and their families have been gratified that the mysterious condition affecting their families is beginning to be understood.

“When I first contacted the families we located, it was a huge relief to them to know that there are other people like them and that someone is working on this disorder.”

The research was funded by the National Institutes of Health, The Jeffrey Modell Foundation, The Foundation of the American Thoracic Society, The Pulmonary Fibrosis Foundation, and The Nina Ireland Program for Lung Health at UCSF.

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A mother’s genes can influence the bacteria in her baby’s gut

Research may have applications for protecting preemies from range of intestinal diseases.

Zachary Lewis (left) and David Mills, UC Davis

By Phyllis Brown, UC Davis

Researchers at UC Davis have found that a gene, which is not active in some mothers, produces a breast milk sugar that influences the development of the community of gut bacteria in their infants. The sugars produced by these mothers, called “secretors,” are not digested by the infant, but instead nourish specific bacteria that colonize their babies’ guts soon after birth.

Mothers known as “non-secretors” have a non-functional fucosyltransferase 2 (FUT2) gene, which alters the composition of their breast milk sugars and changes how the microbial community, or microbiota, of their infants’ guts develop.

The research may have applications in a clinical setting for protecting premature infants from a range of intestinal diseases including necrotizing enterocolitis (NEC), a condition that is the second most common cause of death among premature infants in the United States.

The researchers emphasized that the finding does not suggest that breast milk from mothers without an active copy of the gene is less nourishing or healthy. Rather, it conveys the subtle and elegant choreography of one part of the human microbiome: The relationships between the mothers’ genetics, the composition of her breast milk and the development of their infants’ gut microbiota. It also reveals clues for enriching desirable bacteria in populations at risk of intestinal diseases — such as preemies.

“In no way is the nonsecretor mother’s milk less healthy, and their babies are at no greater risk,” said David Mills, Peter J. Shields Endowed Chair in Dairy Food Science at UC Davis and senior study author. “What this work does show us is that the mother’s genotype matters, and that it influences the breast milk, which clearly drives the establishment of microbes in the intestines of their babies.”

The research examining the differences in infant gut microbial populations arising from differences in human milk oligosaccharides (sugars), “Maternal Fucosyltransferase 2 Status Affects the Gut Bifidobacterial Communities of Breastfed Infants,” is published online today (April 9) in the journal Microbiome, a BioMedCentral journal.

Varieties of Bifidobacterium inhabit the gastrointestinal tracts and mouths of mammals and are one of the major genera of bacteria that make up the microbial community of the infant colon. The relationship between human genetics, breast milk and Bifidobacterium appears to have developed throughout mammalian evolution.

Development of a healthy gut microbiota can have a lifelong effect on health, and early intervention in the establishment of that microbiota could have lifelong positive effects: The early establishment of bifidobacteria has been shown to be associated with improved immune response to vaccines, development of the infants’ immature immune system, and protection against pathogens.

Bifidobacterium are known to consume the 2′-fucosylated glycans (sugars) found in the breast milk of women with the fucosyltransferase 2 mammary gene. The study found that, on average, Bifidobacterium were established earlier and more frequently in infants fed by women with an active copy of the gene, the secretors, than without one, the non-secretors.

The authors found that the intestinal tracts of infants fed by non-secretor mothers are delayed in establishing a bifidobacteria-dominated microbiota. The delay, the authors said, may be due to difficulties in the infant acquiring a species of bifidobacteria that is geared toward consuming the specific milk sugar delivered by the mother.

The research was conducted using milk samples from 44 mothers in the UC Davis Foods for Health Institute Lactation Study and fecal samples from their infants at four different time points. The researchers determined the secretor status of the mothers: 12 were non-secretor and 32 were secretor mothers. They also measured the amount and type of breast milk sugars and the amount of lactate (a beneficial molecule produced by bifidobacteria) in the infant’s feces.

The researchers determined that more infants fed by secretor mothers had high levels of bifidobacteria — 60 percent of infants versus 37.5 percent at day 6 and 80 percent versus 50 percent at day 120 –- and that infants who had more bifidobacteria had lower amounts of milk sugars left over and higher amounts of lactate in their feces.

One question that remains is whether this pattern holds true in infants living in other places.

“We are beginning to observe that infants from different parts of the world have different patterns of colonization by microbes,” said lead study author Zachary T. Lewis, a postdoctoral fellow.

“The types and levels of bacteria encountered by infants in developing countries is different from the types and levels of bacteria encountered by the babies in our UC Davis cohort, and that might account for some of the differences,” he said.

Maternal secretor status is likely only one of the many factors that influence the infant gut microbiota, Lewis said. The researchers will explore this question further in future studies.

The researchers said that understanding the mechanism behind the observed secretor/non-secretor differences may prove critical to compensating for it in situations where the infants are vulnerable, such as by providing carefully chosen pre- or probiotics. For example, prebiotics and probiotics frequently are given to premature infants  to protect them against NEC, which causes portions of the bowel to necrotize, or die.

“This work significantly advances our efforts to decipher how human milk amazingly orchestrates colonization of the infant gut by helpful bacteria, which then protects and guides intestinal development in the early stages of life. Understanding this incredible sequence of events will provide examples for how to repair this process where it has been disrupted, such as in premature infants or colicky babies,” Mills said.

Other study authors include Jennifer T. Smilowitz, Evan Parker, Danielle G. Lemay and Carlito Lebrilla, all of UC Davis; Sarah M. Totten of UC Davis and Stanford University: Mina Popovic of University of Moedna and Reggio Emilia, Italy; and Maxwell Van Tassel Michael J. Miller and Young-Su Jin of the University of Illinois Urbana-Champagne.

The research was supported by the University of California Discovery Grant Program, the UC Davis Research Investments in the Sciences and Engineering (RISE) Program, the California Dairy Research Foundation, the Bill and Melinda Gates Foundation, National Institutes of Health awards R01HD059127, R01HD065122, 8R01HD061923, R21AT006180, R01AT007079 and the Peter J. Shields Endowed Chair in Dairy Food Science.

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UC Davis leads $4M NIH grant to study skull disorder in infants

International team includes researchers from UC Irvine, UCSF.

Simeon Boyd, UC Davis

By Phyllis Brown, UC Davis

Simeon Boyd, UC Davis professor of genetics and pediatrics, has received a nearly $4 million, five-year grant from the National Institute of Dental and Craniofacial Research to lead a team of physicians and scientists from more than 10 centers in the United States and seven international sites, including Australia, Brazil, Bulgaria, Germany, Hungary, Italy and the United Kingdom, to study craniosynostosis, the premature fusion of the bony plates of the skull in infants.

The researchers are members of the International Craniosynostosis Consortium, whose goal is to identify the genetic and environmental causes of craniosynostosis, which affects approximately 1 in 2,500 newborns worldwide, in order to find clues to prevention, better treatments and, eventually, a cure.

“Our goal is not only to identify the genetic causes of all types of craniosynostosis, but also to facilitate the early detection of the condition, by identifying biomarkers. This may allow for nonsurgical therapeutic intervention in utero in the future,” said Boyd, who is a researcher affiliated with the UC Davis MIND Institute. The conditions also have neurodevelopmental consequences: Approximately 50 percent of patients with craniosynostosis also may have learning disabilities.

During fetal development, the skull is made up of separate bony plates that allow the child’s head to grow after birth. The borders between the plates do not normally fuse completely until a child is about 2, leaving temporary soft spots at the intersections of the seams of the skull.

In craniosynostosis the bones fuse early, causing the child to have an abnormally shaped head. The disorder can lead to complications due to brain compression, such as visual problems and learning disabilities.

“This is not only a skull disease,” Boyd said. “It is a perturbation of the brain and the skull, in which the growing brain is abnormal and causes increased distension of the envelope of the brain so that signaling molecules that normally would keep the sutures open do not function properly.”

Depending upon the severity of the condition, children born with craniosynostosis frequently may require extensive neurosurgical intervention to separate the fused bones of the skull so that the child’s brain can grow.

There are a number of different types of craniosynostosis, depending on which suture is prematurely fused. For example, when the sagittal suture at the top of the head is fused the condition is called in sagittal synostosis, also known as scaphocephaly. Sagittal synostosis is the most common form of the disorder. In coronal synostosis the coronal sutures, which run from the top of the head to the ears, are fused. Several named conditions, such as Muenke syndrome, have craniosynostosis among their symptoms.

In 2012, Boyd and his consortium colleagues published a landmark study in Nature Genetics, which found that two areas of the human genome are associated with a form of the disorder, sagittal craniosynostosis. Although the condition had long been believed to be partially determined by genes – it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than fraternal twins – the genes associated with the disorder had not been previously identified.

Identification of the genetic basis for the conditions is only a first step in preventive and therapeutic strategies, Boyd said.

“We want to prevent babies from being born with these disorders,” he said.

Consortium researchers from the United States include:

  • Jon Bernstein, Stanford University
  •  Michael Cunningham, University of Washington
  •  John Graham, Cedars-Sinai
  •  Virginia Kimonis, UC Irvine
  •  Ophir Klein, UC San Francisco
  •  Pedro Sanchez-Lara, Children’s Hospital Los Angeles
  •  Joan Richtsmeier, Pennsylvania State University
  •  Paul Romitti, University of Iowa
  •  Joan Stoler, Boston Children’s Hospital

International collaborators include:

  •  Andrew Wilkie, Oxford University, United Kingdom
  •  Wanda Lattanzi, Universita Cattolica del Sacro Cuore, Italy
  •  Tony Roscioli, University of Sydney, Australia
  •  Emil Simeonov and Radka Kaneva, Medical University, Sofia Bulgaria
  •  Bernd Wollnik, University of Cologne, Germany
  •  Eva Olah, University of Debrecen, Hungary
  •  Maria Rita Passos-Bueno, University of Sao Paolo, Brazil

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New genetic method promises to advance gene research, control insect pests

In two years, molecular biologists have witnessed a revolution in genome manipulation.

A rare fruit fly in which the left half has been mutated by MCR (hence the pale color) while the right half remains normal. (Photo by Valentino Gantz, UC San Diego)

By Kim McDonald, UC San Diego

Biologists at UC San Diego have developed a new method for generating mutations in both copies of a gene in a single generation that could rapidly accelerate genetic research on diverse species and provide scientists with a powerful new tool to control insect-borne diseases such as malaria as well as animal and plant pests.

Their achievement was published today (March 19) in an advance online paper in the journal Science. It was accomplished by two biologists at UC San Diego working on the fruit fly Drosophila melanogaster who employed a new genomic technology to change how mutations could spread through a population — a concept long established in plants by the father of modern genetics, Gregor Mendel.

“Mendel conducted classic genetic experiments with peas that revealed the fundamental of inheritance in many organisms including humans,” explains Ethan Bier, a professor of biology at UC San Diego whose graduate student, Valentino Gantz, developed the method.  “According to these simple rules of inheritance, the fertilized egg receives one copy of most genes from our mothers and one from our fathers so that the resulting individual has two copies of each gene.”

One advantage of having two copies of a gene is that if one copy carries a non-functional mutation, then the other “good” copy typically can provide sufficient activity to sustain normal function.  Thus, most mutations resulting in loss of gene function are known as recessive, meaning that an organism must inherit two mutant copies of the gene from its parents before an overt defect is observed, as is the case in humans with muscular dystrophy, cystic fibrosis or Tay Sachs disease.

“Because individuals carrying a single mutant copy of a gene often mate with an individual with two normal copies of gene, defects can be hidden for a generation and then show up in the grandchildren,” Bier adds. “This is how genetics has been understood for over a century in diverse organisms including humans, most animals we are familiar with, and many plants.”

But in the past two years, Bier and other molecular biologists have witnessed a veritable revolution in genome manipulation.

“It is now routine to generate virtually any change in the genome of an organism of choice at will,” he notes. “The technology is based on a bacterial anti-viral defense mechanism known as the Cas9/CRISPR system.”

By employing this development in their experiments with laboratory fruit flies, Gantz and Bier demonstrated that by arranging the standard components of this anti-viral defense system in a novel configuration, a mutation generated on one copy of a chromosome in fruit flies spreads automatically to the other chromosome. The end result, Bier says, is that both copies of a gene could be inactivated “in a single shot.”

The two biologists call their new genetic method the “mutagenic chain reaction,” or MCR.

“MCR is remarkably active in all cells of the body with one result being that such mutations are transmitted to offspring via the germline with 95 percent efficiency,” says Gantz, the first author of the paper. “Thus, nearly all gametes of an MCR individual carry the mutation in contrast to a typical mutant carrier in which only half of the reproductive cells are mutant.”

Bier says “there are several profound consequences of MCR. First, the ability to mutate both copies of a gene in a single generation should greatly accelerate genetic research in diverse species. For example, to generate mutations in two genes at once in an organism is typically time consuming, because it requires two generations, and involved, because it requires genetic testing to identify rare progeny carrying both mutations. Now, one should simply be able to cross individuals harboring two different MCR mutants to each other and all their direct progeny should be mutant for both genes.”

“MCR should also be highly effective for dispersing genetic elements in populations to control insect borne diseases such as malaria, dengue and chikungunya as well as animal and plant pests,” he adds. “For example, in the case of malaria, several groups have created genetic cassettes that when introduced into mosquitoes prevent the malarial parasite from propagating thereby blocking infection. A major challenge in the field, however, has been devising a way to disseminate these gene cassettes throughout mosquito populations. MCR offers an obvious solution to this problem since the incorporation of an anti-malarial gene cassette into an MCR element should result in the rapid spread of the gene cassette through the target population. For example, if one in 100 individuals initially carried the cassette, the cassette should spread to virtually all individuals in as few as 10 generations, which is less than one season for mosquitoes.”

It also may be possible to use MCR to spread genes among cells within an individual using modified viruses to carry the genetic elements, Gantz points out. “Since MCR works by targeting specific DNA sequences, in cases where diseased cells have altered DNA as in HIV-infected individuals or some types of cancer, MCR-based methods should be able to distinguish diseased from healthy cells and then be used to selectively either destroy or modify the diseased cells.”

The two biologists note in their paper that while applications of MCR offer potential solutions to important problems in health and human welfare, it could also pose serious potential risks in the wrong hands.

“Could an accidental release of MCR-bearing organisms into the environment result in their spreading potentially deleterious mutation to the vast majority of individuals in a wild population?” says Bier. “We don’t know and would advocate that scientists examine this possibility before permitting experiments using the new method to be used in open laboratories. It is also possible that MCR technology could be intentionally misused, which should be considered as a risk on par with that associated with nefarious uses of select agents.”

Gantz and Bier showed in their experiments, which were conducted in a biosafety laboratory with a high-level of containment to prevent the accidental release of any deleterious mutant genotypes, that propagation of an MCR mutation in flies is remarkably efficient, with a gene conversion rate of about 95 percent.

As a consequence, the two researchers say stringent safety protocols for handling MCR organisms and the prompt establishment of regulatory guidelines for performing experiments with such organisms are imperative. “Development of methods for reversing MCR spread would also provide a means for mitigating risk,” says Gantz.

Bier concurs with others who have raised serious concerns about strategies to disperse genetic elements in pest populations that one other step needs to be taken by scientists. “In an analogy to the famous Asilomar conference concerns held to address concerns raised at the dawn of recombinant DNA technology in the 1970s,” he says, “perhaps a similar meeting should be convened to discuss how MCR technology should be regulated at both federal and institutional levels to assure that it is employed safely to achieve its full potential to ameliorate the human condition.”

The study was funded by two grants (R01 GM067247 and R56 NS029870) from the National Institutes of Health and a generous gift from Sarah Sandell and Michael Marshall. The UC San Diego Technology Transfer Office has applied for a patent to license the new technology.

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New clues about risk of cancer from low-dose radiation

Berkeley Lab research could lead to ways to ID people particularly susceptible to cancer.

By Dan Krotz, Berkeley Lab

Scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have uncovered new clues about the risk of cancer from low-dose radiation, which in this research they define as equivalent to 100 millisieverts or roughly the dose received from ten full-body CT scans.

They studied mice and found their risk of mammary cancer from low-dose radiation depends a great deal on their genetic makeup. They also learned key details about how genes and the cells immediately surrounding a tumor (also called the tumor microenvironment) affect cancer risk.

In mice that are susceptible to mammary cancer from low-dose radiation, the scientists identified more than a dozen regions in their genomes that contribute to an individual’s sensitivity to low-dose radiation. These genome-environment interactions only become significantly pronounced when the mouse is challenged by low-dose radiation.

The interactions also have a big impact at the cellular level. They change how the tumor microenvironment responds to cancer. Some of these changes can increase the risk of cancer development, the scientists found.

They report their research March 9 in the journal Scientific Reports.

Because mice and humans share many genes, the research could shed light on the effects of low-dose radiation on people. The current model for predicting cancer risk from ionizing radiation holds that risk is directly proportional to dose. But there’s a growing understanding that this linear relationship may not be appropriate at lower doses, since both beneficial and detrimental effects have been reported.

“Our research reinforces this view. We found that cancer susceptibility is related to the complex interplay between exposure to low-dose radiation, an individual mouse’s genes, and their tumor microenvironment,” says Jian-Hua Mao of Berkeley Lab’s Life Sciences Division.

Mao led the research in close collaboration with fellow Life Science Division researchers Gary Karpen, Eleanor Blakely, Mina Bissell and Antoine Snijders, and Mary Helen Barcellos-Hoff of New York University School of Medicine.

The identification of these genetic risk factors could help scientists determine whether some people have a higher cancer risk after exposure to low-dose radiation. It could lead to genetic screening tests that identify people who may be better served by non-radiation therapies and imaging methods.

The scientists used a comprehensive systems biology approach to explore the relationship between genes, low-dose radiation, and cancer. To start, Mao and colleagues developed a genetically diverse mouse population that mimics the diversity of people. They crossed a mouse strain that is highly resistant to cancer with a strain that is highly susceptible. This yielded 350 genetically unique mice. Some were resistant to cancer, some were susceptible, and many were in between.

Next, Mao and colleagues developed a way to study how genes and the tumor microenvironment influence cancer development. They removed epithelial cells from the fourth mammary gland of each mouse, leaving behind the stromal tissue. Half of the mice were then exposed to a single, whole-body, low dose of radiation. They then implanted genetically identical epithelial cells, which were prone to cancer, into the fourth mammary glands that were previously cleared of their epithelial cells.

“We have genetically different mice, but we implanted the same epithelial cells into all of them,” says Mao. “This enabled us to study how genes and the tumor microenvironment — not the tumor itself — affect tumor growth.”

The scientists then tracked each mouse for 18 months. They monitored their tumor development, the function of their immune systems, and the production of cell-signaling proteins called cytokines. The researchers also removed cancerous tissue and examined it under a microscope.

They found that low-dose radiation didn’t change the risk of cancer in most mice. A small minority of mice was actually protected from cancer development by low-dose radiation. And a small minority became more susceptible.

In this latter group, they found thirteen gene-environment interactions, also called “genetic loci,” which contribute to the tumor susceptibility when the mouse is exposed to low-dose radiation. How exactly these genetic loci affect the tumor microenvironment and cancer development is not yet entirely understood.

“In mice that were susceptible to cancer, we found that their genes strongly regulate the contribution of the tumor microenvironment to cancer development following exposure to low-dose radiation,” says Mao.

“If we can identify similar genetic loci in people, and if we could find biomarkers for these gene-environment interactions, then perhaps we could develop a simple blood test that identifies people who are at high risk of cancer from low-dose radiation,” says Mao.

The research was supported by the Department of Energy’s Office of Science.

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New method devised to ID disease markers, step toward personalized medicine

UCLA research holds promise for treating many diseases.

By Stuart Wolpert, UCLA

UCLA life scientists have created an accurate new method to identify genetic markers for many diseases — a significant step toward a new era of personalized medicine, tailored to each person’s DNA and RNA.

The powerful method, called GIREMI (pronounced Gir-REMY), will help scientists to inexpensively identify RNA editing sites, genetic mutations and single nucleotide polymorphisms — tiny variations in a genetic sequence — and can be used to diagnose and predict the risk of a wide range of diseases from cancers to schizophrenia, said Xinshu (Grace) Xiao, senior author of the research and a UCLA associate professor of integrative biology and physiology in the UCLA College.

Details about GIREMI were published March 2 in the advance online edition of the journal Nature Methods. The research was funded by the National Institutes of Health and the National Science Foundation.

Xiao is making the software available on her website as a free download, enabling scientists worldwide to use this potent method in their own research on any number of diseases. President Obama’s budget encourages doctors to design individually tailored treatments based on genetic and molecular differences. This approach, which is called personalized medicine or precision medicine, holds the potential of “delivering the right treatment at the right time, every time, to the right person,” Obama said.

Genes contain RNA editing sites, which are not yet well understood, but appear to hold clues to many diseases. One might think that whatever is in the DNA we inherited from our parents would eventually be expressed in our proteins, but it turns out there is a modification process, called RNA editing, that can contribute to different types of cancer, autism, Alzheimer’s disease, Parkinson’s and many others, Xiao said.

RNA editing modifies nucleotides, whose patterns carry the data required for constructing proteins, which provide the components of cells and tissues — in our genetic material. If you had an “A” nucleotide in your DNA, for example, it may be modified into a “G.”

RNA editing is different from mutations. A mutation is written incorrectly in our genes. In RNA editing, our genetic material is normal, but modifications occur later when a gene is expressed.

GIREMI was researched and designed during the past two years by Xiao and Qing Zhang, a postdoctoral scholar in her laboratory. It is the most accurate and sensitive method for identifying RNA editing sites, as well as SNPs and mutations in RNA. Differentiating SNPs, most of which appear not to be harmful, from RNA editing sites has been very difficult and previously required sequencing a person’s entire genome.

“We can predict RNA editing sites and SNPs without sequencing the whole genome,” said Xiao, a member of UCLA’s Institute for Quantitative and Computational Biosciences, Molecular Biology Institute and also the Jonsson Comprehensive Cancer Center. “Now you don’t have to spend thousands of dollars sequencing the DNA; you can sequence only the RNA. Our method will be easily applicable to all the existing RNA data sets, and will help to identify SNPs and mutations at a large cost reduction from current methods.”

RNA editing is at an early stage. “We are trying to discover as many editing sites as possible,” said Xiao, whose research group is working to apply GIREMI to many diseases. “This method can be easily applied to any RNA sequencing data sets to discover new RNA editing sites that are specific to a certain disease.”

Many RNA editing sites are specific to the brain, Xiao and Zhang found, indicating RNA editing is involved in brain function and neurological disorders. There are more than 10,000 known RNA editing sites in the brain and probably many more, she said.

People have “abundant differences” in RNA editing sites. Studying 93 people whose RNA has been sequenced, Xiao and Zhang found that each person has unique RNA editing sites in their immune system’s lymphoblast cells, which are precursors of white blood cells that protect us from infectious diseases and foreign invaders.

RNA has been widely known as a cellular messenger that makes proteins and carries out DNA’s instructions to other parts of the cell, but is now understood to perform sophisticated chemical reactions and is believed to perform an extraordinary number of other functions, at least some of which are unknown.

Xiao’s research was funded by NIH grants R01HG006264 and U01HG007013, and NSF grant 1262134.

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High school students help grow ‘genetically engineered machine’

UCSF researchers help high school students dive into growing field of synthetic biology.

In addition to their prize-winning science project, the 2014 UCSF iGEM team morphed into superheroes as a creative way to teach synthetic biology to visitors at The Exploratorium.

By Kathleen Masterson, UC San Francisco

Taking molecular parts from living organisms to engineer biological systems sounds a bit like science fiction, but with the help of UCSF researchers, high school students are diving into this growing field of synthetic biology.

It’s all part of a global synthetic biology competition called iGEM.

The international competition aims to engage students in the constantly evolving world of synthetic biology, which is part molecular biology, part systems biology and part genetic engineering. While the “Giant Jamboree” is a fun, lively event, the lab work and presentation preparation are serious work – and real science findings come out of the competition.

This year UCSF’s team won “Best Presentation,” competing against 225 teams hailing from across the globe. Of the two UCSF presenters, one was Eleanor Amidei, who was 17 years old at the time.

To prepare for the competition, the students spend all summer designing their experiments, running them, building a website, developing a presentation and a few other requirements, including submitting a genetic fragment to the synthetic biology bank at MIT.

“At first it was really overwhelming,” said Amidei, who is now a freshmen at UC Berkeley. “It was just scary to be thrown into lab environment. But you kind of just pick up the work as you’re going; you go with it, you read articles, you study more about what you’re doing and it becomes easy, it becomes second nature.”

Bringing high schoolers into the lab

When Wendell Lim, Ph.D., formed the first UCSF team eight years ago, he needed to include participants younger than graduate students to meet the iGEM contest eligibility requirement. Instead of bringing in college students, he partnered with high school teacher George Cachianes who teaches a two-year biotechnology program at Lincoln High School in San Francisco. Every year, a few of the top high school students are invited to join the iGEM team.

This year’s team also partnered with two UC Berkeley undergrads who bring additional programming and graphic design elements to the team skill set.

Lim said the experience benefits both the high school students and the Ph.D. students, who learn to be better mentors.

“What is really unique about this experience is that most of the time, when you do an internship in a lab, you’re assigned to one person who tells you what to do, who gives you instructions,” he said.

But here the group is really a team, said Lim. There’s a lot of brainstorming, and the students, few undergrads, postdocs, all really work together to shape the project. “We’ve defined the sandbox we’ll play in, but exactly what we do and how we do it – they’re a part of defining.”

Real science findings

This year the “sandbox” focused on testing yeast cells to determine if they exhibit collective behavior. That’s a loose term for the “group think” behavior exhibited by seemingly choreographed flocks of birds or tightly synchronized schools of fish swirling in a flash. This kind of group response also occurs in some cells and even electrons – and in tiny yeast cells.

The team discovered that the presence of the group actually influences the behavior of the yeast cells. Though the cells are genetically the same, they respond differently when isolated and respond in synchronized manner when together as a group.

This behavior hadn’t been shown in yeast, said Kara Helmke, the education and outreach coordinator for UCSF’s Center for Systems and Synthetic Biology who works with the iGEM teams.

“The findings were something we didn’t even realize would be possible,” Helmke said. “It was great we could demonstrate it.”

Beyond getting results in the lab, the UCSF team is producing new scientists: Of the more than 60 high school alumni of the program, all are pursuing or have completed science degrees.

“Biotechnology is really a unique aspect of San Francisco and important part of the economy, and it’s exciting to help train the next generation of people,” said Helmke.

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Brain region vulnerable to aging is larger in those with longevity gene variant

1 in 5 carry KLOTHO allele associated with better cognition.

The dorsolateral prefrontal cortex, depicted in blue and red, is larger and linked with better function in those who carry one copy of the KLOTHO gene variant. (Illustration by Michael Griffin Kelly)

By Laura Kurtzman, UC San Francisco

People who carry a variant of a gene that is associated with longevity also have larger volumes in a front part of the brain involved in planning and decision-making, according to researchers at UC San Francisco.

The finding bolsters their previous discovery that middle-aged and older people who carry a single copy of the KLOTHO allele, called KL-VS, performed better on a wide range of cognitive tests. When they modeled KL-VS in mice, they found this strengthened the connections between neurons and enhanced learning and memory.

KLOTHO codes for a protein, called klotho, which is produced in the kidney and brain and regulates many different processes in the body. About 1 in 5 people carry a single copy of KL-VS, which increases klotho levels and is associated with a longer lifespan and better heart and kidney function. A small minority, about 3 percent, carries two copies, which is associated with a shorter lifespan.

Examining part of prefrontal cortex

In the current study, published today (Jan. 27), in Annals of Clinical and Translational Neurology, researchers scanned the brains of 422 cognitively normal men and women aged 53 and older to see if the size of any brain area correlated with carrying one, two or no copies of the allele.

They found that the KLOTHO gene variant predicted the size of a region called the right dorsolateral prefrontal cortex (rDLPFC), which is especially vulnerable to atrophy as people age. Deterioration in this area may be one reason why older people have difficulty suppressing distracting information and doing more than one thing at a time.

Researchers found that the rDLPFC shrank with age in all three groups, but those with one copy of KL-VS – about a quarter of the study group – had larger volumes than either non-carriers or those with two copies. Researchers also found that the size of the rDLPFC predicted how well the three groups performed on cognitive tests, such as working memory – the ability to keep a small amount of newly acquired information in mind – and processing speed. Both tests are considered to be good measures of the planning and decision-making functions that the rDLPFC controls.

“We’ve known for a long time that people lose cognitive abilities as they age, but now we’re beginning to understand that factors like klotho can give people a boost and confer resilience in aging,” said senior author Dena Dubal, M.D., Ph.D., assistant professor of neurology at UCSF and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease. “Genetic variation in KLOTHO could help us predict brain health and find ways to protect people from the devastating diseases that happen to us as we grow old, like Alzheimer’s and other dementias.”

Bigger size means better function

In statistical tests, the researchers concluded that the larger rDLPFC volumes seen in single copy KL-VS carriers accounted for just 12 percent of the overall effect that the variant had on the abilities tested.

However, the allele may have other effects on the brain, such as increasing levels or changing the actions of the klotho protein to enhance synaptic plasticity, or the connections between neurons. In a previous experiment, they found that raising klotho in mice increased the action of a cell receptor critical to forming memories.

“The brain region enhanced by genetic variation in KLOTHO is vulnerable in aging and several psychiatric and neurologic diseases including schizophrenia, depression, substance abuse and frontotemporal dementia,” said Jennifer Yokoyama, Ph.D., first author and assistant professor of neurology at UCSF. “In this case, bigger size means better function. It will be important to determine whether the structural boost associated with carrying one copy of KL-VS can offset the cognitive deficits caused by disease.”

Other authors of the study include Virginia Sturm, Luke Bonham, Joel Kramer and Bruce Miller of UCSF; Eric Klein and Giovanni Coppola of UCLA; Lei Yu and David Bennett of Rush University Medical Center; and Konstantinos Arfanakis of Rush and the Illinois Institute of Technology.

The study was funded by the Larry L. Hillblom Foundation, the National Institute on Aging, the American Federation for Aging Research, the Coulter-Weeks Foundation and the Bakar Foundation.

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