A University of Iowa biologist and researcher in the Department of Biology and Roy J. Carver Center for Genomics, along with colleagues at Harvard and in the Carver Center for Genomics, describes a new and more effective way of identifying where important RNA transcripts are located in the human genome in a paper published in the June 28 online issue of the journal Nature Genetics.

The studies helped demonstrate that mutations that cause colorectal cancer were not altering the expression of novel RNA transcripts on a region of the 8th chromosome and helped show that the mutations were likely altering regulatory regions of a known cancer gene, referred to as c-Myc.

John Manak, assistant professor of biology in the UI College of Liberal Arts and Sciences, said that the new technique should help researchers to discover new genes as well as new RNA transcript isoforms for any organism, including humans, with much greater precision and with less worry of identifying false positives. Manak worked with another Iowa colleague, Harsha Doddapaneni, to employ the methodology.

"This methodology sorts through complex data generated from a genomics platform called a tiling microarray and allows researchers to get to the real genes associated with disease much faster than previously possible," said Manak. “Imagine a gumball in a jar of marbles. If you are able to identify the gumball with a high degree of accuracy, you won’t wind up with a mouthful of broken teeth. You want to get to the relevant stuff and leave the rest behind.”

"The technique changes the way of analyzing this type of genomic data. In the past, this technique was prone to erroneously identifying new transcripts and genes due to the fact that the technique did not have the proper internal controls. The old way of doing it provided evidence for RNA transcripts that really weren’t there at all. Using our new method, researchers can now subtract artifacts, or false data, from their results and they will have the real data," he said.

Manak’s collaborators at Harvard University found that an inherited variant located on a particular region of the 8th chromosome of the human genome (8q24) has a significant association with colorectal cancer. Manak and his fellow researchers found that the region containing the variant is not transcribed but is actually a “transcriptional enhancer” of the known cancer gene c-myc (enhancers are short regions of DNA that regulate transcription, which, in turn, is defined as the synthesis of RNA from a DNA template). That information and other data provide strong support for c-Myc being the causative gene for this type of colorectal cancer.

"Years of work are now called into question," Manak said. "Basically, any transcriptional data generated with tiling arrays, especially studies that propose large amounts of novel transcription, must be re-examined. With this new technique, we force researchers to carefully re-evaluate their old data."

STORY SOURCE: University of Iowa News Services, 300 Plaza Centre One, Suite 371, Iowa City, Iowa 52242-2500
MEDIA CONTACT: Gary Galluzzo, writer, 319-384-0009, gary-galluzzo@uiowa.edu

A University of Iowa-led international research team has found a new gene associated with the brain disorder epilepsy. While the PRICKLE1 gene mutation was specific to a rare form of epilepsy, the study results could help lead to new ideas for overall epilepsy treatment. The findings, which involved nearly two dozen institutions from six different countries, appear in the Nov. 7 issue of the American Journal of Human Genetics.

In epilepsy, nerve cells in the brain signal abnormally and cause repeated seizures that can include strange sensations, severe muscle spasms and loss of consciousness. The seizures may not have lasting effects but can affect activities, such as limiting a person's ability to drive. Most seizures do not cause brain damage but some types of epilepsy lead to physical disabilities and cognitive problems. Medications can control symptoms, but there is no cure.

"The study results were surprising not only because the PRICKLE1 gene had never been associated with epilepsy but also because the gene was not associated with any other human disease," said the study's lead author Alex Bassuk, M.D., Ph.D., assistant professor of pediatrics at the UI Roy J. and Lucille A. Carver College of Medicine and a pediatric neurologist with UI Children's Hospital.

The nine families involved in the study all lived in the Middle East and came from one of three family lines. Of the 47 individuals in the three family lines, 23 had a form of progressive myoclonus epilepsy accompanied by ataxia -- a condition that causes imbalance. One family line has been extensively described by Hatem El-Shanti, M.D., a UI adjunct professor of pediatrics who now leads genetics research for the country of Qatar. The two other family lines had been researched by Sam Berkovic, M.D., at the University of Melbourne in Australia.

"By sharing and analyzing data sets, we realized there was a common mutation in the PRICKLE1 gene in the family members with this form of epilepsy," Bassuk said.

To verify that the mutation might be related to the epilepsy, the team needed to test it in an animal model. This next step to find a suitable animal model involved a surprising coincidence: Bassuk, who had only recently joined the UI, realized through online research that the PRICKLE1 gene in zebrafish had been previously identified by another UI researcher, Diane Slusarki, Ph.D., associate professor of biology in the UI College of Liberal Arts and Sciences.

"I walked across the river to Diane's side of campus, and we designed an experiment to test the human mutation in the zebrafish," Bassuk said. It was 'Iowa luck.'"

Slusarki and Bassuk's collaboration revealed that the mutated PRICKLE1 gene does not behave normally in zebrafish. Bassuk noted that collaboration, whether on-campus or international, was essential to the success of the research study.

"We never could have done, or could continue to do this type of research, with just one person thinking about it," he said. "From the clinicians who found and took histories on the study participants, to antibody testing at Stanford University to DNA shared from colleagues in Japan, the study required a lot of collaboration and coordination. And of course, we greatly appreciated the participation of the Mideastern families."

Bassuk, and colleagues are now developing other animal models to investigate how PRICKLE1 gene is involved in epilepsy, and are investigating whether PRICKLE1 mutations are involved in the general population of patients with epilepsy. With that information, there is potential to develop new drugs for people with different forms of epilepsy in the general population, as well as for the study participants with the disease.

This study was supported in part by funding from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, the NIH National Center for Research Resources, and the Howard Hughes Medical Institute.

STORY SOURCE: University of Iowa Health Science Relations, 5137 Westlawn, Iowa City, Iowa 5224-1178
MEDIA CONTACT: Becky Soglin, 319 335-6660 becky-soglin@uiowa.edu

Image: "PRICKLE1 gene expression appears in green in human brain cells, with neurons appearing in red and nuclei in blue. Mutated PRICKLE1 gene has been implicated as a cause of a certain form of epilepsy."

Image Credit: American Journal of Human Genetics, Vol. 83, Issue 5, Bassuk et al., Figure 3e from "Homozygous Mutation in Human PRICKLE1 Causes an Autosomal-Recessive Progressive Myoclonus Epilepsy-Ataxia Syndrome," 572-581, Copyright Elsevier, Nov. 7, 2008.

John Manak, assistant professor of biology in the UI College of Liberal Arts and Sciences and researcher in the Roy J. Carver Center for Comparative Genomics, published his research in the Sept. 4 online edition of the journal Public Library of Science-Genetics. He and his collaborators found that a class of DNA bound proteins normally thought to be involved in the repression of genes is also bound to active genes.

By looking at the whole organism as well as in a particular tissue, they were able to hone in on specific functions of these proteins. Since members of this class of proteins have been shown to produce cancers when altered, these data show that linkages between the genes of drosophila (fruit fly) and humans are gradually becoming clearer, bringing scientists closer to the goal of one day understanding the genetic causes of various cancers and other diseases in man.

"I use the drosophila homologues of human genes to help understand how the human genes function," Manak said. "I tease out how the products of these genes function normally. Then I try to understand how the processes they are involved in go awry when the genes are mutated.

"My lab uses a methodology I developed in fruit flies to map mutations to the genes they affect in humans. I am using this strategy to try to identify hard-to-find mutations in a variety of human diseases and disorders," he said.

Manak noted that at least 60 percent of the genes involved in human disease and cancer are conserved in flies. The genes he is studying encode proteins that bind to DNA or chromatin in the cell nucleus. He and his colleagues hope to determine where and how these proteins bind across the entire fly genome, and how these proteins act to assemble the basic building blocks of chromatin.

He said that because several of these proteins are homologous to both tumor suppressor and tumor promoting proteins in humans, the ultimate goal will be to determine not only how these proteins function in the context of normal cell growth, but also how the loss or alteration of these proteins can lead to cancer.

His co-authors include: Camilla Kwong, Lisa Meadows, Steven Russell and Rob White of the University of Cambridge; Ian Bell of Affymetrix Inc.; and researcher Boris Adryan.

STORY SOURCE: University of Iowa News Services, 300 Plaza Centre One, Suite 371, Iowa City, Iowa 52242-2500
MEDIA CONTACT: Gary Galluzzo, 319-384-0009, gary-galluzzo@uiowa.edu

Professor Jonathan Poulton of the Department of Biology has been named an "Outstanding Honors Teacher" for 2007-2008 . Professor Poulton was chosen by the students of the University Honors Program for this award. The award is in recognition of Professor Poulton's tireless efforts on behalf of the honors students, the Department of Biology and the College of Liberal Arts and Sciences to assist and teach honors students, keep them on track for graduation and problem solve if necessary.

What can a tiny marine alga that resembles a little brown ball tell scientists about how different types of organisms are related on the family tree of all life on Earth?

Quite a bit, it turns out, when it stands at a critical junction where one form of life can provide a clear evolutionary connection between otherwise distant cousins, according to John Logsdon (left), associate professor of biology in the University of Iowa College of Liberal Arts and Sciences.

In the Feb. 21 issue of the journal Nature, Logsdon and his colleagues announced the discovery of a new type of eukaryotic algae that provides just such a bridge between two previously thought-to-be separate branches on the tree of life. Called Chromera velia, the organism is now the closest-known photosynthetic relative to apicomplexan parasites (like the malaria parasite, Plasmodium falciparum) -- much closer than their distant algal relatives called dinoflagellates (some of which cause harmful "red-tides"). Together, these unicellular organisms, along with ciliates (like Paramecium), are called "alveolates."

Logsdon said the find sheds light on a formerly dark corner of the evolution of photosynthesis and indicates that further, similar discoveries lie ahead. Also, this new organism will be a powerful model for studying parasitism and disease in Apicomplexa. "Chromera opens new chapters in the evolutionary history of eukaryotic cells and will provide important clues to understand the biology of apicomplexan parasites and how they have evolved. In turn, this basic knowledge will be crucial in developing new therapeutics for the treatment of widespread diseases such as malaria and toxoplasmosis," said Logsdon.

Logsdon, who also directs the UI Roy J. Carver Center for Comparative Genomics, said the discovery is one more piece of a larger puzzle that seeks to fill in the picture of how all life on earth is interrelated. He currently serves with UI biology professor Debashish Bhattacharya as co-principal investigator on a $1.6 million National Science Foundation (NSF) project "Assembling the Tree of Eukaryotic Diversity" that seeks to decipher the evolutionary relationships primarily among microbial eukaryotes. The collaborative project is part of a larger NSF-funded effort to construct a comprehensive family tree of life on Earth called "Assembling the Tree of Life."

Logsdon noted: "it's not often that we find an organism that fits on the tree of life as a major "missing link" of sorts. Quite often we are looking at relatives that, while sharing a clear common ancestor, have diverged into separate, distinct lineages. This was previously the case for Apicomplexa, which derive from photosynthetic ancestors, but are very distant from their formerly closest photosynthetic cousins, the dinoflagellates. Our study provides a clear demonstration that there is much left to discover and learn about the diversity of life on earth, especially in the microscopic world."

Logsdon's colleagues on the project include lead authors Robert B. Moore of the University of Sydney, Australia, where he did the initial work with senior author Dee A. Carter; and Miroslav Obornik of the Biology Center of the Academy of Sciences and the University of South Bohemia, Czech Republic. Moore is formerly of the UI Roy J. Carver Center for Comparative Genomics where he worked on this project in Logsdon's laboratory.

STORY SOURCE: University of Iowa News Services, 300 Plaza Centre One, Suite 371, Iowa City, Iowa 52242-2500.
MEDIA CONTACT: Gary Galluzzo, 319-384-0009, gary-galluzzo@uiowa.edu

Professor Joseph Frankel was chosen by a College of Liberal Arts and Sciences Teaching Awards Committee to receive a 2008 Collegiate Teaching Award. This award recognizes Professor Frankel's exemplary performance as a teacher and reflects the high esteem with which colleagues and students regard the quality of his teaching. Professor Frankel has been director of undergraduate studies in the Biology department since 1999, where he has had a major role in the design of the curriculum and tracks within the major. He directs and teaches the General Education course Principles of Biology II. Colleagues praise him for his insightful analysis of how students learn science - through principles and concepts, stories about these concepts, and hypothesis testing. Students praise his energy, enthusiasm about Biology, attentiveness to their learning, and accessibility. A developmental biologist with a highly productive research record, he also teaches advanced undergraduate courses in cell and developmental biology. The College of Liberal Arts and Sciences will recognize the award at the annual Faculty Honors Celebration this spring and at the 2008 University of Iowa convocation. Congratulations Professor Frankel!

This semester, The Department of Biology added a new Neurobiology teaching lab in the Biology Building. The lab is being team taught by Associate Professors Mike Dailey and Alan Kay and is an upper level biology course which requires the consent of the instructor to register. The course will give students a “hands on” laboratory experience focusing on Neurobiology. The main focus of the lab is to develop fundamental technical skills necessary for success in biomedical and health related careers, and to provide specific training in the principles and practices of modern neurobiological and neurophysiological research. Included in the lab are computer-based simulations, electrophysiology, cell and tissue culture, and microscopy and digital imaging to explore nervous system structure and function in diverse invertebrate and vertebrate organisms. The state-of-the-art lab includes computer monitors to allow the professor to demonstrate a technique while students watch at each lab station. Students will be assisted in the labs by Teaching Assistants and a course lab coordinator.

The Department of Biology has completed the search for a new DEO! Bernd Fritzsch will join us in July 2008 to begin leading the department. We are looking forward to his leadership and vision. Dr. Fritzsch is currently a Professor, Director for Basic Research and former Assistant Dean for Research at Creighton University in Omaha, Nebraska. He is known to his colleagues as an energetic leader, a great mentor, and a scholar. He is passionate about science and experimental discovery. He also works well with a variety of people and is known as being a perceptive and a very effective leader. His contributions to understanding of the sensory system and development of the auditory/vestibular system are well known. He describes himself as a molecular developmental neurobiologist with a strong interest in the evolution and development of the ear and the application of research insights toward curing specific aspects of hearing loss: molecular rescue of sensory neurons and restoration of the hearing organ, the organ of Corti. We are really looking forward to his leadership and the contributions he will make to our department! Welcome Dr. Fritzsch!

Professor Robert Malone in the Dept. of Biology at the University of Iowa has received a $450,000, 3 year grant from the National Science Foundation. This grant focuses on the behavior of chromosomes during the biological process called meiosis, those special cell divisions which occur during the formation of gametes (e.g., sperm or eggs). This unique process is highly conserved and the events which occur are very similar in organisms varying from maize to man to simple single cells like yeast. The work investigates a new mechanism by which two steps of chromosome behavior unique to meiosis are coordinated and regulated so that they both occur at the proper time to insure the proper number of chromosomes in each gamete.

Three University of Iowa biologists are among some 100 scientists who contributed to a study, published in the Nov. 8 issue of the Journal Nature, that is one of the most comprehensive genomic studies of its kind and will greatly aid scientists conducting basic research in disease, genetics and many other fields. The study involved a comparative analysis of the genomes of 12 species of Drosophila (fruit flies) and illustrated how the rates and patterns of genetic change can vary significantly among closely related species, thereby indicating mechanisms of evolutionary change, according to assistant professors Bryant McAllister and Josep Comeron and assistant research scientist Ana Llopart, all in the UI College of Liberal Arts and Sciences' Department of Biological Sciences. "The study's genome sequences will add to the formidable genetic tools that have made the fruit fly a pre-eminent model for animal genetics and help drive fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behavior, physiology, and evolution," McAllister said. "The Drosophila species chosen for sequencing represent a small subset of the diversity among flies, yet we identified many genetic changes that may underlie differences in the ecology and behavior of the various species." Said Comeron, "This paper summarizes years of collaborative work among many laboratories interested in understanding how genes and genomes evolve. The analysis of complete genomes of 12 related species of fruit flies allows us to investigate a wide variety of evolutionary processes with an unprecedented level of detail. Ultimately, these '12 genomes' will provide an exceptional insight into the relative contribution of natural selection on protein evolution, gene gain/loss, the evolution of 'junk' DNA, etc." Of the 12 Drosophila species involved in the study, the genomes of 10 were presented for the first time, perhaps reflective of the fact that the study represents a four-year effort of so many individuals. "Although the actual sequencing of these 10 genomes took less than one year thanks to modern DNA sequencing technologies, three additional years were required to give meaning to this massive amount of genetic information through the development of new analytical and theoretical tools," Llopart said. "Future studies involving non-Drosophila genomes will benefit from having these new tools." In their paper, the researchers note that the study has provided a powerful means for answering questions -- not only about evolution, but also about the function of Drosophila genome features -- and that it has raised more questions than it has answered. "Because much of this rich and extraordinary comparative genomic dataset remains to be explored, we believe that these 12 Drosophila genome sequences will serve as a powerful tool for gleaning further insight into genetic, developmental, regulatory and evolutionary processes," they conclude. The complete Nature article, "Evolution of genes and genomes on the Drosophila phylogeny," can be found at http://www.nature.com/nature/journal/v450/n7167/full/nature06341.html

STORY SOURCE: University of Iowa News Services, 300 Plaza Centre One, Suite371, Iowa City, Iowa 52242-2500
MEDIA CONTACT: Josep Comeron, Department of Biology, 319-335-0628, josep-comeron@uiowa.edu; Bryant McAllister, Department of Biology, 319-335-2604, bryant-mcallister@uiowa.edu; Gary Galluzzo, University News Services, 319-384-0009, gary-galluzzo@uiowa.edu

A University of Iowa biologist has received a five-year, $1.47 million grant from the National Institute of Neurological Disorders and Stroke, a part of the National Institutes of Health (NIH), to study how neurons in the brain are wired together. Joshua Weiner, assistant professor and Presidential Biological Scholar in the UI College of Liberal Arts and Science Department of Biological Sciences, says he will use the grant to study defects in nerve cell connecting points, called synapses, that are believed to underlie a wide range of debilitating neurological and psychiatric disorders, including autism, Alzheimer's disease, mental retardation, and schizophrenia. "What my lab would really like to understand is how, during brain development, nerve cells, called neurons, establish connections with each other," he says. "In particular, we're fascinated by the exquisite specificity with which these cells form synapses. Neurons 'know' how to wire up with each other in the correct patterns needed for the brain to process information." He adds that researchers have long understood that proteins on the surface of neurons act as a kind of "molecular Velcro" to hold synapses together. He notes also that a particular family of proteins, called gamma-protocadherin, is a great candidate for mediating such synaptic adhesion in a specific way because the proteins are so diverse, with different neurons having various arrangements of some 22 proteins. "We had already shown that gamma-protocadherins are critical for the development of the nervous system," he says. "In our new, NIH-funded work, we will determine their function in a number of identified circuits, which will help us get a handle on their possible role in synaptic specificity." His UI colleagues on the project are: Andrew Garrett, neuroscience doctoral student; Tuhina Prasad, biology doctoral student; and Leah Fuller, research assistant. Weiner, who received his doctorate from the University of California in 1999 and joined the UI faculty in 2004, says he hopes that their work will advance public health by contributing to the basic science foundation needed for the development of new therapeutic approaches to neurological and psychiatric disorders.

STORY SOURCE: University of Iowa News Services, 300 Plaza Centre One, Suite 371, Iowa City, Iowa 52242-2500
MEDIA CONTACTS: Joshua Weiner, assistant professor of biological sciences, 319-335-0091, joshua-weiner@uiowa.edu; Gary Galluzzo, University News Services, 319-384-0009, gary-galluzzo@uiowa.edu

Is a particular type of microscopic animal -- one thought to have reproduced asexually for at least 35-40 million years -- actually capable of having sex? A University of Iowa biologist hopes that his answer to that question will help solve a long-standing mystery in evolutionary biology: Why do organisms reproduce by means of sex at all? John Logsdon, associate professor in the UI College of Liberal Arts and Sciences Department of Biological Sciences and director of the Roy J. Carver Center for Comparative Genomics, has received a five-year, $1,128,500 research grant from the National Institutes of Health (NIH) to study sex and meiosis in asexual rotifers.