CARNEGIE MELLON UNIVERSITY RESEARCH REVEALS HOW CELLS PROCESS LARGE GENES

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CARNEGIE MELLON UNIVERSITY RESEARCH REVEALS HOW CELLS PROCESS LARGE GENES
02 August 2006 - Carnegie Mellon Universtity

Important messages require accurate transmission. Big genes are especially challenging because they combine many coding segments (exons) that lie between long stretches of noncoding elements (introns). During processing, introns are snipped out and exons pasted together to form a template for proteins called messenger RNA.

Mistakes in RNA processing can reduce the expression of a functional protein or, worse, produce an abnormal protein that interferes with normal cell behavior. But just how a cell's molecular machinery eliminates long introns without making errors has puzzled scientists for years.

Now, investigators at Carnegie Mellon University have discovered that a novel mechanism, called recursive splicing, removes long introns by steadily paring them down in a predictable fashion and joining the remaining exons. The findings are published this summer in Genetics. This process, which the investigators discovered in the fruit fly Drosophila, has been conserved over tens of millions of years of insect evolution and also appears likely to occur in humans, according to the investigators.

"While some scientists have suspected that large introns might not be removed in one piece through direct splicing, no one had identified how this could happen. Now we have identified a way," said Antonio-Javier Lopez, professor of biological sciences at Carnegie Mellon. Ultimately, recursive splicing could be responsible for thwarting molecular mishaps in the expression of large human genes associated with diseases like muscular dystrophy, cystic fibrosis and cancer.

"We found that many large introns are removed by multiple recursive splicing steps," Lopez said. "These steps involve the sequential excision of smaller subfragments. Our work also indicates that most recursive splicing events leave no clues in the final mRNA. This is why they have not been detected before now."

These previously undetected events could have profound implications for predicting what constitutes a gene and for studying gene expression, mutation and evolution, according to Lopez.

For example, recursive splicing must now be taken into account when evaluating mutations that disrupt gene expression and produce a dysfunctional or non-functional protein.

"Current data indicate that at least 15 percent of disease-causing mutations occur at standard signals where intron removal takes place through direct splicing. Mutations at recursive splice sites may cause additional diseases, but until now we haven't looked for them."

Knowledge of recursive splicing also will help investigators predict structures of genes that span large intervals of DNA, Lopez said.

Recursive splicing relies on the unusual activity of a ratchetting point, a pattern of chemical groups (nucleotides) previously discovered within the genome by Lopez. One end of a ratchetting point contains a sequence of nucleotides similar to the signal normally found at the beginning of an intron. This signal is juxtaposed with another sequence like that normally found at the end of an intron. Such a unique pairing allows a ratchetting point to function sequentially as an acceptor for splicing to an upstream exon and then as a donor for splicing to the next downstream ratchetting point or exon. As the process goes from ratchetting point to ratchetting point, small signature loops of RNA called lariats are released from the intron. Repeated over and over, recursive splicing eventually binds, or ligates, two distant exons.

Lopez's team developed molecular tools to analyze the lariats released from any intron during splicing in vivo. In his analyses, he found that the production of recursive lariats greatly exceeded that of direct lariats, indicating that recursive splicing is the predominant processing pathway for long introns. Lopez combined these experimental data with computational and phylogenetic analyses of several fruitfly and other insect species.

"Our experimental results agreed with the computational findings, indicating that these ratchetting points mediate the removal of intron subfragments in one direction as the gene is transcribed initially from DNA into RNA," Lopez said.

Lopez found that predicted recursive splice sites were 10 times more likely than expected to be found in introns greater than 200 kilobases in length, and 92 percent of them were conserved over at least 25 million years of insect evolution. This discovery strongly suggests that recursive splicing plays a special role in the correct expression of large genes. Bioinformatic and phylogenetic analyses conducted by Lopez also indicate that recursive splicing plays a role in at least 124 fruitfly introns, with up to seven potential cutting steps identified for a single intron. Similar analyses suggest that the same process also occurs in large introns of mammals, including humans, and the Lopez team is now testing this hypothesis experimentally.

http://www.cmu.edu

About: Carnegie Mellon Universtity
The Carnegie Institution of Washington (www.carnegieinstitution.org) has been a pioneering force in basic scientific research since 1902. It is a private, nonprofit organization with six research departments throughout the U.S. Carnegie scientists are leaders in plant biology, developmental biology, astronomy, materials science, global ecology, and Earth and planetary science.

Since its founding in 1900 by industrialist and philanthropist Andrew Carnegie, Carnegie Mellon University has been a pragmatic institution, adapting rapidly to change. In fewer than 100 years it has changed its name three times--each transition marking a milestone in the institution's 20th century evolution.

Whether it was Carnegie Technical Schools, as it was in its first 12 years, Carnegie Institute of Technology, its name from 1912 to 1967, or Carnegie Mellon University, three primary purposes formed its foundation. Throughout this century, Carnegie Mellon has focused on delivering distinctive and first-quality education, fostering research, creativity and discovery, and using the new knowledge created on campus to serve our larger society.

When Arthur A. Hamerschlag served as the school's first president, Carnegie Technical Schools' 12 professors and six administrators sought to educate the sons and daughters of Pittsburgh workers for employment in the region's growing industries.

These educators served the vision of Carnegie by organizing into four faculties: the School of Science and Technology, the School of Fine and Applied Arts, the School of Apprentices and Journeymen, and the Margaret Morrison Carnegie School for Women.

In its earliest years, the institution served primarily part-time and undergraduate students. The faculty, many of whom did not have doctor's degrees, focused on teaching and curriculum development.

But research efforts began as early as 1916 when the Division of Applied Psychology of the Carnegie Institute of Technology developed rating scales for job placement. This rating system was used to classify two million men for placement in the armed forces during World War I. Research bureaus were organized in coal mining, nuclear physics, applied chemistry and metallurgy.

And by granting the nation's first undergraduate degree in drama in 1917, the institution began a tradition of leadership in the arts that spanned the century.

Through research and the education of its students during the administration of President Thomas S. Baker in the 1920s and '30s, the institution began its strong tradition of transferring knowledge and skills to industry and government.

Building on this firm foundation, the administration of President Robert E. Doherty introduced a new approach to education that would be used as a model by similar institutions around the nation. The Carnegie Plan for Professional Education, initiated in 1939-40, required engineering and science students to take a quarter of their courses in a new Humanistic and Social Relations sequence. In addition, its curriculum focused on teaching students problem-solving techniques, a hallmark of the Carnegie Mellon educational experience today.

While the Doherty administration has been credited with this educational innovation, it also oversaw growth in the institution's research capability. Between 1936 and 1950, the number of graduate students grew from 36 to more than 260. The research budget ballooned from $156,000 to $1 million.

In the 1950s, the newly formed Graduate School of Industrial Administration, endowed by William Larimer Mellon, emerged as one of the three or four best business schools in the nation. (In 2004 the school was renamed the David A. Tepper School of Business after benefactor and alumnus David Tepper (MBA '82).) Today, the school is recognized as a pioneer in the field of management science and one of the top business schools in the world.

The Warner administration oversaw the institution's burgeoning research enterprise. This period of research growth was aided by the work of the institution's Computation Center, founded in 1956 to provide computing services to the campus. A major grant from benefactor Richard K. Mellon in 1965 aided the establishment of a Computer Science Department, a department which would be the genesis of Carnegie Mellon's worldwide reputation in computer science.

By the end of the Warner administration and the start of the administration of President H. Guyford Stever in 1966, Carnegie Tech had most elements of a university. Its merger in 1967 with the Mellon Institute created Carnegie Mellon University and brought a $60 million endowment, extensive research facilities and renowned research personnel to the institution.

Five years later, President Richard M. Cyert (1972-90) began a tenure that was characterized by unparalleled growth and development. The university's research budget soared from about $12 million annually in the early 1970s to more than $110 million in the late 1980s. The work of researchers in new fields such as robotics and software engineering helped the university build on its reputation for innovative ideas and pragmatic solutions to the problems of industry and society. Carnegie Mellon began to be recognized as a truly national research university able to attract students from across the nation and around the world.

The Cyert administration stressed strategic planning and comparative advantage, pursuing opportunities in areas in which Carnegie Mellon could outdistance its competitors.

An archetypal example of this approach was the introduction of the university's "Andrew" computing network in the mid-1980s. This pioneering network, which linked all computers and workstations on campus, set the standard for educational computing and firmly established the university as a leader in the uses of technology in education and research.

Education and teaching also benefited in this period with the establishment of a University Teaching Center to improve faculty teaching and the renovation of many of the university's classrooms.

Cognizant of the university's heritage, President Robert Mehrabian (1990-97) invited alumni from the era of the institution's first president, Arthur A. Hamerschlag, to attend his inauguration in 1990. President Mehrabian emphasized Carnegie Mellon's traditional strengths in education, research and service to society while focusing on initiatives for leadership in the 21st century.

With the appointment of the university's first Vice Provost for Education, President Mehrabian placed renewed emphasis early in his administration on the quality of undergraduate education. He also moved aggressively to complete the most ambitious campus building plan since the Warner era. The University Center, which opened in August 1996, and the Purnell Center for the Arts, to be completed by the fall of 1999, are keys to enhancing the quality of life on campus, another priority of the Mehrabian administration.

Confronted by shrinking governmental support of university research, President Mehrabian diversified the university's research agenda. He stressed the need to build strong relationships with the business world, matching industry's needs with the university's areas of research strength. He also put new emphasis on productivity, improvement of administrative services and strategic management of university resources.

President Mehrabian established strong, new partnerships with the greater Pittsburgh community. He led a community-wide economic development initiative, spurred collaboration with primary and secondary schools, and worked closely with local community groups.

On April 15, 1997, Jared L. Cohon, former dean of Yale University's School of Forestry and Environmental Studies, was elected by the university's Board of Trustees to succeed President Mehrabian, who resigned to spend more time with his family in California.

"Since I was chosen, since this wonderful event has occurred, it has made me reflect on why you are choosing me," President Cohon said in his first speech to the university community. "And I've said to people since this was announced that the more I think about it, the more I realize how well I think this institution and I fit together. We'll see if that's true. I think it is.

"When I was at Johns Hopkins we used to always hold up Carnegie Mellon as an example," Cohon said. "So, for many years I've ... been jealous of what has been accomplished here across departmental lines. I celebrate that. I think it is so valuable in every aspect of this university and it will position Carnegie Mellon to be even better...."

During Cohon's presidency, Carnegie Mellon has continued its trajectory of innovation and growth. Today, President Cohon is leading implementation of a comprehensive strategic plan that aims to leverage the university's existing strengths to benefit society in the areas of biotechnology and the life sciences, information and security technology, environmental science and practices, the fine arts and humanities.

The university is also committed to broadening and enhancing undergraduate education to allow students to explore various disciplines while maintaining a core focus in their primary area of study. Realizing that today's graduates must understand international issues, Carnegie Mellon is committed to providing a global education for its students and is striving to expand its international offerings and to increase its presence on a global scale. Increasing diversity, in all aspects, and fostering the economic development of southwestern Pennsylvania, are also top priorities.

Over the years Carnegie Mellon's leaders have reflected Andrew Carnegie's original dedication and commitment to this institution. In his 1900 letter to the mayor of Pittsburgh establishing Carnegie Technical Schools, Andrew Carnegie wrote, "My heart is in the work." These words have been echoed by students, faculty and administrators throughout this century and they live on the Carnegie Mellon campus today.

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