New study explains process leading to many proteins from one gene

DALLAS - April 14, 2005 - New findings from researchers at UT Southwestern Medical Center help explain how the 20,000 to 25,000 genes in the human genome can make the hundreds of thousands of different proteins in our bodies.

Genes are segments of DNA that carry instructions for making proteins, which in turn carry out all of life's functions. Through a natural process called "alternative splicing," information contained in genes is modified so that one gene is capable of making several different proteins.                                 

 
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UT Southwestern's Dr. Harold "Skip" Garner, professor of biochemistry and internal medicine, used a supercomputer in his analysis of the human genome to find regions of the genetic code prone to a process called alternative splicing. Through alternative splicing, information contained in genes is modified so that one gene is capable of making several different proteins.

"Alternative splicing is a key mechanism for achieving a diverse range of proteins, which contributes to the complexity of higher organisms," said Dr. Harold "Skip" Garner, professor of biochemistry and internal medicine at UT Southwestern and senior author of a new study aimed at understanding how and why alternative splicing occurs in humans.

The study is available online and will be published in the April 15 issue of the journal Bioinformatics.

Errors in alternative splicing can result in truncated or unstable proteins, some of which are responsible for human diseases such as prostate cancer and schizophrenia, Dr. Garner said. But errors also can result in proteins with new functions that help drive evolutionary changes.

"Alternative splicing appears to occur in 30 percent to 60 percent of human genes, so understanding the regulatory mechanisms guiding the process is fundamentally important to almost all biological issues," said Dr. Garner.

Alternative splicing can be likened to alternative versions of a favorite cookie recipe. If the original recipe (the gene) calls for raisins, walnuts and chocolate chips, and you copy the recipe but leave out the raisins, you'll still get a cookie (protein) from your version, just a different cookie. Omit a necessary ingredient, such as flour, and you'll have a mess (nonfunctioning or malfunctioning protein).

Similarly, the information in genes is not directly converted into proteins, but first is copied by special enzymes into RNA, or more specifically, pre-messenger RNA.

While the entire gene is copied into pre-mRNA, not all of that information will be used to make a protein. RNA segments called exons carry the protein-making information, while the segments between exons, called introns, are snipped out of pre-mRNA by special proteins. Exons also may be snipped out. Once snipping is complete, the remaining exons are spliced back together to form a fully functional, mature mRNA molecule, which goes on to create a protein.

Using computers, the UT Southwestern researchers scanned the human genome and found that the presence of certain DNA sequences called "tandem repeats" that lie between exons are highly correlated with the process of alternative splicing.  They found a large number of tandem repeats on either side of exons destined to be spliced out of the pre-mRNA. The tandem repeat sequences also were complementary and could bind to each other. 

"The complementary tandem repeat sequences on either side of an exon allow the DNA to loop back on itself, bind together, pinch off the loop containing a particular exon and then splice it out," Dr. Garner explained.

The chemical units that make up an organism's DNA are abbreviated with the letters A, C, T and G. Strings of these letters form genes and spell out genetic instructions.  Tandem repeats have DNA sequences with the same series of letters repeated many times, such as CACACACACACA.

Tandem repeats are "hot spots" where errors can easily be made during the copying process; for example, an extra CA could be added or deleted from the correct sequence. These errors could then result in a gene improperly splicing out an exon, thus making the wrong protein, Dr. Garner said. His research group has previously shown that these sequences are highly variable in cancer, and he said the new findings could go a long way toward understanding the genetic nature of how cancers start and progress.

"With this new understanding, we can now predict all genes that can re-arrange in this way and even predict which might splice improperly, resulting in disease," he said.

Former UT Southwestern research associate Dr. Yun Lian was a co-author of the study.

The research was funded by the National Cancer Institute, the National Heart, Lung and Blood Institute and the M.R. and Evelyn Hudson Foundation.


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Media Contact: Amanda Siegfried
214-648-3404
e-mail: amanda.siegfried@utsouthwestern.edu


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