Human Complexity And Diversity Spring From A Surprisingly Few (Relatively Speaking) Genes

In April 2003, scientists completed the massive Human Genome Project, recording for the first time in history the location and sequence of every gene in the human body.

One result of the international project came as a bit of a shock. Scientists discovered that the body has only 30,000 genes, far fewer than the 50,000 to 140,000 they had expected to find.

Moreover, scientists learned that some less complex, less diverse organisms had more, or proportionally more genes than human beings. The rice genome contains 50,000 genes and the fly contains 14,000, to cite two examples.

The lack of correlation between genome size and an organism’s complexity raised a question – how do complexity and diversity arise in higher life forms?

The unexpected finding, says Stefan Maas, necessitates a clearer understanding of the role played in protein diversity by processes that take place after DNA is transcribed to RNA and after RNA is translated to proteins.

Maas studies RNA editing, a phenomenon discovered in ion channels of the brain a decade ago at the University of Heidelberg in Germany, where Maas earned his Ph.D.

Shedding light on evolutionary processes

RNA editing involves the process by which cells use their genetic code to manufacture proteins. More specifically, says Maas, RNA editing “describes the posttranscriptional alteration of gene sequences by mechanisms including the deletion, insertion and modification of nucleotides.” Nucleotides are compounds that form the basic constituents of DNA and RNA.

Often working in tandem with another RNA modification mechanism called alternative splicing, RNA editing, says Maas, can “increase exponentially the number of gene products generated from a single gene.”

A greater understanding of RNA editing, scientists believe, might potentially shed light on evolutionary processes and might lead to new strategies for combatting some diseases. In fact, says Maas, scientists have learned that a type of RNA editing called A-to-I editing, which leads to changes in protein structure and function and in gene regulation, regulates crucial functions of neurotransmitter receptors in the brains of mammals.

Disturbances in A-to-I RNA editing have been implicated in several human diseases, such as amyotrophic lateral sclerosis (Lou Gehrig’s Disease), epilepsy and depression. Maas’s group has analyzed brain tumor tissues and tissues from a healthy brain.

“RNA editing, because of its effect on the ion channel, is very important for normal brain function,” says Maas. “We have found an impairment to RNA editing in malignant brain-tumor tissue. This suggests that epileptic seizures in patients with brain tumors could be caused by an editing deficiency with regard to the channel molecule.”

Maas’s research group recently discovered that A-to-I editing, in which adenosine is converted to inosine, is widespread among human genes and occurs frequently in a common genetic sequence known as the Alu repeat.

In December, an article written by Maas and his collaborator, Alekos Athanasiadis of M.I.T., titled “Widespread A-to-I RNA Editing of Alu-Containing mRNAs in the Human Transcriptome,” was published by the journal PloS Biology.

The article culminated two years of study, which began while Maas was at M.I.T., where he worked as a research scientist before joining the Lehigh faculty in 2003.

Maas’s group began their study by looking systematically on the genomic scale for genes that might be subject to A-to-I editing.

“One of the major puzzles in the field of RNA editing at that time,” he says, “was that only a few genes affected by RNA editing, perhaps two dozen, had been found, all in the brain. Most of them were discovered by serendipity. There was strong evidence that there should be many more affected genes, as many as several thousand, or about 10 percent of all human genes.”

Looking for the smoking gun

To find genes affected by RNA editing, Maas and his colleagues used experimental analysis and computational methods, poring through the databases where sequences of new genes had been deposited.

“We used computational sequence analysis to look for the smoking gun of A-to-I editing in these sequences,” says Maas. “We looked for any sign that the sequences might be subject to editing.

“The sequence and frequency of the Alu element in the human genome are a major factor in why genes undergo RNA editing,” says Maas. “If you look at any gene sequence, you find more than one Alu element in the gene, and usually about a dozen.”

Scientists estimate that of 100,000 types of RNA molecules so far analyzed computationally, 1,400 are strong candidates for RNA editing. Maas’s group has validated about 50 of these in molecular biological experiments and has concluded that most are indeed affected by RNA editing. The group has also characterized why certain Alu elements are edited and where on the gene sequence the editing is occurring.

For the future, says Maas, “We hope to refine the computational search to be able to identify additional candidate sequences for editing with high certainty. We want to make more precise predictions regarding how a sequence subject to editing should look.

“In addition, we want to find out what the consequences of this massive editing are for gene function.”

Maas will present his research at the Gordon Research Conference on RNA editing in January in Ventura, Calif.