Tuesday, December 17, 2013

Exonic Transcription Factor Binding Affects Codon Choice

"Genomes contain both a genetic code specifying amino acids and a regulatory code specifying transcription factor (TF) recognition sequences. We used genomic deoxyribonuclease I footprinting to map nucleotide resolution TF occupancy across the human exome in 81 diverse cell types. We found that ~15% of human codons are dual-use codons (“duons”) that simultaneously specify both amino acids and TF recognition sites."
UW:
Rather than being a “second code,” as the University’s article states, it is really “a different (but already recognized) use of the existing code, now identified as occurring at a greater frequency in areas that use the same code for proteins.”

A research team led by Dr. John Stamatoyannopoulos, University of Washington associate professor of genome sciences and of medicine, made the discovery. The findings are reported in the Dec. 13 issue of Science.

The work is part of the Encyclopedia of DNA Elements Project, also known as ENCODE. The National Human Genome Research Institute funded the multi-year, international effort. ENCODE aims to discover where and how the directions for biological functions are stored in the human genome.

“For over 40 years we have assumed that DNA changes affecting the genetic code solely impact how proteins are made,” said Stamatoyannopoulos. “Now we know that this basic assumption about reading the human genome missed half of the picture. These new findings highlight that DNA is an incredibly powerful information storage device, which nature has fully exploited in unexpected ways.”

The genetic code uses a 64-combination alphabet called codons. The UW team discovered that some codons, which they called duons, can have two meanings, one related to protein sequence, and one related to gene control. These two meanings seem to have evolved in concert with each other. The gene control instructions appear to help stabilize certain beneficial features of proteins and how they are made.

The discovery of duons has major implications for how scientists and physicians interpret a patient’s genome and will open new doors to the diagnosis and treatment of disease.

“The fact that the genetic code can simultaneously write two kinds of information means that many DNA changes that appear to alter protein sequences may actually cause disease by disrupting gene control programs or even both mechanisms simultaneously,” said Stamatoyannopoulos.

Grants from the National Institutes of Health U54HG004592, U54HG007010, and UO1E51156 and National Institute of Diabetes and Digestive and Kidney Diseases FDK095678A funded the research.

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