Different codons, same amino acid
Study shows that synonymous codon usage varies in human tissues, perhaps due
to evolution

By Melissa Phillips

The genomes of species from bacteria to Drosophila show unique biases for
particular synonymous codons-varying triplet base pairs that code for the
same amino acids-but it has been unclear if such codon preferences exist in
mammals. In a paper published in PNAS this week, a group led by Joshua B.
Plotkin of the Bauer Center for Genomic Research at Harvard shows that cell
usage of synonymous codons is systematically different between human
tissues. In addition, the authors make a case that these codon choices
result from evolutionary selection.

Plotkin and his colleagues analyzed genes expressed preferentially in six
human tissues-brain, liver, uterus, testis, ovary, and vulva-and found
synonymous codon biases between gene sets. In particular, they compared
brain-specific genes to liver-specific genes; uterus genes to testis genes;
and ovary genes to vulva genes. All three pairs differed significantly from
each other in their synonymous codon usage.
"We can even predict which genes are turned on in which tissues largely on
the basis of their synonymous codon usage," Plotkin told The Scientist.
"These codon biases may be partly responsible for determining which genes
are expressed in which tissues."

Previous studies have shown functional selection of codons in simpler
organisms, Plotkin said. Mammalian genomes, however, are complicated by the
presence of isochores, long stretches of homogeneous DNA sequence that are
biased to be either rich or poor in GC content.

"Most mammalian genomes have huge variations in GC content from region to
region, and that controls codon usage to a large degree," Plotkin said.
"People haven't normally thought that codon usage could have any sort of
functional importance, because it seems to be controlled by which isochore
the gene happens to fall in. But the fact that we find such systematic
differences between tissues is suggestive that there really is some
functional reason."

One possible mechanism linking synonymous codon choice and tissue-specific
gene expression is local transfer RNA abundance, Plotkin said. "The tRNA
pools may differ in brain from the pools in liver, and so if the codon usage
of a gene is calibrated to the tRNA pools that exist in the brain, that gene
will be translated more efficiently in brain." Other mechanisms could also
be at work, Plotkin said, such as mRNA modifications or secondary structure.

In a second part of the study, Plotkin and his colleagues compared codon
preference in human tissue genes to orthologous genes in the mouse. Previous
work has shown that base usage is similar between human and mouse not only
in coding sequences, but also in untranslated regions, hinting that
selection is not responsible for codon similarities. Plotkin's team found
that codon usage for brain-specific genes is significantly more similar
between the two species than would be expected by chance, even when
controlling for sequence similarity between the two genomes.

Read the rest at TheScientist
http://www.biomedcentral.com/news/20040817/01

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