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Nonsense SNPs Quite Common in Human Genomes, Study Finds

NEW YORK (GenomeWeb News) – Nonsense SNPs, which can truncate and can even inactivate proteins, are more common in the genomes of healthy individuals than previously believed, according to a paper appearing online today in the American Journal of Human Genetics.

Researchers from the Wellcome Trust Sanger Institute detected nearly 170 nonsense SNPs when they genotyped roughly 1,100 healthy individuals from populations around the world. Their subsequent analysis suggests that these mutations can frequently exist without causing disease. And while most nonsense SNPs produce a slight evolutionary drawback, some actually seem to be advantageous.

"We knew that these mutations existed and that many have been associated with genetic diseases, but we were amazed to find that they were so common in the general population," lead author Bryndis Yngvadottir, a graduate student at the Sanger Institute, said in a statement.

Nonsense SNPs, genetic variants that produce a premature stop codon, are usually thought to be detrimental since they can lead to truncated or inactive proteins. For instance, about ten percent of cystic fibrosis cases are due to nonsense mutations causing a premature stop codon in the cystic fibrosis transmembrane conductance regulator gene.

Even so, some researchers have theorized that a certain amount of gene loss isn't such a bad thing. The thrifty gene theory suggests that some genes that were once useful are no longer necessary or desirable. And some researchers, such as the University of Washington Genome Center's Maynard Olson, have proposed that gene loss may even contribute to evolution.

"There is a theory that 'less is more' where genes are concerned and we already knew of a couple examples of advantageous gene loss," senior author Chris Tyler-Smith, head of the Sanger Institute's Human Evolution Team, said in a statement. "But this is the first large-scale investigation of its significance for recent human evolution."

Tyler-Smith and his team used the Illumina GoldenGate assay to genotype 805 nonsense SNPs in 1,151 individuals from 56 different populations using HapMap data. They also assessed 731 synonymous SNPs.

Their results suggest that nonsense variants are unexpectedly common: in the samples tested, 167 genes contained 169 nonsense SNPs. Of these, just eight nonsense SNPs turned up in the Human Gene Mutation Database, which catalogues mutations linked to human diseases.

The average individual tested carried some 14 homozygous (stop/stop) and about 18 heterozygous (stop/normal) nonsense SNPs. Based on their results, the researchers calculated that, on average, such SNPs cause individuals to vary at 24 genes.

And 99 of the nonsense SNPs were homozygous in at least one sample. That, in turn, suggests that nearly 100 out of 20,000 — or roughly one out of every 200 — genes is expendable.

"Truncation or loss of these 99 genes is therefore compatible with normal adult life and cannot be strongly disadvantageous," they wrote. "Confirmation of this expectation is found in the presence of 18 of the 169 nonsense SNPs in the Venter genome."

When the team used gene ontology to assess what sorts of genes carried nonsense mutations, detected an over-representation of genes related to smell and nervous system function.

Although the researchers found evidence for some weak negative selection, which may slowly weed nonsense variants out of the genome, they also detected examples of nonsense SNPs that appear to be beneficial.

For example, based on their re-sequencing of a gene called MAGEE2 in 91 humans and one chimpanzee, the researchers concluded that nonsense SNPs in MAGEE2 are advantageous in East Asian populations. "[W]e have absolutely no idea what this gene does, or why some people are better off without it," Tyler-Smith said.

Given the new results, the researchers suggested that it may be necessary to look more carefully at drugs such as PTC Therapeutics' PTC124 (ataluren) that are designed to promote read-through of premature stop codons created by nonsense mutations.

"Such treatment would, if effective, also promote the expression of endogenous non-target genes carrying nonsense SNPs, and the consequences should be evaluated," the researchers concluded. "We need to understand the full extent of human genetic variation in order to reap the full benefits of present and future medicine."

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