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Copy Number Variation Subject to Natural Selection in Drosophila

NEW YORK (GenomeWeb News) – The location and frequency of copy number variations are subject to natural selection in fruit flies, according to new research.
A team of researchers led by University of Chicago evolutionary biologist Manyuan Long used full genome tiling arrays to map duplications and deletions across the Drosophila melanogaster genome. Their findings, published online today in Science Express, suggest that — to different degrees — both types of polymorphisms are molded by purifying selection.
“We’re specifically interested in how new genetic systems evolve,” co-lead author J.J. Emerson, now a post-doctoral researcher at the Academia Sinica in Taiwan, told GenomeWeb Daily News today. “People have just started studying this sort of thing at the genome level.”
In general, copy number polymorphisms contribute to genetic variation in humans and other organisms, affecting everything from gene dosage to gene regulation. Consequently, the processes have the potential to influence evolution. Gene duplications are thought to be particularly evolutionarily relevant and may be the “first step leading to new functionalization,” Long told GenomeWeb Daily News.
With tiling technology, Long explained, his team was able to design reverse genetics experiments that allowed them to examine genomic variations — and the evolutionary forces acting on them. “This is the first study to use rigorous population genetics and evolutionary analysis to detect the role of natural selection in the genomic distribution of duplication polymorphisms,” he wrote in an e-mail. “So in questions to ask and methodology to use, this work is complementary to the earlier human work.”
Long also emphasized that the work builds on research by Harvard University evolutionary biologists Erik Dopman and Daniel Hartl. Last December, that duo published a paper in the Proceedings of the National Academy of Sciences in which they started characterizing copy number polymorphisms in the Drosophila genome and predicting the role of selection in shaping these variations.
For the latest study, Long and his team looked at the genomes of 15 natural Drosophila strains from sub-Saharan Africa using Affymetrix tiling arrays to uncover copy number polymorphisms at three million sites — roughly 35 base pair intervals — across the fruit fly euchromatic genome. They compared these to a Drosophila reference genome as well as another lab strain genome, with known deletions and duplications, derived from that reference strain.
After adjusting for false positive variations, the team found 2,658 different copy number polymorphisms, most of which were small. In contrast to one hypothesis suggesting that deletions may be beneficial for helping Drosophila maintain a small genome, Emerson said, they found that deletions were deleterious overall. Even more surprising, Long said, was the finding that most duplications were under selective pressure, too.
There were exceptions, though. Whole-gene duplications, which are “clean duplications” that don’t affect gene structure, were often under neutral or even positive selection, Emerson said. In particular, he added, whole-gene duplications tend to be more common for genes evolving in genetic “arms races,” such as those for insecticide response.
In every region tested, duplications outnumbered deletions. And these duplications tended to be larger than deletions. That made the researchers suspect that deletions are under stronger purifying selection than duplications.
“[T]he dearth of deletions observed in our data, as well as the smaller size of the deleted variants, suggest that they are far more deleterious than duplications and that larger mutations are more deleterious than smaller ones,” the authors wrote.
But the genomic location had a hand in selection, too, the researchers noted. In general, duplications were more common in intergenic regions — especially pericentromeric regions — than in introns, exons, or DNA on the X-chromosome, although some eight percent of genes were fully or partly duplicated. There also seemed to be far fewer deletions within exons than in either introns or intergenic regions. Just two percent of genes were partially or completely deleted.
“Anything that affects the coding region is disproportionately less common,” Emerson said.
Based on this and other data, the researchers proposed that purifying natural selection weeds out much of the copy number variation that would otherwise be present, a notion they verified by looking for rare variants that are more common in the presence of such selection.
“[T]he regional patterns of duplicate and deletion variation showed strong evidence for the pervasive action of natural selection, both in their patterns of polymorphism and in their distribution in the genome,” the authors concluded. 
In the future, Long’s team plans to examine the role of selection on copy number polymorphisms in the genomes of other species and to look at the functional implications of the polymorphisms they detected.
“There’s a lot of interest in following up on some of these specific genes,” Emerson said.

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