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CONSTANCE FINNEY
Intestinal worms helped shape human interleukin genes.
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Thank parasites for making our interleukins into the inflammatory defenders they are today, according to a population genetics study by Fumagalli et al. on page 1395. However, you might also blame the bugs for sculpting some of those genes into risk factors for intestinal disorders.
Parasite-driven selection leaves a footprint on host genomes in the form of single-nucleotide polymorphisms (SNPs). Genetic variation (multiple SNPs) at a particular locus can be maintained within a population if a certain SNP helps the host fend off infections in one environment, but hinders the host in another environment with different parasitic pressures.
Here, Fumagalli et al. sift through 1,052 SNPs in human interleukin genes from roughly 1,000 people worldwide. Of 91 genes assessed, 44 bore signatures of selection, meaning that the genetic variation was due neither to chance nor to the migration of populations over time. And some of that variation correlated with parasitic diversity, indicating that parasites drove selection.
Parasitic worms appear to have applied a more powerful selective pressure on certain interleukin genes than did viruses, bacteria, or fungi (assuming that pathogen diversity has remained relatively stable over time). That isn't surprising, says senior author Manuela Sironi, because worms typically evolve slower than bacteria or viruses, giving their hosts time to adapt.
Worm-driven selection of SNPs in genes encoding IL-10 and IL-4 might have been predicted based on their known roles in promoting the Th2 responses needed to fight off worm infections. Without the IL-4 receptor, for example, mice cannot expel certain nematodes. SNPs in the gene encoding IL-19 correlated strongly with worm diversity as well. Because this cytokine promotes inflammation in the skin, the authors suggest that it might protect against skin-borne infections.
Surprisingly, six of the nine known risk alleles for Crohn's and celiac disease also appeared to be selected for by pathogen diversity. Like most of these disease-associated SNPs, those in the Crohn's risk gene IL12B correlated more closely with viral, bacterial, and fungal diversity than with worm diversity. In theory, these risky alleles have been maintained because they promote vigorous Th1 responses, which help fend off viruses and bacteria. But overly exuberant Th1 responses also contribute to inflammatory bowel diseases.
Other pathogen-selected SNPs were more puzzling. For example, SNPs in the gene encoding an IL receptor-associate protein, IL1RAPL1, correlated with worm diversity, yet the protein functions in brain development and has no reported role in the immune response.
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