Expression of Certain Genes Changes with the Seasons

Cambridge's John Todd and his colleagues uncovered more than 4,000 genes whose expression patterns vary between summer and winter months. During the winter, immune system genes like IL-6 receptor and C-reactive protein are more highly expressed, they found, suggesting that these changes could be linked to seasonal fluctuations in disease.

Researchers have long known, they added, that there are seasonal influences on a number of conditions, including cardiovascular disease, psychiatric disorders, and autoimmune diseases like multiple sclerosis and type 1 diabetes.

"In some ways, it's obvious — it helps explain why so many diseases, from heart disease to mental illness, are much worse in the winter months — but no one had appreciated the extent to which this actually occurred," Todd said in a statement.

The researchers hypothesized that the anti-inflammatory circadian transcription factor ARNTL likely exhibited a seasonal gene expression pattern, and to test this hypothesis, they assayed its expression and the expression of tens of thousands of other genes in 454 blood samples from 109 children from the German BABYDIET cohort using an Affymetrix GeneChip array.

ARNTL mRNA levels, the researchers reported, peaked in the summer months and declined in the winter. The housekeeping genes B2M and GAPDH did not show seasonal variations, though some circadian clock-related genes did.

Overall, Todd and his colleagues found that nearly a quarter of the genome, or 5,136 of the 22,822 genes they examined, exhibited significant seasonal fluctuations in expression. Some 2,311 genes had increased expression in the summer months — June, July, and August — while 2,826 genes were more highly expressed in the winter months — December, January, and February.

While they broadly replicated their finding in two additional cohorts and in adipose tissue from another group, Todd and his colleagues noted that the Australians in their samples exhibited the opposite pattern. Their ARNTL mRNA levels were highest in December, January, and February, or the Southern Hemisphere summer.

In addition, the effect was somewhat different in the Icelandic population, the researchers reported, and speculated that it could be due to the effect of long summer days in Iceland.

In the non-Icelandic populations, the researchers found that the expression of these seasonal genes largely correlated with the expression of about a dozen genes that mark the various blood cells present in peripheral blood, and noted that the total number of white blood cells, lymphocytes, monocytes, and eosinophils also shift seasonally as do the mean corpuscular volume and the mean corpuscular hemoglobin of erythrocytes.

However, in an equatorial cohort of 4,200 healthy people in Gambia, the researchers found seasonal fluctuations in the number of total white blood cells, lymphocytes, monocytes, and platelets, though not granulocytes.

Further, the researchers noted that the seasonal patterns in the Gambian cohort differed from those observed in the UK cohort. In the Gambian cohort, the seasonally expressed cell types peaked during the rainy season — June through October — which is a time marked by increased infectious disease burden there, including of malaria, Todd and his colleagues added.

Using the BABYDIET data, the researchers constructed modules of co-regulated seasonal mRNAs. The seven winter-expressed modules, they found, were enriched for genes involved in pro-inflammatory processes, as compared to the summer-expressed modules. For instance, B-cell receptor signaling, FcR-gamma-associated processes, lysosomes, chemokine signaling, and phagosomes were all strongly associated with winter-expressed modules.

Meanwhile, RNA transport, RNA degradation, ubiquitin-mediated proteolysis, and splicesosome-related processes were more common among the summer-expressed modules.

This suggests "that a more inflammatory status of the immune system predominates in winter," the researchers said.

In the winter, the human immune system appears to be primed to respond to any threat, the researchers said. This could be "a direct consequence of our co-evolution with infectious organisms and increased inter-species competition during winter, especially as humans migrated out of Africa to colder, more seasonally pronounced latitudes," Todd and his colleagues added.