The SomaLogic Blog

Attention to Details

12/06/2016

During the 2016 Olympics, an oversight occurred. At first, it might have seemed minor, but it really ruffled some feathers and caused major embarrassment for the Olympic committee. So, what happened? The Olympic committee approved and used incorrect Chinese flags with the smaller yellow stars pointing in the wrong direction.1 The mistake was caught and deep apologies were made. If greater attention had been paid to even these seemingly tiny details, then this situation would not have happened.

In science, minute changes that may seem subtle or inconsequential can also have a huge impact. For example, a single-nucleotide polymorphism (SNP) is a change of one nucleotide that can occur anywhere in a genome. Many times, the single change is no big deal. Other times, the change can happen in a spot that affects how a resulting protein is made, perhaps leading to disease, changing a patient’s response to medication, or making a person more vulnerable to toxins.2 Negative outcomes from these seemingly innocuous scenarios are not inconsequential.

Detecting SNPs at the DNA level is the conventional way for finding them. However, SNPs can also be detected at the protein level by SomaLogic’s SOMAscan® assay. SomaLogic researchers have documented that certain SOMAmer® reagents (a modified single-stranded DNA that is seminal to the SOMAscan assay) can distinguish between proteins resulting from SNPs and normal proteins in human plasma.3 For example, a SNP causes an amino acid change (histidine to arginine) at position 167 in the low affinity immunoglobulin gamma Fc region receptor II-a protein (FCGR2A for short) in about 44% of the population. The protein version of FCGR2A used to create the SOMAmer reagent carried the SNP. When the SOMAscan assay was performed using samples from healthy individuals, a “bimodal distribution” was observed in both plasma and serum, suggesting that some of the individuals did not possess the SNP version of the protein. In other words, the SOMAmer reagent in the assay could not bind to the “non-SNP” version of the protein.

To confirm this hypothesis, the scientists performed a series of binding experiments. Using purified normal FCGR2A and mutant FCGR2A (i.e., the one that contains the SNP), they measured the affinity of the SOMAmer reagent to these two proteins. While they observed very good affinity to the mutant FCGR2A, the binding to the normal protein was significantly weaker. An additional experiment using a closely related protein to dissect the binding pattern of the SOMAmer reagent ultimately supported the hypothesis.

This work demonstrates how the subtlest change in a protein can affect experimental results. Paying attention to the bimodal data of the SOMAscan assay revealed marvelous insight into the SOMAmer reagent’s specificity for that particular protein. This should not be the cause for any embarrassment, and no apologies are needed.

References

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