Genes contain all instructions needed to build an organism in form of DNA. Humans share around 99.5% of DNA, but it is the remaining 0.5% that contain the small genetic variations that make us unique. Subtle differences in genes can, for example, influence the colour of our hair or eyes.
To build gene products, such as proteins, DNA first needs to be transcribed into RNA. Some genetic variants can affect how a gene is transcribed into an RNA molecule, for example by making it be transcribed too much or too little, which can lead to diseases. These variants can also influence where the transcription begins through a process called promoter usage. This can lead to shorter or longer RNAs, which can have different biological impacts.
With current research methods, it is difficult to detect changes in the latter kind of alteration. As a result, it is harder to distinguish these from other types of changes. Now, Alasoo et al. wanted to find out what proportion of genetic variants that alter traits influence promoter usage, compared to other changes. To do so, a new computational method was developed to directly measure how genetic variants influence different parts of the RNA, such as promoters, middle sections and ends. The method was then applied to datasets of human immune cells. The experiments revealed that genetic variants often influence promoter usage. Many of the effects could only be found when cells are exposed to external stimuli, such as bacteria.
The results highlight that to discover genes responsible for human traits and disease we need to consider all the possible ways genetic differences between individuals could alter the gene products. Large published datasets could be reanalyzed using this method to identify new genes that could be implicated in human health and disease, potentially leading to new treatment options in future.