Our genomes help to determine who we are — the countless variations between individuals that encode the complexity of tissues and functions throughout the body.

Since scientists first decoded a draft of the human genome more than 15 years ago, many questions have lingered, two of which have been addressed in a major new study co-led by a Princeton University computer scientist: Is it possible, despite the complexity of billions of bits of genetic information and their variations between people, to develop a mechanistic model for how healthy bodies function? Furthermore, can this model be used to understand how certain diseases emerge?

On October 11, scientists came the closest yet to delivering an answer of “yes.” An international group of researchers in the Genotype-Tissue Expression (GTEx) Consortium published findings about how genetic variation affects gene regulation in 44 human tissue types. Reported in the journal Nature, the data help to establish a baseline understanding of the diversity of genetic roles in maintaining human tissues. The researchers said the work demonstrates that, in fact, multi-tissue, multi-individual data can be used to identify the mechanisms of gene regulation and help to study the genetic basis of complex diseases.

The research that led to these findings is part of a larger effort to better understand gene regulation and expression, carried out by the GTEx Consortium, a National Institutes of Health-funded group that includes researchers from around 80 institutions founded in 2010.

“The ultimate goal is to understand gene expression and gene regulation in a diversity of tissue types,” said Barbara Engelhardt, an assistant professor in the Department of Computer Science at Princeton University, who is one of four corresponding authors of the paper and a GTEx principal investigator. “This is absolutely critical to understanding how dysregulation may lead to disease.”

Scientists are only beginning to reveal, for example, how genetic variation in our 22,000 genes — as well as “non-coding” regions in the genome — help to shape complex traits, from a person’s height to whether he or she develops autism. Further, scientists seek to understand interactions between multiple genes and the environment. The same unknowns hold true for how genetic variation contributes to disorders such as schizophrenia and Parkinson’s disease.

Teasing apart these complexities first requires characterizing how healthy tissues function, which in turn requires tissue samples. To obtain those samples, GTEx researchers requested consent from family members to collect small pieces of up to 50 different tissues immediately after a donor’s death. Samples range from various organs and blood, and include 10 brain sub-regions. This work represents data across 449 donors.

“These types of tissue are incredibly difficult to get from healthy living donors,” Engelhardt said. “With endless thanks to the donors, we have these samples as a resource. We can now explain observed relationships between genotype and disease by looking at the effects of the genotypes that lead to higher risk of the disease on gene expression levels in disease-specific tissues, including brain.”

While the research is ongoing, this latest study represents the largest analysis to date, including over 7,000 tissue samples.

Engelhardt’s group was responsible for mapping associations between genetic variants and gene expression levels on different chromosomes, a connection known as “trans-expression quantitative trait loci (trans-eQTLS).” In contrast, cis-eQTLs — which account for the majority of genetic variation that affects gene expression — regulate genes located nearby on the same chromosome. Trans-eQTLs in particular have proven especially difficult to identify because of their biological and statistical complexity, Engelhardt said, but they might hold clues for explaining complex tra