Here’s what you’ll learn when reading this story:

• Humans are closely related to chimpanzees and bonobos, but what are the key factors that make humans genetically different?
• A new study looks at the process of DNA methylation, in which chemical tags known as methyl groups turn genes on and off and regulate the production of encodable proteins.
• The study found that cis-acting variations dominated genetic changes by influencing areas of the genome known as CpG sites, where methylation occurs.

Humans may be the only surviving species in the genus Homo—pour one out for Homo neanderthalensis—but we still have close relatives sharing the planet with us. It's a well-known, often-touted fact that chimpanzees and bonobos, which are both members of the genus Pan, share up to an incredible 99 percent of their genes with humans, even though we evolutionarily separated from our primate cousins 6 to 8 million years ago. But that doesn’t mean we’re the same—lots of traits and behaviors distinguish us from primates.

In a new study published in the journal eLife, scientists from Stanford University and the Weizmann Institute of Science in Israel examined what exactly caused those differences between humans and chimpanzees. One of the key processes explored in the paper is DNA methylation, a chemical modification that the National Human Genome Research Institute describes as attaching methyl groups “to a particular location within DNA where they turn a gene on or off, thereby regulating the production of proteins that the gene encodes.” These genetic variations come in two different specific flavors, known as cis-acting (DNA or RNA sequences that regulate genes on the same molecule) and trans-acting (which regulate expression on target genes in different DNA molecules).

“While gene expression divergence has long been considered the primary driver of human evolution, identifying the molecular mechanisms underlying uniquely human traits remains challenging,” the authors write. “While recent advances have enabled quantification of human-specific divergence…the role of DNA methylation…in coordinating these changes and driving human-specific traits has not been fully explored.”

To take a look at this unexplored frontier, scientists created a wonderfully strange experiment. First, they fused together human and chimpanzee stem cells and grew hybrid neurons, liver cells, and muscle tissue. The idea wasn’t to make some human-chimp hybrid—scientists have already tried and it wasn’t a good idea—but to see the relationship between cis-acting and trans-acting DNA methylation. Because these fused cells exist in the same cellular environment, researchers can more clearly distinguish methylation differences caused by local DNA sequence effects (cis) from those driven by broader, diffusible cellular factors (trans).

What they found is that cis-regulatory mechanisms were the primary drivers of methylation differences across the genome. In particular, they zeroed in on single-letter mutations that create or destroy something called CpG sites. CpG sites are spots in the genome where a cytosine sits next to a guanine, and they serve as key targets for methylation, which helps silence genes. When a mutation destroys a CpG site, the tag is lost; when a new CpG is created, a new site for tagging appears. Critically, these changes don’t just affect the mutated spot. They ripple outward, altering methylation patterns at neighboring CpG sites up to 50 base pairs away.

Over evolutionary time, this cascade of small local changes has produced distinct epigenetic landscapes in humans and chimpanzees. Those differences, in turn, appear to have shaped a surprising range of human-specific traits: genes involved in cognition and synaptic plasticity in brain cells, delayed growth patterns during development, craniofacial and dental features, and even heightened susceptibility to hepatitis C infection all showed signs of coordinated, lineage-specific shifts in methylation and gene expression.

“Our findings provide a framework for understanding how DNA methylation divergence contributes to human-specific traits,” the authors write. “We demonstrate that while both cis- and trans-regulatory mechanisms shape interspecies methylation differences, cis-acting factors predominate, thus directly linking genomic sequence variation and epigenetic divergence.”