Neanderthal DNA in Modern Human Genomes Is Not Silent

Far from being silent remnants, Neanderthal genes play a profound role in how modern human genes are expressed.

Neanderthals may have gone extinct 30,000 years ago, but they still live on inside us. Ever since scientists discovered that Neanderthal DNA comprises roughly 2 percent of the genomes of modern humans of European and Asian heritage, they’ve speculated about how exactly those lingering genes affect us today. Now we’ve found that even though most humans hardly resemble Neanderthals in appearance, their DNA still influences how our genes work today.

Humans and Neanderthals began splitting on the evolutionary tree about 700,000 years ago, but continued to interbreed up until at least 50,000 years ago. Despite a genetic incompatibility that may have made reproduction difficult, enough hybrid human-Neanderthals were born to enshrine bits of their DNA throughout the human genome. Previous research has found that the Neanderthal DNA sequences and genes found in modern humans are linked to depression, fat metabolism and a host of other traits and conditions.

However, just because we can see a gene doesn’t mean we know how it works. Genes can be expressed at different strengths, and sometimes not at all. It all comes down to how that DNA is used by the RNA in our cells, which follows DNA’s instructions to make proteins. Cells can “regulate” various genes by choosing to use them, ignore them or modify them to make RNA. Unfortunately, unlike relatively permanent DNA, RNA is unstable and thus rarely found in fossils, making it difficult to analyze how the cells of extinct organisms actually utilized their DNA.

In a study published yesterday in the journal Cell, University of Washington genetics researcher Rajiv McCoy and co-authors got around the lack of ancient Neanderthal data by instead looking in their living descendants: today’s hybrid humans. “[We set out to use] gene expression from modern humans to get an idea of how gene flow from Neanderthals is impacting human gene expression,” says McCoy.

Using a dataset of the genomes of more than 400 deceased people, the researchers looked for instances of heterozygous genes: genes that are the result of a person inheriting a human gene from one parent and a Neanderthal gene from another. The dataset included samples of tissues from 52 different parts of the body, McCoys says, allowing the researchers to compare how human and Neanderthal genes were expressed in these different areas by comparing how much of each gene was transcribed into RNA.

Through analyzing these individuals with human and Neanderthal alleles, or gene variations, McCoy and his team found differences in human and Neanderthal gene expression in 25 percent of the areas they tested. Those differences had potential effects in traits ranging from height to likelihood of contracting lupus. “It really spans the whole spectrum of human genes,” says McCoy.

The researchers were also able to compare how strongly or weakly the human and Neanderthal genes were expressed in different body parts.

Interestingly, McCoy says, they found that Neanderthal genes in the brains and testes of the people tested were expressed more weakly than genes in other areas. The reason for this is likely unequal evolution: As humans continued to evolve away from Neanderthals, McCoy says, it’s likely that those body parts have evolved faster than others. Thus, they diverged further from the Neanderthal genes, and are less likely to be expressed by cells there.

For Vanderbilt University geneticist Tony Capra, who was not involved in this study, the reduced gene expression in the testes may be a sign of how mutations from Neanderthals might have reduced the fertility of early human-Neanderthal hybrids. “It further illustrates that Neanderthal DNA that remains in modern humans has the potential to influence diverse traits,” says Capra, who has done work scanning electronic medical records to look for the effects of Neanderthal DNA on our health.

“This is a very comprehensive study of the impact of Neanderthal introgression on gene expression in modern humans,” adds Fernando Racimo, a researcher at New York Genome Center who also wasn’t involved in the study. Racimo says he would like to see research into other cases of human hybridization, specifically ancient Denovisans and Australian aboriginals, whose genes live on in the inhabitants of Australia’s Melanesian islands.

McCoy says studying the genetic legacies of Melanesian people is on his wish list, but that will have to wait until RNA samples are collected. “I mooch off of other people’s data,” he jokes.

The technique used in this study could be applied within the human species too, McCoy adds. Comparing allele expression in different areas of the body and among different people could help scientists pin down more of the intricacies of gene expression, he says. But even by just probing the role of Neanderthal DNA in our genomes, we can still better understand how our disparate genes work together to make us.