Neanderthal DNA contributes to human gene expression

February 23, 2017, Cell Press
This visual abstract depicts the findings of McCoy et al., who show genome-wide interrogation of the functional differences between modern human and Neanderthal alleles reveals that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have a measurable impact on gene expression that may contribute to phenotypic variation in modern humans. Credit: McCoy et al./Cell 2017

The last Neanderthal died 40,000 years ago, but much of their genome lives on, in bits and pieces, through modern humans. The impact of Neanderthals' genetic contribution has been uncertain: Do these snippets affect our genome's function, or are they just silent passengers along for the ride? In Cell on February 23, researchers report evidence that Neanderthal DNA sequences still influence how genes are turned on or off in modern humans. Neanderthal genes' effects on gene expression likely contribute to traits such as height and susceptibility to schizophrenia or lupus, the researchers found.

"Even 50,000 years after the last human-Neanderthal mating, we can still see measurable impacts on ," says geneticist and study co-author Joshua Akey of the University of Washington School of Medicine. "And those variations in gene expression contribute to human phenotypic variation and disease susceptibility."

Previous studies have found correlations between Neanderthal genes and traits such as fat metabolism, depression, and lupus risk. However, figuring out the mechanism behind the correlations has proved difficult. DNA can be extracted from fossils and sequenced, but RNA cannot. Without this source of information, scientists can't be sure exactly if Neanderthal genes functioned differently than their modern human counterparts. They can, however, look to gene expression in modern humans who possess Neanderthal ancestry.

In this study, researchers analyzed RNA sequences in a dataset called the Genotype-Tissue Expression (GTEx) Project, looking for people who carried both Neanderthal and modern human versions of any given gene—one version from each parent. For each such gene, the investigators then compared expression of the two alleles head-to-head in 52 different tissues.

"We find that for about 25% of all those sites that we tested, we can detect a difference in expression between the Neanderthal allele and the modern human allele," says the study's first author, UW postdoctoral researcher Rajiv McCoy.

Expression of Neanderthal alleles tended to be especially low in the brain and the testes, suggesting that those tissues may have experienced more rapid evolution since we diverged from Neanderthals approximately 700,000 years ago. "We can infer that maybe the greatest differences in gene regulation exist in the brain and testes between modern humans and Neanderthals," says Akey.

One example uncovered by this study is a Neanderthal allele of a gene called ADAMTSL3 that decreases risk of schizophrenia, while also influencing height. "Previous work by others had already suggested that this allele affects alternative splicing. Our results support this molecular model, while also revealing that the causal mutation was inherited from Neanderthals," says McCoy. Alternative splicing refers to a process in which mRNAs are modified before they leave the cell's nucleus. When the Neanderthal mutation is present, the cell's machinery removes a segment of the mRNA that is expressed in the modern human version. The cell ends up making a modified protein because of a single mutation from a Neanderthal ancestor.

The connection between that modified protein, height, and schizophrenia still requires more investigation, but it's an example of how small differences between modern humans and Neanderthals can contribute to variation in people.

"Hybridization between modern humans and Neanderthals increased genomic complexity," explains Akey. "Hybridization wasn't just something that happened 50,000 years ago that we don't have to worry about anymore. Those little bits and pieces, our Neanderthal relics, are influencing gene expression in pervasive and important ways."

Next steps may include investigating whether Denisovans—another species of hominins that crossbred with —are contributing to gene expression, as well as applying the side-by-side method of expression analysis more broadly. For this study, McCoy and his colleagues had to develop a new statistical approach to sift through the immense amount of RNA data, but the same technique could be used to compare gene expression differences between modern human alleles.

Explore further: Long ago humans and Neanderthals Interbred: What happened to Neanderthal genes?

More information: Cell, McCoy et al.: "Impacts of Neanderthal-introgressed sequences on the landscape of human gene expression" , DOI: 10.1016/j.cell.2017.01.038

Related Stories

Recommended for you

How beetle larvae thrive on carrion

October 15, 2018

The burying beetle Nicrophorus vespilloides buries the cadavers of small animals in soil to use them as a food source for its offspring. However, the carcass and thus the breeding site are highly susceptible to microbial ...

Discovery of a simple mechanism for color detection

October 15, 2018

Color vision, consisting of ocular color detection, is achieved with complicated neural mechanisms in the eyes. Researchers from Osaka City University in Japan have found color detection with a simple mechanism in the fish ...


Adjust slider to filter visible comments by rank

Display comments: newest first

3 / 5 (2) Feb 23, 2017
Quote "The last Neanderthal died 40,000 years ago"
That's ridiculous since the modern human is mix of both spices.
Once they mixed the resulting species was a mix of both so neither species died out or they both died out.
Depending on how you look at it.
And to further this complex modern human we mix in Denisovans. If their genes are part of us, they live also. :-)
5 / 5 (1) Feb 23, 2017
Actually, modern humans didn't die out, they still exist in Africa.
1 / 5 (1) Feb 23, 2017
Now you have confused me. :-) I don't know what planet your from. :-)
But I thought all humans that exist today are modern humans.
If there are actual separate species(Not Races) then our constitution does not protect them.
Now, I have read that the neanderthals genes did not exist there but I find that highly unlikely that none do because migration seems to happen in all directions although primarily in one direction.
not rated yet Feb 24, 2017
Guess now we know where Presidential genes named after playing cards come from.
1 / 5 (2) Feb 24, 2017
Guess now we know where Presidential genes named after playing cards come from.

Your right! Definitely superior.
You do realize the three traits that the worlds greatest rulers have had in common?
Alexander the Great, GENGHIS KHAN, Casar etc.
1st. Tremendous ego
2nd. Dream of making their country great.
3rd Rose to be head of their nation.
Amid lots of jealousy and false petty slander by some their countrymen

5 / 5 (3) Feb 24, 2017

... Alexander the Great, GENGHIS KHAN, Casar etc.....

All best known for slaughtering/subjugating foreigners. I would rather see humanity get PAST that.
1.8 / 5 (5) Feb 24, 2017
Why does derkis promote violence?

We hope to outgrow that animalistic stuff.
3 / 5 (2) Feb 24, 2017
All best known for slaughtering/subjugating foreigners. I would rather see humanity get PAST that.

Why does derkis promote violence?

Alexander the Great, GENGHIS KHAN, Casar etc.
As usual YOU were to interested in what YOU had to say to notice the "etc." at the end

We hope to outgrow that animalistic stuff.

And I am hoping to win the lottery. And I stand a much better chance.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.