An encounter with a mysterious and extinct human relative – the Denisovans – left a mark on the immune traits of modern Papuans, especially those living on the island of New Guinea.
This is a new finding that we describe in a study published today in PLoS Genetics. It further suggests that our modern human diversity did not simply evolve – parts of it were passed down to us from other extinct human groups.
The DNA of our evolutionary cousins
Man is the only living species in the Homo gender. But until 50,000 years ago, our ancestors coexisted — and sometimes interacted — with multiple other Homo groups around the world. We know most of them only from rare archaeological remains, which offer tantalizing glimpses of our evolutionary cousins.
But for two groups, there is something else: DNA. Thanks to advances in technology, scientists have recovered DNA from fossils and sequenced it. As a result, we now have complete genome sequences of the best-known archaic hominins, the Neanderthals, and a much more elusive group, the Denisovans.
Read more: New clues to the life and times of the Denisovans, a little-known ancient group of humans
Although numerous Neanderthal fossils have been unearthed across Europe since their first identification in the 1860s, the number of known Denisovan fossils fits in the palm of one hand – literally!
The genome sequence we have is from the smallest bone in a little finger. It belonged to the 60,000-year-old remains of a teenage girl from a cave in Siberia, the largest known Denisovan fossil until recently.
Traces of ancestors
These genome sequences have transformed the way we think about our departed relatives. For one thing, they quickly demonstrated that as humans expanded outside of Africa, we had sex – and children – with these other populations.
Traces of their genomes remain in individuals alive today, passed down through hundreds of generations.
Read more: Evolutionary study suggests prehistoric human fossils ‘hide in plain sight’ in Southeast Asia
In the case of the Neanderthals, these traces are found today in all individuals of non-African descent. In the case of the Denisovans, small traces of their genome are found in people across Asia – particularly in Papua New Guinea and the island nations of Southeast Asia, where individuals may owe up to 4 to 5% of their genome to these. the ancestors.
But identifying these DNA fragments in our genomes is only the beginning.
DNA makes the difference
The real challenge is to find the biological consequences of this DNA for the people who carry it – which, remember, are the vast majority of humans. Our specific research question was to identify the molecular processes that could be affected by its presence.
Neanderthal DNA studies have shown that genetic variants inherited from them can alter the expression levels of certain human genes, for example. We also know that Neanderthals contributed to our immune system (including differences in how people respond to COVID-19 infection) and variation in skin and hair color.
Read more: What teeth can tell about the life and environment of ancient humans and Neanderthals
But it’s never been clear if Denisovan’s DNA left similar patterns in modern humans.
In 2019, a study revealed the genomic coordinates where Denisovan’s DNA could be found in the genome of Papuan individuals – that is, the indigenous people of the island of New Guinea – living today. .
This led us to begin to study these regions, to understand the cellular and biological processes that could be affected by Denisovan DNA. We took a hybrid approach to this question, first making computational predictions and then following up with lab experiments to validate our results.
Additionally, we took advantage of known Neanderthal DNA from these individuals to highlight any Denisovan-specific contributions. This gave us a more integrated understanding of how encounters with these relatives left potential biological and evolutionary consequences in modern humans.
A Unique Denisovan Contribution
We have noticed that in Papuans, Denisovans and Neanderthals, genetic variants occasionally occur in parts of the genome responsible for modulating the expression levels of neighboring genes.
However, only Denisovan variants are consistently predicted to occur and affect elements controlling expression levels of immune system-related genes.
Thus, these different DNA sources could contribute to the genetic and phenotypic diversity of Papuans in different ways.
To validate our predictions, we designed an experiment comparing five Denisovan sequences to their modern human counterpart and tested their ability to actually affect gene expression levels inside a particular type of immune cell called a lymphocyte.
In two of the five cases, the Denisovan variants had a different measurable impact on gene expression levels than their modern human counterpart. And they impact genes known to be important players in the response to infectious microbes, including viruses.
The fact that the Denisovans, but not the Neanderthals, seem to have contributed to the immune system of today’s Papuans also tells us something about these ancient peoples.
Although little is known about the life span of Denisovans in Asia, it does suggest that their immune systems changed to adapt to infectious diseases in their environment.
When humans settled 60,000 years ago, these pieces of DNA likely contributed to our success in colonizing this part of the world.
Although our study is the first to elucidate the contribution of Denisovan DNA to modern human genetic diversity, there are still exciting questions to be addressed. In particular, it is unclear whether the overall contributions of Denisovan and Neanderthal genetic variants systematically differ from each other.
It is also important to note that we tested genetic variants in immune cells under resting conditions. This means that the same genetic variant or other genetic variants can have different effects in the environment – this will be an important question for future studies.
Read more: First-ever genetic analysis of a Neanderthal family paints a fascinating picture of a close-knit community
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