What have we learned from the Neanderthals in recent times?
Modern humans are, technically, a young species. Current evidence suggests that we emerged from East Africa around 200,000 years ago. While that may seem like a long time in the context of human lifespan, if you consider that early humans were estimated to have diverged from chimpanzee lineages around 6 million years ago, we’re pretty new.
Before us, archaic humans roamed the Earth, including Homo neanderthalensis – Neanderthals – our closest relatives. Before the extinction of the Neanderthals, they cohabited on Earth with our ancestors for some time, the exact duration of which remains somewhat elusive; however, it was certainly long enough for interbreeding to occur.
The result of our ancestors’ breeding with the Neanderthals is that we humans today have archaic genetic mutations of the extinct species. This information has indeed been written and stored in our genomes for thousands of years, but it is only recently that we have developed the tools to read, analyze and interpret it. In 1997, Swedish geneticist Svante Pääbo became the first individual to extract and sequence mitochondrial DNA from a Neanderthal sample. Since 1997, the costs and complexities associated with performing DNA analyzes have declined dramatically, and a growing number of research groups are exploring “old” samples. From these studies, scientists can infer how Neanderthal mutations impact the phenotypes of humans today. What have we learned from recent research?
Progesterone is a steroid hormone that belongs to the progestogen family. It is released by the ovaries and plays a central role in menstruation, pregnancy, libido and embryogenesis. In order for the hormone to induce an effect in the body, it must bind to its receptor, a protein encoded by the RPG gene located on chromosome 11. This receptor is abundant in the endometrium, and the binding of progesterone leads to a molecular cascade of events that helps prepare the uterus for – and maintain – pregnancy. Proteins are subject to genetic mutations which can alter their structure and functionality. A variant of the progesterone receptor that carries a missense substitution is derived from Neanderthals. The oldest modern human carrying this variant – known as V66OL – is a 40,000-year-old woman from Tianyuan Cave in China.
Researchers at the Max Planck Institute for Evolutionary Anthropology in Germany and the Karolinska Institute in Sweden wanted to study the impact (if any) of the Neanderthal variant on modern carriers of the gene.1 They analyzed biobank data from over 450,000 people and found that nearly one in three women had inherited the progesterone receptor; 29% have one and 3% have two. Women who carried the variant were less likely to bleed or miscarry during pregnancy and were likely to give birth to more children than those who did not carry the variant.
“These results suggest that the Neanderthal variant of the receptor has a favorable effect on fertility,” said Hugo zeberg, researcher in the Department of Neuroscience of the Karolinska Institute and the Max Planck Institute for Evolutionary Anthropology.
We continue to experience the first “modern” global pandemic, caused by SARS-CoV-2. Who would have thought that archaic genes and proteins would both increase and decrease our risk of disease? Alas, this is what science suggests.
In 2020, a number of large-scale studies identified a cluster of genes located on chromosome three (chr3p21.31) as a locus of genetic susceptibility in COVID-19 patients. The exact explanation of Why this group of genes is associated with the severity of the disease remains to be understood. However, scientists like Zeberg and Pääbo have been able to identify or it comes from – Neanderthals.
Zeberg and Pääbo analyzed the frequency of the cluster in modern humans and identified it in ~ 50% of the population in South Asia. In Europe, however, only one in six people was a carrier. The highest frequency of the cluster was identified in Bangladesh (63% of the population are carriers).2
“The Neanderthal haplotype may therefore be a substantial contributor to the risk of COVID-19 in some populations in addition to other risk factors, notably advanced age. In apparent agreement with this, people of Bangladeshi descent in the Kingdom United have about twice the risk of dying from COVID-19 than the general population (95% CI risk ratio: 1.7-2.4), ”the study authors wrote.
In modern life, we continue to experience the global COVID-19 pandemic caused by SARS-CoV-2. Researchers at the Lady Davis Institute (LDI) at the Jewish General Hospital suggest that a protein transmitted by Neanderthals may offer some protection against COVID-19, which currently has limited treatment options.3
Using proteomics-based methods, Dr. Brent Richards and his colleagues analyzed proteins circulating in the blood in a large number of COVID-19 patients and controls, to identify whether particular proteins are associated with disease and could be used as drug targets. They found that an increase in the level of an isoform version of a protein known as OAS1 was associated with a reduction in mortality or ventilation, hospitalization, and susceptibility to COVID-19. . It is the result of more than 14,134 cases of COVID-19 and 1.2 million assessed checks.
“Interestingly, for non-African people, this protective effect is likely inherited from a form derived from Neanderthal OAS1 called p46,” said Dr Sirui Zhou, post-doctoral researcher at LDI. The researchers suggest that OAS1 likely emerged in people of European descent through interbreeding and increased in prevalence due to evolutionary pressures. They also suggest that this version of the protein likely played a protective role in past pandemics.
“Our recommendation is that drugs that trigger an increase in OAS1 levels be more studied for their effect on COVID-19 outcomes so that we can better treat infected patients ”, mentionned Dr Richards.
A team of scientists led by Cleber Trujillo, a former researcher at the University of California, San Diego, used a genome-editing technology known as CRISPR-Cas9 to replace a modern gene – NOVA1, necessary for neurodevelopment – with its ancestral form expressed in Neanderthal populations. The researchers wanted to know more about the evolution of the human brain and the genes that were at the heart of this process.
Trujillo and his colleagues inserted the archaic version of NOVA1 in mini brain models known as organoids which are created using stem cells. As a control measure, cortical organoids were also created, expressing the modern variant of NOVA1. RNA from cortical organoids was collected and sequenced to determine if differences in gene expression could be detected. By comparing cortical organoids which were homozygous for the archaic allele with organoids which were homozygous for the modern human allele, 277 differentially expressed genes were identified; many of which are known to be involved in different stages of neurodevelopment.
Organoids carrying the archaic form of NOVA1 have also been shown to mature much faster than those carrying the modern allele, which scientists say may explain why humans have evolved to a higher level of complexity.
“By having slow neurodevelopment, our brains could reach a higher level of complexity,” said Professor Alysson Muotri of UCSD, Explain. “We have to take care of our infants until they become independent, and as a result, they will develop more complex brains. A baby chimpanzee can outsmart a human brain, but it does not reach the same complexity. is true for most species.We humans are an outlier in that sense.
The “golden years” of the estate
Neanderthal research has advanced considerably over the past decade, which has been rightly dubbed the “Golden Years”. Knowledge of our relationship with this ancient species continues to grow, and after that, so does the list of questions we ask ourselves about what, exactly, makes us humans. As Peeters and Zwart wrote, “Neanderthal research forces us to reconsider the tendency to frame early human history in terms of“ them ”and“ us. ”The more information we can clarify regarding the evolutionary path of our current human phenotype, the more likely we are to unravel the molecular mechanisms that contribute to human disease.
1. Zeberg H, Kelso J, Pääbo S. The Neanderthal progesterone receptor. Molecular biology and evolution. 2020; 37 (9): 2655-2660. doi: 10.1093 / molbev / msaa119.
2. Zeberg H, Pääbo S. The main genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature. 2020; 587 (7835): 610-612. doi: 10.1038 / s41586-020-2818-3.
3. Zhou S, Butler-Laporte G, Nakanishi T, et al. An OAS1 Neanderthal isoform protects individuals of European descent from the susceptibility and severity of COVID-19. Nat Med. 2021; 27 (4): 659-667. doi: 10.1038 / s41591-021-01281-1.