What Have We Learned From the Neanderthals Lately?

Modern humans are, technically, a young species. Current evidence suggests that we emerged from East Africa approximately 200,000 years ago. While that may seem like a long period of time in the context of the human life span, if you consider that the first humans were estimated to have diverged from chimpanzee lineages approximately 6 million years ago, we are pretty brand new. 

Before us, archaic humans roamed the Earth, including Homo neanderthalensis – the Neanderthals – our closest relatives. Before Neanderthals became extinct, they cohabited the Earth with our ancestors for a period of time, the exact duration of which remains somewhat elusive; however, it was certainly enough time for interbreeding to occur.

The result of our ancestors reproducing with Neanderthals is that we present-day humans possess archaic genetic mutations from the extinct species. This information has effectively been written and stored in our genomes for thousands of years, but only recently have we developed the tools to read, analyze and interpret it. In 1997, the 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 conducting DNA analysis have dramatically reduced, and a growing number of research groups are exploring "ancient" samples. From these studies, scientists can infer how mutations from the Neanderthals impact the phenotypes of present-day humans. What have we learned from recent research?  

Neanderthal Gene Variant Associated With Increased Fertility

Progesterone is a steroid hormone that belongs to the progestogen family. It is released from the ovaries and plays a central role in menstruation, pregnancy, libido and embryogenesis. For the hormone to induce an effect in the body, it must bind to its receptor, a protein that is encoded by the PGR gene located on chromosome 11. This receptor is in high abundance in the endometrium, and the binding of progesterone leads to a molecular cascade of events that helps to prepare the uterus for – and to maintain – pregnancy. Proteins are subject to genetic mutations that can change their structure and functionality. A variant of the progesterone receptor that carries a missense substitution is derived from Neanderthals. The oldest modern human that carries this variant – known as V66OL – is a 40,000-year-old woman from the Tianyuan Cave in China.

Researchers at the Max Planck Institute for Evolutionary Anthropology in Germany and Karolinska Institute in Sweden wanted to investigate what impact (if any) the Neanderthal variant has on modern carriers of the gene.¹ They analyzed biobank data from over 450,000 individuals and found that almost one in three women have inherited the progesterone receptor; 29% carry one copy, and 3% carry two copies. Women carrying the variant were less likely to experience bleeding or miscarriage in pregnancy and were likely to give birth to more children than those that did not carry the variant.

“These findings suggest that the Neandertal variant of the receptor has a favorable effect on fertility,” said Hugo Zeberg, researcher at the Department of Neuroscience at Karolinska Institute and the Max Planck Institute for Evolutionary Anthropology.

Neanderthal Gene Variants Both Increase and Decrease COVID-19 Risk

We continue to live through 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, that is what science suggests. 

In 2020, a number of large-scale studies identified a gene cluster located on chromosome three (chr3p21.31) as a genetic susceptibility locus in COVID-19 patients. The exact explanation as to why this gene cluster is associated with disease severity remains to be fully understood. However, scientists including Zeberg and Pääbo were able to identify where it came 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 individuals were carriers. The highest frequency of the cluster was identified in Bangladesh (63% of the population are carriers).²

"The Neanderthal haplotype may thus be a substantial contributor to COVID-19 risk in certain populations besides other risk factors, most notably advanced age. In apparent agreement with this, individuals of Bangladeshi origin in the UK have about two times higher risk to die from COVID-19 than the general population (hazard ratio 95% CI: 1.7–2.4)," the study authors wrote.

Neanderthal Protein May Reduce the Severity of COVID-19

In modern day life, we continue to live through 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 passed down from Neanderthals might offer some protection against COVID-19, which currently has limited treatment options.³

Using proteomics-based methods, Dr. Brent Richards and colleagues analyzed circulating proteins in the blood across large numbers of COVID-19 patients and controls, to identify whether any particular proteins are associated with the disease that 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 reduced COVID-19 death or ventilation, hospitalization and susceptibility. This was the result in over 14,134 COVID-19 cases and 1.2 million controls assessed.

"Interestingly, for non-African peoples, this protective effect is likely inherited from a Neanderthal derived form of OAS1 called p46," said Dr. Sirui Zhou, a post-doctoral fellow at LDI. The researchers propose that OAS1 likely emerged in people of European ancestry through interbreeding and has increased in prevalence due to evolutionary pressures. They also suggest that this version of the protein is likely to have served a protective role in earlier pandemics.

"Our recommendation is that those medications that trigger increased OAS1 levels be further studied for their effect on COVID-19 outcomes so that we may better treat infected patients,” said Dr. Richards.

Modern Brains Genetically Wired To Evolve Slower Than Neanderthal Brains

A team of scientists led by Cleber Trujillo, former researcher at the University of California San Diego, used a genome-editing technology known as CRISPR-Cas9 to replace a modern gene – NOVA1,  required for neurodevelopment – with its ancestral form that was expressed in Neanderthal populations. The researchers wanted to know more about how the human brain evolved and the genes that were central to this process.

Trujillo and colleagues inserted the archaic version of NOVA1 into mini brain models known as organoids that are created using stem cells. As a control measure, cortical organoids were also created that expressed the modern variant of NOVA1. RNA from the cortical organoids was gathered and sequenced to investigate whether any differences in gene expression could be detected. Comparing cortical organoids that were homozygous for the archaic allele with organoids that 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.

The organoids carrying the archaic form of NOVA1 were also found to mature much faster than those carrying the modern allele, which the scientists suggest could be why humans have evolved a higher level of complexity.

"By having a slow neurodevelopment, our brains might achieve a higher level of complexity," Professor Alysson Muotri from UCSD, explained. "We need to take care of our infants until they become independent, and consequently, they will develop more complex brains. A baby chimpanzee can outsmart a human brain, but it does not reach the same complexity. This is true for most species. We humans are an outlier in this sense."

The "golden years" of the field

Neanderthal research has majorly advanced over the last ten years, which have been aptly nicknamed the "golden years". Knowledge of our relatedness to this ancient species continues to grow, and subsequently, so does the list of questions we have about what, exactly, makes us human. 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 that we can clarify regarding the evolutionary pathway to our current human phenotype, the more likely we are to unravel the molecular mechanisms that contribute to human disease.  

References:

1. Zeberg H, Kelso J, Pääbo S. The Neandertal progesterone receptor. Molecular Biology and Evolution. 2020;37(9):2655-2660. doi:10.1093/molbev/msaa119.

2. Zeberg H, Pääbo S. The major 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. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity. Nat Med. 2021;27(4):659-667. doi:10.1038/s41591-021-01281-1.