Infographic showing that modern humans may have the GHRd3 deletion. However, all four archaic hominins who studied three Neanderthals as well as one Denisovan also had the deletion. Credit: Credit to Rebecca Farnham/Marie Saitou/University at Buffalo. Genome assembly diagrams generated by the Integrative Genomics Viewer (IGV, https://igv.org/doc/IGVdesktop).
A new study examines the evolution and function the human growth hormone receptor gene and questions what factors in the past might have influenced these vital pieces of DNA.
Multiple avenues of research have shown that people can survive in circumstances where resources are scarce or uncertain by using a shorter version of the genea variation known as GHRd3.
Science Advances will publish the findings on September 24th.
The study tells us that GHRd3 was discovered about 1-2 million years ago and is likely to be the dominant version in modern humans' ancestors, as well in Neanderthals or Denisovans.
Omer Gokcumen, University of Buffalo evolutionary biologist, says that this means that "in the last 50,000 years or more, this variant has become less common" and there is a significant decrease in the prevalence of this variant among East Asian population we studied. In this case, the estimated allele frequency dropped from 85% to 15% over the past 30,000 years. The question is: "Why?" This variant was favored in the past but lost its evolutionary favour recently. Is this a small blip in the vast complexity of genomes?
This research provides new insight into GHRd3's function, which may help to explain these evolutionary changes. It also suggests that this variant might be helpful in dealing with nutritional stress.
Gokcumen, Ph.D. is an associate professor of biological sciences at the UB College of Arts and Sciences. "We believe that this variant can be beneficial where there are periods of hunger, which was the case in most of human evolution." He speculates that GHRd3's declining prominence in human history may be due to "Maybe the rapid technological, cultural, and scientific advances of the past 50,000 year have created a buffer against some fluctuations in resources that were so beneficial in the past."
Marie Saitou (Ph.D.), tenure-track researcher at the Norwegian University of Life Sciences, and a former postdoctoral researcher at UB's Gokcumen lab, says that GHRd3 is "interesting because it is a very frequent deletion that is variable among you and me among human." These kinds of fundamental genes are not subject to change in humans, but they are highly conserved in animals.
Skyler Resendez (Ph.D.), a recent UB graduate, was the leader of the work. He is also a postdoctoral fellow at Jacobs School of Medicine & Biomedical Sciences and is currently a research associate at the Ross Eye Institute and as an associate professor of ophthalmology at Jacobs School. This study incorporated advanced population genetics methods and research in a mouse model in order to understand the complex history and function of genetic variants.
Take a closer look at the possible functions of GHRd3.
The body's response is controlled by the growth hormone receptor gene, which activates processes that promote growth.
Scientists looked at the genomes many modern people, four archaic hominins, three Neanderthals and one Denisovan to study the gene's evolution history. All four of them had the GHRd3 variant.
The modern functions of GHRd3 were also examined by the team. The researchers discovered that GHRd3 was associated with better outcomes for children who had survived and endured severe malnutrition.
Studies on mice also supported the notion that GHRd3 regulates the body's response when there is food shortage. The study showed that male mice carrying the variant shared some biological similarities with mice that had less access to foodtraits, which may help them survive nutritional stress.
Scientists found that male mice with GHRd3 were 2 months younger than their counterparts who had the variant. This could be beneficial during times of nutritional stress when smaller animals require less food. GHRd3's effects on females were less prominent than in males. Male and female mice with the variant were the same size when fed a low-calorie diet. Usually, males are much larger than their female counterparts.
"Our study shows that a common genetic variant can have sex- and environmental-specific effects. We observed in mice that Ghrd3 causes a female-like expression pattern of dozens genes in male livers when there is calorie restriction. This could potentially lead to observed size reduction," Saitou said.
"Females already smaller in stature may experience negative evolutionary consequences if their body weight drops." Mu states that it is an interesting and reasonable hypothesis that a genetic variant which may alter the response to nutritional stress has evolved in specific ways.
Resendez states that despite its presence in humans, this rare genetic deletion has never been seen in any other living species. This makes it difficult for scientists to study. Scientists have now been able to modify genomes in a specific way. We were able to create a mouse model with the deletion in order to observe its effects closely and control them.
Gokcumen states, "It's an exciting time to do research on human evolutionary, where it's now possible to combine data from ancient genomes and gene editing technologies with advanced mathematical approaches to tell a human story in all its messy glory."
Learn more about how genetic variation has evolved in the human genome
Science Advances (2021): More information on Sex-specific Phenotypic Effects and Evolutionary History of an Ancient Polymorphic Deletion of the Human Growth Hormone Receptor, Science Advances (2021). Information from Science Advances Sex-specific Phenotypic Effects and Evolutionary History of an Ancient Polymorphic Deletion of the Human Growth Hormone Receptor, (2021). DOI: 10.1126/sciadv.abi4476
