Gokcumen studies possible functions of GHRd3

“It is an exciting time for doing research on human evolution, where it is now possible to integrate data from ancient genomes, gene-editing technologies and advanced mathematical approaches to tell the human story in all its messy glory,” says UB evolutionary biologist Omer Gokcumen. Read the news article by Charlotte Hsu.

Omer Gokumen.

Omer Gokcumen, PhD

Research News

Scientists see glimmers of human history in gene tied to growth

Model of DNA highlighting one gene.

By CHARLOTTE HSU

Published September 27, 2021

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headshot of Omer Gokcumen.
“It is an exciting time for doing research on human evolution, where it is now possible to integrate data from ancient genomes, gene-editing technologies and advanced mathematical approaches to tell the human story in all its messy glory. ”
Omer Gokcumen, associate professor
Department of Biological Sciences

A new study delves into the evolution and function of the human growth hormone receptor gene, and asks what forces in humanity’s past may have driven changes to this vital piece of DNA.

The research shows, through multiple avenues, that a shortened version of the gene — a variant known as GHRd3 — may help people survive in situations where resources are scarce or unpredictable.

Findings were published Sept. 24 in Science Advances.

Here’s the story the study tells: GHRd3 emerged about 1-2 million years ago, and was likely the overwhelmingly predominant version of the gene in the ancestors of modern humans, as well as in Neanderthals and Denisovans.

Then, “In the last 50,000 years or so, this variant becomes less prevalent, and you have a massive decrease in the frequency of this variant among East Asian populations we studied, where we see the estimated allele frequency drop from 85% to 15% during the last 30,000 years,” says UB evolutionary biologist Omer Gokcumen. “So the question becomes: Why? Was this variant favored in the past, and it fell out of evolutionary favor recently? Or is what we are observing just a blip among the complexity of genomes?”

The research provides new insights into the function of GHRd3 that may help explain why these evolutionary changes occurred, demonstrating that the variant may be useful in coping with nutritional stress.

“We think that this variant is beneficial where there are periods of starvation, which was the case for most of human evolution,” says Gokcumen, associate professor of biological sciences, College of Arts and Sciences. With regard to GHRd3’s waning prominence in recent human history, he speculates that, “Maybe the rapid technological and cultural advances over the past 50,000 years have created a buffer against some of the fluctuations in resources that made GHRd3 so advantageous in the past.”

“GHRd3 is interesting because it is a very common deletion that is variable between you and me among humans,” says Marie Saitou, a tenure-track investigator at the Norwegian University of Life Sciences and a former postdoctoral researcher in Gokcumen’s lab at UB. “Normally, these kinds of important fundamental genes do not change between human to human, and are highly conserved in other animals even.”

The work was led by Saitou; Skyler Resendez, a recent UB graduate in biological sciences who is now a postdoctoral fellow in biomedical informatics in the Jacobs School of Medicine and Biomedical Sciences at UB; Xiuqian Mu, associate professor of ophthalmology in the Jacobs School and at the Ross Eye Institute; and Gokcumen. An international team of collaborators contributed perspectives in this study, which integrated advanced population genetics methods with research in a mouse model to understand the complicated history and function of a genetic variant.

Close look at possible functions of GHRd3

The growth hormone receptor gene plays a major role in controlling the body’s response to growth hormone, helping to activate processes that lead to growth.

To study the gene’s evolutionary history, scientists looked at the genomes of many modern humans, as well as those of four archaic hominins — three Neanderthals from different parts of the world, and one Denisovan. All four had the GHRd3 variant.

The team also investigated GHRd3’s modern functions. For example, the researchers found that the GHRd3 variant was associated with better outcomes in a group of children who had endured and survived severe malnutrition.

Additionally, studies on mice supported the idea that GHRd3 helps to regulate the body’s response to food scarcity. Male mice with the variant had some biological similarities to mice that had reduced access to food — traits that may be beneficial in surviving nutritional stress, the study found.

And when scientists placed male mice with GHRd3 on a low-calorie diet, the animals were smaller at 2 months old than counterparts without the variant. This may be beneficial in times of nutritional stress, as smaller bodies need less food. Because the effects of GHRd3 were not as prominent in females, male and female mice carrying the variant ended up being the same size when they were on a low-calorie diet (usually, males are significantly larger than females).

“Our study points to sex- and environment-specific effects of a common genetic variant. In the mice, we observed that GHRd3 leads to a ‘female-like’ expression pattern of dozens of genes in male livers under calorie restriction, which potentially leads to the observed size reduction,” Saitou says.

“Females, already smaller in size, may suffer from negative evolutionary consequences if they lose body weight. Thus, it is a reasonable and also very interesting hypothesis that a genetic variant that may affect response to nutritional stress has evolved in a sex-specific manner,” Mu says.

“Despite its prevalence in human populations, this unique genetic deletion has not been observed in any other living species,” Resendez says. “This makes it difficult to study. However, scientific advancements now give us the ability to edit genomes in a targeted fashion. This allowed us to generate a mouse model containing the deletion so that we could observe its effects closely in a controlled manner.”

“It is an exciting time for doing research on human evolution, where it is now possible to integrate data from ancient genomes, gene-editing technologies and advanced mathematical approaches to tell the human story in all its messy glory,” Gokcumen says.

In addition to Gokcumen, Mu, Resendez and Saitou, the study’s authors included G. Ekin Atilla-Gokcumen and Apoorva Pradhan in the UB Department of Chemistry; Fuguo Wu in the UB Department of Ophthalmology; Natasha Lie and Nancy Hall at the Baylor College of Medicine; Qihui Zhu at The Jackson Laboratory for Genomic Medicine; Charles Lee at The Jackson Laboratory for Genomic Medicine and First Affiliated Hospital of Xi’an Jiaotong University; Laura Reinholdt and Gary Churchill at The Jackson Laboratory in Bar Harbor; Yoko Satta at SOKENDAI; Leo Speidel at University College London and the Francis Crick Institute; Shigeki Nakagome at Trinity College Dublin; and Neil Hanchard at the National Human Genome Research Institute.

The research was supported by the U.S. National Science Foundation; the BrightFocus Foundation; the National Eye Institute and National Institute on Aging, both part of the U.S. National Institutes of Health; the Collaborative Learning and Integrated Mentoring in the Biosciences (CLIMB) program at UB; the Doris Duke Charitable Foundation; and the U.S. Department of Agriculture Agricultural Research Service; the First Affiliated Hospital of Xi’an Jiaotong University; and the Sir Henry Wellcome fellowship.

Faculty Profile

Omer Gokcumen

PhD

Omer Gokcumen.

Omer Gokcumen

PhD

Omer Gokcumen

PhD

Associate Professor
Distinguished Postdoc Mentor Award, 2019

Research Interests

Human and primate evolution, ancient humans (including Neanderthals and Denisovans), anthropological genomics

Education

  • PhD, University of Pennsylvania
  • Postdoctoral Research, Harvard Medical School

Research Statement

Omer Gokcumen is an expert in evolutionary anthropology — the study of how humans evolved and how they differ from non-human primates such as gorillas and chimpanzees. His work is tied to human evolution, including evolutionary adaptation and the evolutionary processes that lead to genetic disease.

Gokcumen’s research examines the role that genomic variants, especially deletions and duplications, play in human disease and biology. His laboratory investigates the evolutionary history of genetic variations tied to interesting traits and diseases in modern and ancient human populations.

Selected Publications

  • Nikkanen, J., Leong, W.A., Krause, W.C., Dermadi, D., Maschek, J.A., Van Ry, T., Cox, J.E., Weiss, E.J., Gokcumen, O.*, Chawla, A., Ingraham, H.A. (2022). Trade-Offs Between Hepatic Host Defense and Metabolic Programs Underlie Sex-Biased Diseases. Science. 378: 290-295.
  • Dos Santos, A.L.C., Owings, A., Sullasi, H.S.L., Gokcumen, O.*, DeGiorgio, M., Lindo, J. Genomic evidence of ancient migrations along South America's Atlantic coast. (2022). Proceedings of the Royal Society B. 289: 20221078.
  • Pajic, P.*, Shen, S., Qu, J., May, A.J., Knox, S., Ruhl, S., Gokcumen, O.* (2022) A mechanism of gene evolution generating mucin function. Science Advances. 8: 34. [Corresponding author].
  • Saitou, M.*, Masuda, N., Gokcumen, O.* (2022). Similarity-based analysis of allele frequency distribution among multiple populations identifies adaptive genomic structural variants. Molecular Biology and Evolution. 39: msab313. [Corresponding Author]. 
  • Saitou, M.*, Resendez, S.*, Pradhan, A.J., Wu, F., Lie, N.C., Hall, N.J., Zhu, Q.,  Reinholdt, L. Satta, Y., Speidel, L., Nakagome, S., Hanchard, N. A., Churchill, G., Lee, C., Atilla-Gokcumen,  G. E., Mu, X., Gokcumen, O.* (2021). Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor. Sci Adv. 7, eabi4476. [Corresponding Author].
  • Starr, I.*, Seiffert-Sinha, K, Sinha, A.A., Gokcumen, O.* (2021). Evolutionary Context of Psoriatic Immune Skin Response. Evolution, Medicine and Public Health. 9: 474-486 [Corresponding Author].  
  • Pliss, A., Kuzmin, A.N., Lita, A., Kumar, R., Celiku, O., Atilla-Gokcumen G.E., Gokcumen, O.*, Chandra, D., Larion, M., Prasad, P.N. (2021). Single Organelle Optical Omics Platform for Cell Science and Biomarker Discovery. Analytical Chemistry. 93:8281.
  • Pradhani et al. (2021). Protein acylation by saturated very long chain fatty acids and endocytosis are involved in necroptosis. Cell Chemical Biology. (In Press)
  • Xu, D., Gokcumen, O*., Khurana, E. (2020). Loss-of-function tolerance of enhancers in the human genome. PLoS Genetics. 6:e1008663.
  • Eaaswarkhanth, E., dos Santos, A.L.*, Gokcumen, O.*, Al-Mulla, F., Thanaraj, T.A. (2020). Genome-Wide Selection Scan in an Arabian Peninsula Population Identifies a TNKS Haplotype Linked to Metabolic Traits and Hypertension. Genome Biology and Evolution, 12:  77–87 [Highlighted in Human Genetics].
  • Gokcumen, O. (2020) Archaic hominin introgression into modern human genomes. Yearbook of Physical Anthropology. 171: 60.
  • Saitou, M.* & Gokcumen, O. (2020). An Evolutionary Perspective on the Impact of Genomic Copy Number Variation on Human Health. Journal of Molecular Evolution. 88: 104.
  • Thamadilok, S., Choi, K.-S., Ruhl, L., Schulte, F., Kazim, A. L., Hardt, M., Gokcumen, O*., Ruhl, S. (2020).Human and Non-Human Primate Lineage-Specific Footprints in the Salivary Proteome. Molecular Biology and Evolution. 37:39-405.
  • O Gokcumen, M Frachetti. The Impact of Ancient Genome Studies in Archaeology.  Annual Review of Anthropology. (2020) 49:277–98
  • Saitou, M*., Gaylord, E., Xu, D.,Neznanova, L., Nathan, S., Grawe, A., Chang, J., Ryan, William., Ruhl, S., Knox, S.M., and Gokcumen, O*.  (2020). Functional Specialization of Human Salivary Glands and Origins of Proteins Intrinsic to Human Saliva. Cell Reports. 33, 108402. [Corresponding Author].
  • Ozgur Taskent, Yen Lung Lin, Ioannis Patramanis, Pavlos Pavlidis and Omer Gokcumen, 2020. Analysis of Haplotypic Variation and Deletion Polymorphisms Point to Multiple Archaic Introgression Events, Including from Altai Neanderthal Lineage. https://doi.org/10.1534/genetics.120.303167

Research News

  • 2022 Interview for BBC 4 - Inside Science on our work on evolution of mucus. (here)
  • 2022 Interviewed for NPR - RadioLab. “Neanderthals’ revenge” episode on our work on ancient alleles in the human genome. (here)
  • 2021 Interviewed for Scientific American on our work on the evolution of human growth hormone receptor. (here)
  • 2021 Interviewed for The Scientist on our work on the evolution of human growth hormone receptor. (here)
  • 2021 Quoted in How Stuff Works - “How human are humans?” by Joanna Thompson. (here)
  • 2020 BBC - Reel
  • 2019 Quoted in NYTimes.

UB Now Highlights

  • 2022 Pajic et al. A mechanism of gene evolution generating mucin function. Press release. Selected highlights: New Scientist, Yahoo News, BBC, GEN, Inverse.
  • 2021 Saitou et al. Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor. Press release.  Selected highlights: Real Clear Science, The Scientist, Scientific American.
  • 2020 Saiotu et al. Functional Specialization of Human Salivary Glands and Origins of Proteins Intrinsic to Human Saliva. Press release.  Selected Highlights: Cosmos, CBC- Radio Active.
  • 2020 Taskent et al.  Analysis of haplotypic variation and deletion polymorphisms point to multiple archaic introgression events, including from Altai Neanderthal lineage. Press release.   Selected Highlights: Futurity, Sputnik, Genetic Literacy Project.