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.


Published September 27, 2021

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


Omer Gokcumen.

Omer Gokcumen


Omer Gokcumen


Associate Professor
Distinguished Postdoc Mentor Award, 2019

Research Interests

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


  • 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.

Research News

Selected Publications

  • 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
  • Saito, M., Gokcumen, O. (2019). Resolving the insertion sites of polymorphic duplications reveals a HERC2 haplotype under selection. Genome Biology and Evolution. evz107  [Corresponding Author].
  • Pajic, P., Pavlidis, P., Dean, K., Neznanova, L., Daugherity, E., Romano R-A., Garneau, D., Globig, A., Ruhl, S., Gokcumen, O. (2019). Independent amylase gene copy number bursts correlate with dietary preferences in mammals. eLife. 8:e44628 [Corresponding Author].
  • Chow J, Starr I*, Jamalzadeh S, Muniz O, Kumar A, Gokcumen, O.*, Ferkey DM, Cullen PJ. 2019. Filamentation Regulatory Pathways Control Adhesion-Dependent Surface Responses in Yeast. Genetics [Internet]:genetics.302004.2019. Available from: http://dx.doi.org/10.1534/genetics.119.302004
  • Lin, Y.-L.*, & Gokcumen, O.* (2019). Fine-Scale Characterization of Genomic Structural Variation in the Human Genome Reveals Adaptive and Biomedically Relevant Hotspots. Genome Biology and Evolution, 11(4), 1136–1151.  [Corresponding Author].Lin, Y-L., Gokcumen, O. (2018). Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots. BioRxiv [preprint]. April 4, 2018. Available here.
  • Pajic, P., Pavlidis, P., Dean, K., Neznanova, L., Daugherity, E., Romano R-A., Garneau, D., Globig, A., Ruhl, S., Gokcumen, O. (2018). Amylase copy number analysis in several mammalian lineages reveals convergent adaptive bursts shaped by diet. BioRxiv [preprint]. June 5, 2018. Available here.
  • Saito, M.*, Satta, Y., Gokcumen, O.* (2018). Complex haplotypes of GSTM1 gene deletions harbor signatures of a selective sweep in East Asian populations. G3. 8:2953.
  • Saito, M*. Lizardo, D., Taskent, R. O.*, Millner, A., Gokcumen, O., Atilla-Gokcumen, G. (2018). An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence. Mol Omics 14, 237 (a journal of Royal Society of Chemistry). [Cover article, co-Corresponding Author]. 
  • Saito, M.*, Satta, Y., Gokcumen, O.*, Ishida, T. (2018). Complex evolution of the GSTM gene family involves sharing of GSTM1 deletion polymorphism in humans and chimpanzees. BMC Genomics. 19:293. [co-Corresponding Author, IF:4.3]. 
  • Quillen, E., Norton, H., Parra, E., Lona-Durazo, F., Ang, K., I, Florin M., Pearson, L., Shriver, M., Lasisi, T., Gokcumen, O., Starr, I*., Lin, YL*., Martin, A., Jablonski, N. (2018). Shades of complexity: New perspectives on the evolution and genetic architecture of human skin. Yearbook of Physical Anthropology. (Early View).
  • Gokcumen, O. (2018). The Year in Genetics Anthropology: New Lands, New Technologies, New Questions. American Anthropologist. 120:266. [Also highlighted in the special virtual issue: “Genetics, Biology, and Race: Understanding Human Difference”].
  • Resendez, S.D.*, Bradley, J.*, Xu, D.*, Gokcumen, O.* (2018). Structural variants in ancient genomes. In: Rajora and Lindqvist, eds. Paleogenomics. Springer Population Genomics Series.
  • Schmidt, C. and Gokcumen, O.* (In press). Primate Genomics and Phylogenetics. In: O’Rourke, eds. A Companion to Anthropological Genetics. Wiley Press
  • Taskent et al. (2017). Variation and functional impact of Neanderthal ancestry in Western Asia.  Genome Biology and Evolution.  evx216. For press release.
  • Xu et al. (2017). VCFtoTree: a user-friendly tool to construct locus-specific alignments and phylogenies from thousands of anthropologically relevant genome sequences. BMC Bioinformatics. 18:426.
  • Xu et al. (2017). Archaic hominin introgression in Africa contributes to functional salivary MUC7 genetic variation. Mol Biol Evol. Press release from UB Press Office. A write-up in the Guardian is here. For further media coverage, please see its Altmetric page.
  • Taskent and Gokcumen (2017). The multiple histories of Western Asia: Perspectives from ancient, and modern genomes. PrePrint (before proofs). Hum. Bio.
  • Lizardo et al. (2017). Regulation of lipids is central to replicative senescence.  Molecular BioSystems. 13, 498-509 – This study was also recognized by the Royal Society of Chemistry as an article of particular interest.
  • Pajic et al. (2016). The psoriasis-associated deletion of late cornified envelope genes LCE3B and LCE3C has been maintained under balancing selection since Human Denisovan divergence. BMC Evolutionary Biology. 16,265.
  • Muthukrishnan et al. (2016). Atopic Dermatitis Susceptibility Variants In Filaggrin Hitchhike Hornerin Selective Sweep. Genome Biology and Evolution. 8, 3240 – For media coverage, please see its Altmetric page.
  • Xu et al. Recent Evolution of the salivary mucin MUC7. (2016). Scientific Reports. 6, 31791. Press release from UB Press Office. For further media coverage, please see its Altmetric page.
  • Lin et al. (2015). The evolution and functional impact of human deletion variants shared with archaic hominin genomes. Mol Biol Evol. Early Access. [Corresponding Author]. – Press release from UB Press Office. For further media coverage, please see its Altmetric page.  Here is also Omer’s Talk on this paper at EMPH @Tempe 2015.
  • Muthukrishan et al. (2014). Geographic Distribution And Adaptive Significance Of Genomic Structural Variants: An Anthropological Genetics Perspective. Hum Bio. 86(4):260-275. 2014. [Cover Article].