eLife publishes "Balancing selection on genomic deletion polymorphisms in humans"

Deletions in anatomically modern humans (AMHs) that are shared with archaic hominins.

The eLife paper includes the image, titled, Deletions in anatomically modern humans (AMHs) that are shared with archaic hominins.

Alber Aqil, PhD candidate,  and Prof Omer Gokcumen are co-authors of a research paper that examines a key question in biology: why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigation of ancient and possibly adaptive deletions remains an imperative exercise. Their research demonstrates an excess of polymorphisms in present-day humans that predate the modern human-Neanderthal split (ancient polymorphisms), which cannot be explained solely by selectively neutral scenarios. The eLife paper is here. Read the research news article by Corey Nealon.

research news

Gene variations for immune, metabolic conditions have persisted in humans for more than 700,000 years

Homo neanderthalensis adult male. Reconstruction based on Shanidar 1 by John Gurche for the Human Origins Program, NMNH. Date: 225,000 to 28,000 years.

Homo neanderthalensis adult male. Reconstruction based on Shanidar 1 by John Gurche for the Human Origins Program, NMNH. Date: 225,000 to 28,000 years.

By CORY NEALON

Published February 23, 2023

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Alber Aqil.
“Our study contributes to the growing body of evidence suggesting that balancing selection may be an important force in the evolution of genomic variation among humans. ”
Alber Aqil, PhD candidate
Department of Biological Sciences

Like a merchant of old, balancing the weights of two different commodities on a scale, nature can keep different genetic traits in balance as a species evolves over millions of years.

These traits can be beneficial (for example, fending off disease) or harmful (making humans more susceptible to illness), depending on the environment.

The theory behind these evolutionary trade-offs is called balancing selection. A UB-led study published Feb. 21 in eLife explores this phenomenon by analyzing thousands of modern human genomes alongside ancient hominin groups, such as Neanderthal and Denisovan genomes.

The research has “implications for understanding human diversity, the origin of diseases and biological trade-offs that may have shaped our evolution,” says evolutionary biologist Omer Gokcumen, the study’s corresponding author.

Gokcumen, associate professor of biological sciences, College of Arts and Sciences, adds the study shows that many biologically relevant variants “have been segregating among our ancestors for hundreds of thousands, or even millions, of years. These ancient variations are our shared legacy as a species.”

Ties with Neanderthals stronger than previously thought

The work builds upon genetic discoveries in the past decade, including when scientists uncovered that modern humans and Neanderthals interbred as early humans moved out of Africa.

It also coincides with the growth of personalized genetic testing, with many people now claiming that a small percentage of their genome comes from Neanderthals. But, as the eLife study show, humans share much more in common with Neanderthals than those small percentages indicate.

This additional sharing can be traced back to a common ancestor of Neanderthals and humans that lived about 700,000 years ago. This common ancestor bequeathed to the Neanderthals and modern humans a shared legacy in the form of genetic variation.

The research team explored this ancient genetic legacy, focusing on a particular type of genetic variation: deletions.

Gokcumen says the “deletions are strange because they affect large segments. Some of us are missing large chunks of our genome. These deletions should have negative effects and, as a result, be eliminated from the population by natural selection. However, we observed that some deletions are older than modern humans, dating back millions of years ago.”

Gene variations passed down over millions of years

The researchers used computational models to show an excess of these ancient deletions, some of which have persisted since our ancestors first learned to make tools, some 2.6 million years ago. Furthermore, the models found that balancing selection can explain this surplus of ancient deletions.

“Our study contributes to the growing body of evidence suggesting that balancing selection may be an important force in the evolution of genomic variation among humans,” says first author Alber Aqil, a PhD candidate in biological sciences in Gokcumen’s lab.

The investigators found that deletions dating back millions of years are more likely to play an outsized role in metabolic and autoimmune conditions.

Indeed, the persistence of versions of genes that cause severe disease in human populations has long baffled scientists since they expect natural selection to get rid of these versions of genes. It is, after all, very unusual for potentially disease-causing variation to persist for such long periods. The authors argue that balancing selection can solve this riddle.

Aqil says these variations may “protect against infectious diseases, outbreaks and starvation, which have occurred periodically throughout human history. Thus, the findings represent a considerable leap in our understanding of how genetic variations evolve in humans. A variant may be protective against a pathogen or starvation while also underlying certain metabolic or autoimmune disorders, like Crohn’s disease.”

Additional co-authors include Leo Speidel, Sir Henry Wellcome Postdoctoral Fellow at the Genetics Institute of University College London and the Francis Crick Institute, and Pavlos Pavlidis of the Institute of Computer Science, one of eight institutes of the Foundation of Research and Technology-Hellas in Greece.

The research was supported by the National Science Foundation, the Sir Henry Wellcome Fellowship, and the Wellcome Trust.

Faculty Profile

  • Omer Gokcumen

    PhD

    Omer Gokcumen.

    Omer Gokcumen

    PhD

    Omer Gokcumen

    PhD

    Professor
    Distinguished Postdoc Mentor Award, 2019
    Department of Biological Sciences
    College of Arts and Sciences

    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

    • Veilleux, C.C., Garrett, E.C., Pajic, P.*, Saitou, M.*, Ochieng, J., Dagsaan, L.D., Dominy, N.J., Perry, G.H., Gokcumen, O.*,  Melin, A.D. (2023). Veillex Human subsistence and signatures of selection on chemosensory genes. Communications Biology. 6: 683. [co-Corresponding Author].
    • Lu, D., Parisi, L.R., Gokcumen, O.*, Attila-Gokcumen, E.A. SREBP activation contributes to fatty acid accumulations in necroptosis. (2023). RSC Chem Biol. 4: 310–322.
    • Aqil, A*, Gill, S., Gokcumen, O.*, Malhi, R.S., Reese, E.A., Smith J.L., Heaton, T.T., Lindqvist, C. A paleogenome from a Holocene individual supports genetic continuity in Southeast Alaska (2023). iScience. 26, 106581
    • Sun, Y.H., Cui, H., Song, Chi., Shen, J.T., Zhuo, X., Wang, R.H., Yu, X., Ndamba, R., Mu, Q., Gu, H., Wang, D., Murthy, G.G., Li, P., Liang, F., Liu, L., Tao, Q., Wang, Y., Orlowski, S., Xu, Q., Zhou, H., Jagne, J., Gokcumen, O.*, Anthony, N., Zhao, X., Li, X.Z.. Amniotes co-opt intrinsic genetic instability to protect germ-line genome integrity. (2023). Nature Communications. 14:812. 
    • Dos Santos, A.L.C.*, Sullasi, H.S.L., Gokcumen, O.*, Lindo, J., DeGiorgio, M. Spatiotemporal fluctuations of population structure in the Americas revealed by a meta-analysis of the first decade of archaeogenomes (2022). American Journal of Biological Anthropology. 180: 703-714.
    • A Aqil, L Speidel, P Pavlidis, O Gokcumen (2023) Balancing selection on genomic deletion polymorphisms in human. Elife. 12, e79111.
    • 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 News 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.
    Back to top
    • 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].