Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity

doi:10.1016/j.cub.2018.10.065

. 2019 Jan 7;29(1):120-127.e5.

doi: 10.1016/j.cub.2018.10.065. Epub 2018 Dec 13.

Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity

Philipp Gunz¹, Amanda K Tilot², Katharina Wittfeld³, Alexander Teumer⁴, Chin Yang Shapland², Theo G M van Erp⁵, Michael Dannemann⁶, Benjamin Vernot⁶, Simon Neubauer⁷, Tulio Guadalupe², Guillén Fernández⁸, Han G Brunner⁹, Wolfgang Enard¹⁰, James Fallon¹¹, Norbert Hosten¹², Uwe Völker¹³, Antonio Profico¹⁴, Fabio Di Vincenzo¹⁵, Giorgio Manzi¹⁴, Janet Kelso⁶, Beate St Pourcain¹⁶, Jean-Jacques Hublin⁷, Barbara Franke¹⁷, Svante Pääbo⁶, Fabio Macciardi¹⁸, Hans J Grabe¹⁹, Simon E Fisher²⁰

Affiliations

¹ Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany. Electronic address: gunz@eva.mpg.de.
² Language and Genetics Department, Max Planck Institute for Psycholinguistics, P.O. Box 310, 6500 AH, Nijmegen, the Netherlands.
³ Department of Psychiatry and Psychotherapy, University of Greifswald, Ellernholzstr. 1-2, 17489 Greifswald, Germany; German Center for Neurodegenerative Diseases (DZNE), Partner Site Rostock/Greifswald, Ellernholzstr. 1-2, 17489 Greifswald, Germany.
⁴ Institute for Community Medicine, University Medicine Greifswald, Walter-Rathenau Str. 48, 17475 Greifswald, Germany.
⁵ Clinical and Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, 5251 California Ave, Irvine, CA 92617, USA.
⁶ Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany.
⁷ Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany.
⁸ Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, 6500 GA, Nijmegen, the Netherlands.
⁹ Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, 6500 GA, Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ, Maastricht, the Netherlands.
¹⁰ Anthropology and Human Genomics, Department Biology II, Ludwig Maximilians University Munich, Grosshaderner Str. 2, D-82152 Martinsried, Germany.
¹¹ Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
¹² Institute of Diagnostic Radiology and Neuroradiology, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Ferdinand-Sauerbruch-Str. 1, 17475 Greifswald, Germany.
¹³ Interfaculty Institute of Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany.
¹⁴ Università degli Studi di Roma La Sapienza, Department of Environmental Biology, Piazzale Aldo Moro, 5, 00185, Roma, Italy.
¹⁵ Università degli Studi di Roma La Sapienza, Department of Environmental Biology, Piazzale Aldo Moro, 5, 00185, Roma, Italy; Istituto Italiano di Paleontologia Umana, Via Ulisse Aldrovandi, 18, 00197, Roma, Italy.
¹⁶ Language and Genetics Department, Max Planck Institute for Psycholinguistics, P.O. Box 310, 6500 AH, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
¹⁷ Donders Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands; Departments of Human Genetics and Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁸ Department of Psychiatry and Human Behavior, University of California, Irvine, Sprague Hall - Room 312, Gillespie Neuroscience - Laboratory, Mail Code: 3960, Irvine, CA 92697, USA.
¹⁹ Department of Psychiatry and Psychotherapy, University of Greifswald, Ellernholzstr. 1-2, 17489 Greifswald, Germany.
²⁰ Language and Genetics Department, Max Planck Institute for Psycholinguistics, P.O. Box 310, 6500 AH, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands. Electronic address: simon.fisher@mpi.nl.

PMID: 30554901
PMCID: PMC6380688
DOI: 10.1016/j.cub.2018.10.065

Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity

Philipp Gunz et al. Curr Biol. 2019.

. 2019 Jan 7;29(1):120-127.e5.

doi: 10.1016/j.cub.2018.10.065. Epub 2018 Dec 13.

Authors

Affiliations

¹ Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany. Electronic address: gunz@eva.mpg.de.
² Language and Genetics Department, Max Planck Institute for Psycholinguistics, P.O. Box 310, 6500 AH, Nijmegen, the Netherlands.
³ Department of Psychiatry and Psychotherapy, University of Greifswald, Ellernholzstr. 1-2, 17489 Greifswald, Germany; German Center for Neurodegenerative Diseases (DZNE), Partner Site Rostock/Greifswald, Ellernholzstr. 1-2, 17489 Greifswald, Germany.
⁴ Institute for Community Medicine, University Medicine Greifswald, Walter-Rathenau Str. 48, 17475 Greifswald, Germany.
⁵ Clinical and Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, 5251 California Ave, Irvine, CA 92617, USA.
⁶ Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany.
⁷ Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany.
⁸ Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, 6500 GA, Nijmegen, the Netherlands.
⁹ Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, 6500 GA, Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ, Maastricht, the Netherlands.
¹⁰ Anthropology and Human Genomics, Department Biology II, Ludwig Maximilians University Munich, Grosshaderner Str. 2, D-82152 Martinsried, Germany.
¹¹ Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
¹² Institute of Diagnostic Radiology and Neuroradiology, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Ferdinand-Sauerbruch-Str. 1, 17475 Greifswald, Germany.
¹³ Interfaculty Institute of Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany.
¹⁴ Università degli Studi di Roma La Sapienza, Department of Environmental Biology, Piazzale Aldo Moro, 5, 00185, Roma, Italy.
¹⁵ Università degli Studi di Roma La Sapienza, Department of Environmental Biology, Piazzale Aldo Moro, 5, 00185, Roma, Italy; Istituto Italiano di Paleontologia Umana, Via Ulisse Aldrovandi, 18, 00197, Roma, Italy.
¹⁶ Language and Genetics Department, Max Planck Institute for Psycholinguistics, P.O. Box 310, 6500 AH, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
¹⁷ Donders Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands; Departments of Human Genetics and Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁸ Department of Psychiatry and Human Behavior, University of California, Irvine, Sprague Hall - Room 312, Gillespie Neuroscience - Laboratory, Mail Code: 3960, Irvine, CA 92697, USA.
¹⁹ Department of Psychiatry and Psychotherapy, University of Greifswald, Ellernholzstr. 1-2, 17489 Greifswald, Germany.
²⁰ Language and Genetics Department, Max Planck Institute for Psycholinguistics, P.O. Box 310, 6500 AH, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands. Electronic address: simon.fisher@mpi.nl.

PMID: 30554901
PMCID: PMC6380688
DOI: 10.1016/j.cub.2018.10.065

Erratum in

Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity.
Gunz P, Tilot AK, Wittfeld K, Teumer A, Shapland CY, van Erp TGM, Dannemann M, Vernot B, Neubauer S, Guadalupe T, Fernández G, Brunner HG, Enard W, Fallon J, Hosten N, Völker U, Profico A, Di Vincenzo F, Manzi G, Kelso J, St Pourcain B, Hublin JJ, Franke B, Pääbo S, Macciardi F, Grabe HJ, Fisher SE. Gunz P, et al. Curr Biol. 2019 Mar 4;29(5):895. doi: 10.1016/j.cub.2019.02.008. Curr Biol. 2019. PMID: 30836076 Free PMC article. No abstract available.

Abstract

One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.

Keywords: Neandertal; basal ganglia; brain shape; cerebellum; evolution; gene expression; genetic association; homo sapiens; magnetic resonance imaging; myelination.

PubMed Disclaimer

Conflict of interest statement

DECLARATION OF INTERESTS

Authors declare no competing interests. B.F. received educational speaking fees from Shire and Medice.

Figures

**Figure 1.. Endocranial Shape Differences between Neandertals and Modern Humans**
(A) CT scan of the Neandertal fossil from La Chapelle-aux-Saints with a typical elongated endocranial imprint (red). (B) CT scan of a modern human showing the characteristic globular endocranial shape (blue). Arrows highlight the enlarged posterior cranial fossa (housing the cerebellum) as well as bulging of parietal bones in modern humans compared to Neandertals. (C) Average endocranial shape of adult Neandertals; each vertex of the surface corresponds to a semilandmark. (D) Average endocranial shape of modern humans. Areas shaded in green are relatively larger in modern humans than in Neandertals. (E and F) The semilandmarks used to quantify overall endocranial shape from MRI scans of living people shown on the MNI 152 template in lateral and frontal views, respectively.

**Figure 2.. Globularity Scores of CT and MRI Scans**
(A) Principal component analysis of endocranial shape. 99% confidence ellipses are shown for modern human CT scans from Europe (blue; n = 19), MRI scans of present-day humans (yellow; n = 6,575), and Neandertal CT scans (red; n = 7); two *Homo heidelbergensis* individuals are plotted in black. (B) Frequency plot of globularity scores computed for data shown in (A). This globularity score quantifies overall endocranial shape by projecting each individual onto the vector between the elongated average shape of Neandertals and the globular average shape of present-day humans. Inset shows example MRI scans associated with low (left) and high (right) globularity scores among present-day humans. See also Figure S1.

**Figure 3.. Endocranial Globularity in Modern Humans Is Associated with Introgressed Neandertal Haplotypes**
(A) Association statistics for introgressed Neandertal SNPs (solid line, significance, adjusted for multiple testing; dashed line, suggestive significance). (B) Quantile-quantile plot of association p values, showing the expected uniform distribution, with the outliers representing significant associations. (C) Forest plots depict the effects of the top Neandertal SNPs, for each study and genotyping batch. Boxes are proportional to weight, with whiskers representing the 95% confidence interval; diamonds represent a linear mixed-effect model incorporating all five datasets. (D) Covariate-corrected globularity scores by genotype. All data points are shown; boxes represent 25^th and 75^th percentiles; whiskers represent 1.5 times the interquartile range.

**Figure 4.. Introgressed Neandertal Fragments Associated with Globularity**
(A and C) Detailed views of the kilobase surrounding the Neandertal SNPs within the introgressed haplotypes (brown bars) on chromosomes 1 (A) and 18 (C). (B and D) Expression quantitative trait loci data from the GTEx resource, showing the impact of Neandertal alleles on gene expression for *UBR4* (B) and *PHLPP1* (D), as defined by [24]. See also Figures S3 and S4.

See this image and copyright information in PMC

Comment in

Brain Evolution: Mapping the Inner Neandertal.
Sherwood CC, Bradley BJ. Sherwood CC, et al. Curr Biol. 2019 Feb 4;29(3):R95-R97. doi: 10.1016/j.cub.2018.12.024. Curr Biol. 2019. PMID: 30721683
Neanderthal clues to brain evolution in humans.
El-Showk S. El-Showk S. Nature. 2019 Jul;571(7766):S10-S11. doi: 10.1038/d41586-019-02210-6. Nature. 2019. PMID: 31341308 No abstract available.

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References

1. Lieberman DE, McBratney BM, and Krovitz G (2002). The evolution and development of cranial form in Homo sapiens. Proc. Natl. Acad. Sci. USA 99, 1134–1139. - PMC - PubMed
1. Bruner E, Manzi G, and Arsuaga JL (2003). Encephalization and allometric trajectories in the genus Homo: evidence from the Neandertal and modern lineages. Proc. Natl. Acad. Sci. USA 100, 15335–15340. - PMC - PubMed
1. Bruner E (2004). Geometric morphometrics and paleoneurology: brain shape evolution in the genus Homo. J. Hum. Evol 47, 279–303. - PubMed
1. Neubauer S, Hublin JJ, and Gunz P (2018). The evolution of modern human brain shape. Sci. Adv 4, eaao5961. - PMC - PubMed
1. Kochiyama T, Ogihara N, Tanabe HC, Kondo O, Amano H, Hasegawa K, Suzuki H, Ponce de León M.S., Zollikofer CPE, Bastir M, et al. (2018). Reconstructing the Neanderthal brain using computational anatomy. Sci. Rep 8, 6296. - PMC - PubMed

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[1] Lieberman DE, McBratney BM, and Krovitz G (2002). The evolution and development of cranial form in Homo sapiens. Proc. Natl. Acad. Sci. USA 99, 1134–1139. - PMC - PubMed

[2] Lieberman DE, McBratney BM, and Krovitz G (2002). The evolution and development of cranial form in Homo sapiens. Proc. Natl. Acad. Sci. USA 99, 1134–1139. - PMC - PubMed

[3] Bruner E, Manzi G, and Arsuaga JL (2003). Encephalization and allometric trajectories in the genus Homo: evidence from the Neandertal and modern lineages. Proc. Natl. Acad. Sci. USA 100, 15335–15340. - PMC - PubMed

[4] Bruner E, Manzi G, and Arsuaga JL (2003). Encephalization and allometric trajectories in the genus Homo: evidence from the Neandertal and modern lineages. Proc. Natl. Acad. Sci. USA 100, 15335–15340. - PMC - PubMed

[5] Bruner E (2004). Geometric morphometrics and paleoneurology: brain shape evolution in the genus Homo. J. Hum. Evol 47, 279–303. - PubMed

[6] Bruner E (2004). Geometric morphometrics and paleoneurology: brain shape evolution in the genus Homo. J. Hum. Evol 47, 279–303. - PubMed

[7] Neubauer S, Hublin JJ, and Gunz P (2018). The evolution of modern human brain shape. Sci. Adv 4, eaao5961. - PMC - PubMed

[8] Neubauer S, Hublin JJ, and Gunz P (2018). The evolution of modern human brain shape. Sci. Adv 4, eaao5961. - PMC - PubMed

[9] Kochiyama T, Ogihara N, Tanabe HC, Kondo O, Amano H, Hasegawa K, Suzuki H, Ponce de León M.S., Zollikofer CPE, Bastir M, et al. (2018). Reconstructing the Neanderthal brain using computational anatomy. Sci. Rep 8, 6296. - PMC - PubMed

[10] Kochiyama T, Ogihara N, Tanabe HC, Kondo O, Amano H, Hasegawa K, Suzuki H, Ponce de León M.S., Zollikofer CPE, Bastir M, et al. (2018). Reconstructing the Neanderthal brain using computational anatomy. Sci. Rep 8, 6296. - PMC - PubMed

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Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity

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Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity

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