The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area.

Amanda K Tilot,Sarah M Brotman,Jodie Painter,Neda Jahanshad,Lucía Colodro-Conde,Siyao Liu,Fabio Macciardi,Penelope A Lind,Janita Bralten,Katrina L Grasby,Derrek P Hibar,Ekaterina A Khramtsova,Simon E Fisher,Dan Liang,Lea K Davis,Barbara E Stranger,Paul M Thompson,Jason L Stein,Sarah E Medland

doi:10.1093/cercor/bhaa327

Abstract

Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000–3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure.

Highlights

The size, shape, and neural architecture of the modern human brain reflect the cumulative effects of selective pressures over evolutionary history
We focused our analyses on surface area (SA) given its particular expansion during hominid evolution, well established in prior literature, but as a comparison show results from analyses of thickness in the Supplementary Materials
Magnetic resonance images of the brain were segmented with FreeSurfer (Dale et al 1999) using a gyrally defined atlas (Desikan et al 2006), and visually quality checked based on guidelines provided at the ENIGMA website

Summary

Introduction

The size, shape, and neural architecture of the modern human brain reflect the cumulative effects of selective pressures over evolutionary history. It is thought that these volumetric increases were mainly driven by expansions of neocortical surface area (SA) (Rakic 2009; Lui et al 2011; Geschwind and Rakic 2013), changes in other brain structures, including the cerebellum, likely played a significant role (Barton and Venditti 2014; Miller et al 2019). Skull endocasts of archaic hominins suggest that human-specific refinements to brain structure occurred during the last 300 000 years, most notably the shift toward a more globular shape (Hublin et al 2017; Gunz et al 2019). Neuroanatomical changes in our ancestors were accompanied by increasingly sophisticated tool use, the emergence of proficient spoken language, world-wide migrations, and the development of agriculture, among other innovations (Pääbo 2014)

Results

Discussion

Conclusion