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

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.

Genetic variations within human gained enhancer elements affect human brain sulcal morphology

“…This study on cortical gyrification expands beyond prior work showing genetic variations within human gained enhancers have effects on surface area of multiple cortical regions such as the inferior frontal gyrus, a region known for its involvement in language processing (Tilot et al, 2020). In our study, we showed that genetic variations in genomic regions that have shown different regulatory activity over the last 30 million years of human evolution may have also impacted on the shape of different human sulci, albeit in different regions of the cortex.…”

“…The contributions of each SNP set (defined based on evolutionary annotations) to the total SNP heritability of each sulcal trait were determined using partitioned heritability analyses from the previously obtained GWAS summary statistics, following methods described in Tilot et al 2020 (Tilot et al, 2020) and implemented in the LDSC software package (Finucane et al, 2015). Code used to perform analyses is available at https://bitbucket.org/jasonlouisstein/enigmaevolma6/src/master/.…”

Fine-grained temporal mapping of derived high-frequency variants supports the mosaic nature of the evolution ofHomo sapiens

“…In addition, we are aware that variants enter the genome at one stage and are likely selected for at a (much) later stage [29,30]. As such our study differs from the chronological atlas of natural selection in our species presented in [31] (as well as from other studies focusing on more recent periods of our evolutionary history, such as [32]). This may explain some important discrepancies between the overall temporal profile of genes highlighted in [31] and the distribution of HF variants for these genes in our data (Figure S7).…”

Discovery of 42 Genome-Wide Significant Loci Associated with Dyslexia

“…Enrichment was seen in enhancer and promoter regions with the chromatin marks H3M4me1 and H3K4me3 chromatin marks in multiple central nervous system (CNS) tissues (Supplementary Tables 19 and 20; Supplementary Figures 10 and 11). Reading, an offshoot of spoken language, is a uniquely human trait, but there was no enrichment for a range of annotations related to human evolution spanning the last 30 million to 50,000 years [21] (Supplementary Table 21).…”