In this work, we describe relationships between Neanderthal-derived genetic variation and co-localized cranial and brain morphology in modern humans. The results show that greater NeanderScore is associated with more Neanderthal-like skull shape (corresponding to published shape differences between modern humans and Neanderthals as documented in fossil samples2 and shown in Fig. 1), as well as regional changes in brain morphology underlying these skull changes, specifically in the IPS and visual cortex. This work not only offers an unprecedented window into structure of the Neanderthal brain, but also characterizes the contributions of admixture with H. neanderthalensis to the evolution of the modern human brain.

In examining the associations of NeanderScore with skull shape, it is important to note that the topology of the identified occipito-parieto-temporal patch associated with NeanderScore specifically recapitulates the pattern of expansion in Neanderthal relative to anatomically modern human skulls previously reported from fossil remains (Fig. 1, right)2. This finding provides crucial validation of the NeanderScore measurement and suggests that even in the context of the modern H. sapiens genome, Neanderthal genetic variation is associated with patterns of skull dimensions that mirror known Neanderthal phenotypes.

Additional validation of the NeanderScore metric lies in its comparison with other reports characterizing Neanderthal-derived genetic contributions to modern humans. The coefficient of variation (i.e., the relative standard deviation, independent of the mean and comparable across measures) of the NeanderScore metric is consistent with previous published studies5 that were performed with a different goal: prior studies, unlike ours, sought to test for differences in admixture across populations, and have, therefore, calculated the proportion of the entire genome that was derived from Neanderthals. In those studies, approximately 1.15% of the entire genome of persons of European decent was found to be derived from Neanderthals (standard deviation = 0.08)5. Inherently, that approach and the present one capture related though different characteristics of Neanderthal-derived genetic information and the means (and therefore the standard deviations as well) of these differently derived measures are not the same. Importantly, however, the coefficient of variation in previous studies was also 0.070,5 identical to the coefficient of variation reported here, providing further validity to the NeanderScore measure.

In determining NeanderScore related changes in brain morphology, we found two significant cortical regions, the IPS and primary visual cortex, which both directly underlie the region of skull shape associations. The IPS, though present throughout highly gyrified modern primates28, has been theorized to have undergone substantial evolutionary expansion in hominids, with cross-species functional neuroimaging demonstrating unique visuospatial processing characteristics in modern humans relative to rhesus monkeys32. Additionally, cranial vault analyses of fossil skulls have suggested differences in the parietal lobes of Neanderthals14, 15, and the intraparietal sulcal region in particular has been hypothesized to be a focus for some of these differences33. Moreover, the fact that the IPS is particularly critical for tool manipulation in modern humans34 makes this finding even more intriguing in view of continued debate over the nature and development of Neanderthal tool use35.

The other brain region revealed to have significant associations with NeanderScore was primary visual cortex. This cortical region is responsible for the first steps in processing of visual information in the mammalian cortex and feeds into later brain regions in the ventral and dorsal visual processing streams (which differentially subserve object recognition and visuospatial object location, respectively)36, with the IPS playing a prominent role in the latter. Though the functioning of the primary visual system is relatively conserved in primates, the size of primary visual cortex in modern humans is smaller than would be expected from brain volume37. Our data not only suggest that this may be less the case in Neanderthals, but also are consistent with cranial remains showing more prominent visual systems in Neanderthals than in modern humans15.

It should be noted that we did not find associations of NeanderScore with smaller frontotemporal volumes38 or shortened anterior extension of the temporal lobes13, as might have been hypothesized from previous cranial analyses of H. neanderthalensis, suggesting either that these particular phenotypes, if accurate, are not driven by the allelic variation captured by the NeanderScore measurement, or that such effects are more directly influenced by any of the myriad factors that establish the genetic and biological context of this modern cohort. Additionally, some of these phenotypes may be only partially modulated by genotypic factors inherited from Neanderthals, with an effect too small to be observed in our sample. In contrast, the effect sizes we observed here for the associations of NeanderScore with the skull and brain measures were moderate (average Cohen’s d = 0.58) but appropriate for the sample sizes used.

The analyses reported here were restricted to a sample of individuals of European descent. It is known that the degree of admixture is variable in different modern populations. For example, East Asian populations have been found to have a larger portion of the genome derived from Neanderthals than European populations (up to 20% more), though the admixed regions of the genome are not necessarily overlapping5. This raises the possibility that the findings reported here may not translate to other populations, where Neanderthal introgression may involve other genomic regions that may be functional in different ways. As large neuroimaging and genetic data from different populations become available, future work could investigate this possibility by performing similar analyses in different populations, including using African populations with minimal Neanderthal admixture as potential “null hypothesis” groups.

Finally, our analyses of the relationship of our findings to specific Neanderthal-derived gene variants, revealed a single 53 kb LD block that was significantly associated with the shared variance of the identified Neanderthal-derived brain and skull changes and that encodes for the gene GPR26. In line with our primary hypothesis for this analysis, that such genetic influences would be found in genes preferentially expressed in the human brain, GPR26 in fact encodes a G-protein coupled receptor subtype that is preferentially expressed in the brain29. Interestingly, in human post-mortem brains samples, expression of GPR26 peaks perinatally39, when the visual system is first challenged, indicating that it may play a role in development of the human visual system. Mouse models also show this gene to impact both affective and energy homeostatic functions40, 41. Additionally, this G-protein-coupled receptor has been shown to form oligomers with the 5-HT1a receptor42, perhaps providing a putative mechanism underlying the Neanderthal-related brain changes found here. Although the nature of the influence of this region on modern and archaic human nervous systems is uncertain, a possible link between brain energy regulation, neurodevelopment and mature structure may merit further investigation.

Because the NeanderScore measure employed here is, itself, polygenic, it is likely that the genetic contributions to skull and brain morphology we observed involve a number of different genetic loci. Nonetheless, our exploratory post-hoc genome-wide analysis of the shared variance of these findings identified only a single significant region. It is unlikely that this single locus, the LD block on chromosome 10, fully explains the brain and skull findings, and in fact, the Manhattan plot in Fig. 4 suggests that multiple other regions that do not meet strict Bonferroni corrections may represent some degree of true signal. Our modest sample size may have been underpowered to identify these additional signals. As larger datasets containing both genotype and neuroimaging data of brain and skull become available, future work will likely uncover additional genetic regions contributing to these findings.

Taken together, the associations between Neanderthal sequence variation and co-localized skull and brain morphology in modern humans engender an enduring, living footprint of H. neanderthalensis – a residual echo of shared, intimate history with a fallen lineage close to our own. To the extent that characterization of Neanderthal variation in present-day people can provide insights into archaic human phenotypes, this work can form the basis of future studies aimed at a more thorough understanding of Neanderthal biology. By the same token, we suggest that Neanderthal gene flow into modern humans is not only of evolutionary interest, but may also be functional in the living H. sapiens brain, revealing novel genetic influences on neurodevelopment of the visuospatial system upon which a fuller account of molecular mechanisms of IPS-driven normative mental functions, such as visuospatial integration and tool manipulation, can be built. This, in turn, may inform models of IPS-associated cognitive disability as seen in select developmental and neurological disorders43,44,45,46.