Abstract

Recent advances in paleo-genetics allowed the identification of protein-coding changes apparently fixed on the lineage leading to Homo sapiens, by comparing genomes of present-day humans and archaic hominins. Although such genomic differences are thought to make key contributions to distinctly modern human traits, experimental validation of their potential impact was so far restricted to functional assays and model organisms. With the availability of large-scale genetically informative population databases, it now becomes possible to identify present-day carriers of rare archaic alleles of interest and to directly assess putative phenotypic consequences in living humans. We queried exome sequencing data of around half a million people in the UK Biobank in search of carriers of archaic alleles at 37 genomic positions with supposedly fixed human-specific changes. This search yielded 103 carriers of the archaic allele for 17 positions, with diverging allele counts across ancestries. We contrasted carriers of an exemplary archaic allele in SSH2 with a curated set of non-carriers, observing no deviation from the norm in a range of health, psychological, and cognitive traits. We also identified 62 carriers of the archaic allele of a missense change in the TKTL1 gene, previously reported to have large effects on cortical neurogenesis based on functional analyses in brain organoids and animal models. However, human carriers of the archaic TKTL1 allele did not show differences in anatomical brain measures and qualification level, compared to non-carriers. These results highlight the importance of investigating diverse ancestral populations for a more accurate representation of shared human variation and challenge the notion of permanently fixed genetic changes that set Homo sapiens apart from Neandertals and Denisovans. Lastly, we propose that future investigations should assess effects of multiple archaic alleles in aggregate, since any single genetic change is unlikely to itself explain the emergence of complex human traits.Competing Interest StatementThe authors have declared no competing interest.

Abstract

Compared with our fossil ancestors and Neandertal kin, modern humans have evolved a distinctive skull shape, with a rounder braincase and more delicate face. Competing explanations for this rounder skull have either linked it to changes in brain organisation, or seen it as a by-product of gracilization (evolution of thinner and lighter skeletal anatomy). Here, we combined palaeoanthropological data from hominin fossils and imaging genomics data from living humans to gain insight into evolutionary and developmental mechanisms shaping this uniquely modern human phenotype. We analysed endocranial globularity from magnetic resonance imaging (MRI) brain scans and genetic data of more than 33,000 adults. We discovered 28 genomic loci significantly associated with endocranial globularity. There was genetic overlap with the brain’s ventricular system, white matter microstructure, and sulcal morphology, and with multivariate genetic analyses of reading/language skills, but not with general cognition. The associated genes exhibited enriched expression in the brain during prenatal development and early childhood. The connection to the ventricular system hints at a role for cerebrospinal fluid pressure in shaping the endocranium during development. Genes linked to endocranial globularity also showed enhanced expression in the cardiovascular and female reproductive systems. This finding suggests co-evolutionary pathways whereby changes impacting factors such as energy needs, pregnancy, or fertility concurrently shape the brain and its structure.Competing Interest StatementThe authors have declared no competing interest.

Abstract

Germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders. Heterozygous missense variants at a hotspot encoding a canonical degron lead to SETBP1 accumulation and Schinzel-Giedion syndrome (SGS), a rare severe developmental disorder involving multisystem malformations. Heterozygous loss-of-function variants result in SETBP1 haploinsufficiency disorder which is phenotypically much milder than SGS. Following an initial description of four individuals with atypical SGS carrying heterozygous missense variants adjacent to the degron, a few individual cases of variants outside the degron were reported. Due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of the roles of the gene in brain development, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remain elusive, imposing challenges for diagnosis and patient care. Here, we present a comprehensive investigation of the largest cohort to-date of individuals carrying SETBP1 missense variants outside the degron (n=18, including one in-frame deletion). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1 haploinsufficiency disorder, and primarily characterised by intellectual disability, epilepsy, speech and motor impairment. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding and transcription. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care and aetiology of SETBP1-related disorders.