Abstract

Stuttering is a common neurodevelopmental condition characterized by disfluencies in speech, such as blocks, prolongations, and repetitions. While most children who stutter do so only transiently, there are some for whom stuttering persists into adulthood. Rare-variant screens in families including multiple relatives with persistent stuttering have so far identified six genes carrying putative pathogenic variants hypothesized to act in a monogenic fashion. Here, we applied a complementary study design, searching instead for de novo variants in exomes of 85 independent parent-child trios, each with a child with transient or persistent stuttering. Exome sequencing analysis yielded a pathogenic variant in SPTBN1 as well as likely pathogenic variants in PRPF8, TRIO, and ZBTB7A - four genes previously implicated in neurodevelopmental disorders with or without speech problems. Our results also highlighted two further genes of interest for stuttering: FLT3 and IREB2. We used extensive bioinformatic approaches to investigate overlaps in brain-related processes among the twelve genes associated with monogenic forms of stuttering. Analyses of gene-expression datasets of the developing and adult human brain, and data from a genome-wide association study of human brain structural connectivity, did not find links of monogenic stuttering to specific brain processes. Overall, our results provide the first direct genetic link between stuttering and other neurodevelopmental disorders, including speech delay and aphasia. In addition, we systematically demonstrate a dissimilarity in biological pathways associated with the genes thus far implicated in monogenic forms of stuttering, indicating heterogeneity in the etiological basis of this condition.Competing Interest StatementThe authors have declared no competing interest.Funding StatementEE, AV and SEF are financially supported by the Max Planck Society. EE is also supported by a Veni grant of the Dutch Research Council (NWO; VI.Veni.202.072). The authors also acknowledge receiving a seed grant from the Leibniz Wissenschaftscampus primate cognition to M.S. (Sommer/Mani DM 22-606) Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The medical ethics committee of the Erasmus Medical Center in Rotterdam approved this study (registration number: MEC-2006-349). The medical ethics committee of the Erasmus Medical Center in Rotterdam approved this study (registration number: MEC-2019-0491). The medical ethics committee of the University of Goettingen approved this study (registration number 19/2/15).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

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

Impaired musical rhythm abilities and developmental speech-language related disorders are biologically and clinically intertwined. Prior work examining their relationship has primarily used small samples; here, we studied associations at population-scale by conducting the largest systematic epidemiological investigation to date (total N = 39,092). Based on existing theoretical frameworks, we predicted that rhythm impairment would be a significant risk factor for speech-language disorders in the general adult population. Findings were consistent across multiple independent datasets and rhythm subskills (including beat synchronization and rhythm discrimination), and aggregate meta-analyzed data showed that rhythm impairment is a modest but consistent risk factor for developmental speech, language, and reading disorders (OR = 1.32 [1.14 – 1.49]; p < .0001). Further, cross-trait polygenic score analyses indicate shared genetic architecture between musical rhythm and reading abilities, providing evidence for genetic pleiotropy between rhythm and language-related phenotypes.