Publications

Abstract

Linguistic diversity, now and in the past, is widely regarded to be independent of biological changes that took place after the emergence of Homo sapiens. We show converging evidence from paleoanthropology, speech biomechanics, ethnography, and historical linguistics that labiodental sounds (such as “f” and “v”) were innovated after the Neolithic. Changes in diet attributable to food-processing technologies modified the human bite from an edge-to-edge configuration to one that preserves adolescent overbite and overjet into adulthood. This change favored the emergence and maintenance of labiodentals. Our findings suggest that language is shaped not only by the contingencies of its history, but also by culturally induced changes in human biology.

Abstract

Most people have left‐hemisphere dominance for various aspects of language processing, but only roughly 1% of the adult population has atypically reversed, rightward hemispheric language dominance (RHLD). The genetic‐developmental program that underlies leftward language laterality is unknown, as are the causes of atypical variation. We performed an exploratory whole‐genome‐sequencing study, with the hypothesis that strongly penetrant, rare genetic mutations might sometimes be involved in RHLD. This was by analogy with situs inversus of the visceral organs (left‐right mirror reversal of the heart, lungs and so on), which is sometimes due to monogenic mutations. The genomes of 33 subjects with RHLD were sequenced and analyzed with reference to large population‐genetic data sets, as well as 34 subjects (14 left‐handed) with typical language laterality. The sample was powered to detect rare, highly penetrant, monogenic effects if they would be present in at least 10 of the 33 RHLD cases and no controls, but no individual genes had mutations in more than five RHLD cases while being un‐mutated in controls. A hypothesis derived from invertebrate mechanisms of left‐right axis formation led to the detection of an increased mutation load, in RHLD subjects, within genes involved with the actin cytoskeleton. The latter finding offers a first, tentative insight into molecular genetic influences on hemispheric language dominance.

Abstract

FOXP proteins form a subfamily of evolutionarily conserved transcription factors involved in the development and functioning of several tissues, including the central nervous system. In humans, mutations in FOXP1 and FOXP2 have been implicated in cognitive deficits including intellectual disability and speech disorders. Drosophila exhibits a single ortholog, called FoxP, but due to a lack of characterized mutants, our understanding of the gene remains poor. Here we show that the dimerization property required for mammalian FOXP function is conserved in Drosophila. In flies, FoxP is enriched in the adult brain, showing strong expression in ~1000 neurons of cholinergic, glutamatergic and GABAergic nature. We generate Drosophila loss-of-function mutants and UAS-FoxP transgenic lines for ectopic expression, and use them to characterize FoxP function in the nervous system. At the cellular level, we demonstrate that Drosophila FoxP is required in larvae for synaptic morphogenesis at axonal terminals of the neuromuscular junction and for dendrite development of dorsal multidendritic sensory neurons. In the developing brain, we find that FoxP plays important roles in α-lobe mushroom body formation. Finally, at a behavioral level, we show that Drosophila FoxP is important for locomotion, habituation learning and social space behavior of adult flies. Our work shows that Drosophila FoxP is important for regulating several neurodevelopmental processes and behaviors that are related to human disease or vertebrate disease model phenotypes. This suggests a high degree of functional conservation with vertebrate FOXP orthologues and established flies as a model system for understanding FOXP related pathologies.

Abstract

This paper argues that inter-individual and inter-group variation in language acquisition, perception, processing and production, rooted in our biology, may play a largely neglected role in sound change. We begin by discussing the patterning of these differences, highlighting those related to vocal tract anatomy with a foundation in genetics and development. We use our ArtiVarK database, a large multi-ethnic sample comprising 3D intraoral optical scans, as well as structural, static and real-time MRI scans of vocal tract anatomy and speech articulation, to quantify the articulatory strategies used to produce the North American English /r/ and to statistically show that anatomical factors seem to influence these articulatory strategies. Building on work showing that these alternative articulatory strategies may have indirect coarticulatory effects, we propose two models for how biases due to variation in vocal tract anatomy may affect sound change. The first involves direct overt acoustic effects of such biases that are then reinterpreted by the hearers, while the second is based on indirect coarticulatory phenomena generated by acoustically covert biases that produce overt “at-a-distance” acoustic effects. This view implies that speaker communities might be “poised” for change because they always contain pools of “standing variation” of such biased speakers, and when factors such as the frequency of the biased speakers in the community, their positions in the communicative network or the topology of the network itself change, sound change may rapidly follow as a self-reinforcing network-level phenomenon, akin to a phase transition. Thus, inter-speaker variation in structured and dynamic communicative networks may couple the initiation and actuation of sound change.

Abstract

Linguistic diversity is affected by multiple factors, but it is usually assumed that variation in the anatomy of our speech organs
plays no explanatory role. Here we use realistic computer models of the human speech organs to test whether inter-individual
and inter-group variation in the shape of the hard palate (the bony roof of the mouth) affects acoustics of speech sounds. Based
on 107 midsagittal MRI scans of the hard palate of human participants, we modelled with high accuracy the articulation of a set
of five cross-linguistically representative vowels by agents learning to produce speech sounds. We found that different hard
palate shapes result in subtle differences in the acoustics and articulatory strategies of the produced vowels, and that these
individual-level speech idiosyncrasies are amplified by the repeated transmission of language across generations. Therefore,
we suggest that, besides culture and environment, quantitative biological variation can be amplified, also influencing language.

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Abstract

This chapter discusses the genetic foundations of the human capacity for language. It reviews the molecular structure of the genome and the complex molecular mechanisms that allow genetic information to influence multiple levels of biology. It goes on to describe the active regulation of genes and their formation of complex genetic pathways that in turn control the cellular environment and function. At each of these levels, examples of genes and genetic variants that may influence the human capacity for language are given. Finally, it discusses the value of using animal models to understand the genetic underpinnings of speech and language. From this chapter will emerge the complexity of the genome in action and the multidisciplinary efforts that are currently made to bridge the gap between genetics and language.

Abstract

Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

Abstract

FOXP2 mutations cause a speech and language disorder, raising interest in potential roles of this gene in human evolution. A new study re-evaluates genomic variation at the human FOXP2 locus but finds no evidence of recent adaptive evolution.

Abstract

Disruptions of the FOXP2 gene cause a speech and language disorder involving difficulties in sequencing orofacial movements. FOXP2 is expressed in cortico-striatal and cortico-cerebellar circuits important for fine motor skills, and affected individuals show abnormalities in these brain regions. We selectively disrupted Foxp2 in the cerebellar Purkinje cells, striatum or cortex of mice and assessed the effects on skilled motor behaviour using an operant lever-pressing task. Foxp2 loss in each region impacted behaviour differently, with striatal and Purkinje cell disruptions affecting the variability and the speed of lever-press sequences, respectively. Mice lacking Foxp2 in Purkinje cells showed a prominent phenotype involving slowed lever pressing as well as deficits in skilled locomotion. In vivo recordings from Purkinje cells uncovered an increased simple spike firing rate and decreased modulation of firing during limb movements. This was caused by increased intrinsic excitability rather than changes in excitatory or inhibitory inputs. Our findings show that Foxp2 can modulate different aspects of motor behaviour in distinct brain regions, and uncover an unknown role for Foxp2 in the modulation of Purkinje cell activity that severely impacts skilled movements.

Abstract

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Abstract

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Abstract

One of the features that distinguishes modern humans from our extinct relatives
and ancestors is a globular shape of the braincase [1-4]. As the endocranium
closely mirrors the outer shape of the brain, these differences might reflect
altered neural architecture [4,5]. However, in the absence of fossil brain tissue the
underlying neuroanatomical changes as well as their genetic bases remain
elusive. To better understand the biological foundations of modern human
endocranial shape, we turn to our closest extinct relatives, the Neandertals.
Interbreeding between modern humans and Neandertals has resulted in
introgressed fragments of Neandertal DNA in the genomes of present-day non-
Africans [6,7]. Based on shape analyses of fossil skull endocasts, we derive a
measure of endocranial globularity from structural magnetic resonance imaging
(MRI) scans of thousands of modern humans, and study the effects of
introgressed fragments of Neandertal DNA on this phenotype. We find that
Neandertal alleles on chromosomes 1 and 18 are associated with reduced
endocranial globularity. These alleles influence expression of two nearby genes,
UBR4 and PHLPP1, which are involved in neurogenesis and myelination,
respectively. Our findings show how integration of fossil skull data with archaic
genomics and neuroimaging can suggest developmental mechanisms that may
contribute to the unique modern human endocranial shape.

Abstract

Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA‐L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico‐limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied healthy individuals and used multimodal neuroimaging (sample size range: 219–284 across modalities) and network‐based statistics (NBS) to probe the specificity of MAOA‐L‐related connectomic alterations to cortical‐limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed a distributed network of node links with a significantly increased connectivity in MAOA‐L carriers compared to the carriers of the high expression (H) variant. The hyperconnectivity phenotype primarily consisted of between‐lobe (“anisocoupled”) network links and showed a pronounced involvement of frontal‐temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = .037), resting‐state fMRI (pFWE = .022), and diffusion tensor imaging (pFWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (pFWE = .540). These observations are in line with prior research on the MAOA‐L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences affecting these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic influences and low-frequency genetic variation. To understand these influences, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Abstract

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual’s self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner’s self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual’s weekly alcohol consumption increases partner’s alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10−6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.

Abstract

Aim: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. Materials & methods: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. Results & conclusion: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.

Abstract

Mirror-sensory synaesthetes mirror the pain or touch that they observe in other people on their own bodies. This type of synaesthesia has been associated with enhanced empathy. We investigated whether the enhanced empathy of people with mirror-sensory synesthesia influences the experience of situations involving touch or pain and whether it affects their prosocial decision making. Mirror-sensory synaesthetes (N = 18, all female), verified with a touch-interference paradigm, were compared with a similar number of age-matched control individuals (all female). Participants viewed arousing images depicting pain or touch; we recorded subjective valence and arousal ratings, and physiological responses, hypothesizing more extreme reactions in synaesthetes. The subjective impact of positive and negative images was stronger in synaesthetes than in control participants; the stronger the reported synaesthesia, the more extreme the picture ratings. However, there was no evidence for differential physiological or hormonal responses to arousing pictures. Prosocial decision making was assessed with an economic game assessing altruism, in which participants had to divide money between themselves and a second player. Mirror-sensory synaesthetes donated more money than non-synaesthetes, showing enhanced prosocial behaviour, and also scored higher on the Interpersonal Reactivity Index as a measure of empathy. Our study demonstrates the subjective impact of mirror-sensory synaesthesia and its stimulating influence on prosocial behaviour.

Abstract

The influence of larynx position on vowel articulation is an important topic in understanding speech production, the present-day distribution of linguistic diversity and the evolution of speech and language in our lineage. We introduce here a realistic computer model of the vocal tract, constructed from actual human MRI data, which can learn, using machine learning techniques, to control the articulators in such a way as to produce speech sounds matching as closely as possible to a given set of target vowels. We systematically control the vertical position of the larynx and we quantify the differences between the target and produced vowels for each such position across multiple replications. We report that, indeed, larynx height does affect the accuracy of reproducing the target vowels and the distinctness of the produced vowel system, that there is a “sweet spot” of larynx positions that are optimal for vowel production, but that nevertheless, even extreme larynx positions do not result in a collapsed or heavily distorted vowel space that would make speech unintelligible. Together with other lines of evidence, our results support the view that the vowel space of human languages is influenced by our larynx position, but that other positions of the larynx may also be fully compatible with speech.

Abstract

Neurons of the neocortex are organized into six radial layers, which have appeared at different times during evolution, with the superficial layers representing a more recent acquisition. Input to the neocortex predominantly reaches superficial layers (SL, i.e., layers (L) 2-4), while output is generated in deep layers (DL, i.e., L5-6) [1]. Intracortical connections, which bridge input and output pathways, are key components of cortical circuits because they allow the propagation and processing of information within the neocortex. Two main types of intracortically projecting neurons (ICPN) can be distinguished by their axonal features: L4 spiny stellate neurons (SSN) with short axons projecting locally within cortical columns [2, 3, 4, 5], and SL and DL long-range projection neurons, including callosally projecting neurons (CPNSL and CPNDL) [5, 6]. Here, we investigate the molecular hallmarks that distinguish SSN, CPNSL, and CPNDL and relate their transcriptional signatures with their output connectivity. Specifically, taking advantage of the presence of CPN in both SL and DL, we identify lamina-independent genetic hallmarks of a constant projection motif (i.e., interhemispheric projection). By performing unbiased transcriptomic comparisons between CPNSL, CPNDL and SSN, we provide specific molecular profiles for each of these populations and show that target identity supersedes laminar position in defining ICPN transcriptional diversity. Together, these findings reveal a projection-based organization of transcriptional programs across cortical layers, which we propose reflects conserved strategy to protect canonical circuit structure (and hence function) across a diverse range of neuroanatomies.

Abstract

Hand preference is a conspicuous variation in human behaviour, with a worldwide proportion of around 90% of people preferring to use the right hand for many tasks, and 10% the left hand. We used the large cohort of the UK biobank (~500,000 participants) to study possible relations between early life factors and adult hand preference. The probability of being left-handed was affected by the year and location of birth, likely due to cultural effects. In addition, hand preference was affected by birthweight, being part of a multiple birth, season of birth, breastfeeding, and sex, with each effect remaining significant after accounting for all others. Analysis of genome-wide genotype data showed that left-handedness was very weakly heritable, but shared no genetic basis with birthweight. Although on average left-handers and right-handers differed for a number of early life factors, all together these factors had only a minimal predictive value for individual hand preference.

Abstract

Objective:

Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects.
Methods:

The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen’s d=0.1.
Results:

The largest effect size (Cohen’s d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset.
Conclusions:

Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Abstract

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.

Abstract

Schizophrenia is a common and complex mental disorder with neuroimaging alterations. Recent neuroanatomical pattern recognition studies attempted to distinguish individuals with schizophrenia by structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI). 1, 2 Applications of cutting-edge machine learning approaches in structural neuroimaging studies have revealed potential pathways to classification of schizophrenia based on regional gray matter volume (GMV) or density or cortical thickness. 3–5 Additionally, cortical folding may have high discriminatory value in correctly identifying symptom severity in schizophrenia. 6 Regional GMV and cortical thickness have also been combined in attempts to differentiate individuals with schizophrenia from healthy controls (HCs). 7 Applications of machine learning algorithms to diffusion imaging data analysis to predict individuals with first-episode schizophrenia (FES) have achieved encouraging accuracy. 8–10 White matter (WM) abnormalities in schizophrenia as estimated by DTI appear to be present in the early stage of the disorder, most likely reflecting the developmental stage of the sample of interest.

Abstract

Identifying data-driven biotypes of major depressive disorder (MDD) has promise for the clarification of diagnostic heterogeneity. However, few studies have focused on white-matter abnormalities for MDD subtyping. This study included 116 patients with MDD and 118 demographically-matched healthy controls assessed by diffusion tensor imaging and neurocognitive evaluation. Hierarchical clustering was applied to the major fiber tracts, in conjunction with tract-based spatial statistics, to reveal white-matter alterations associated with MDD. Clinical and neurocognitive differences were compared between identified subgroups and healthy controls. With fractional anisotropy extracted from 20 fiber tracts, cluster analysis revealed 3 subgroups based on the patterns of abnormalities. Patients in each subgroup versus healthy controls showed a stepwise pattern of white-matter alterations as follows: subgroup 1 (25.9% of patient sample), widespread white-matter disruption; subgroup 2 (43.1% of patient sample), intermediate and more localized abnormalities in aspects of the corpus callosum and left cingulate; and subgroup 3 (31.0% of patient sample), possible mild alterations, but no statistically significant tract disruption after controlling for family-wise error. The neurocognitive impairment in each subgroup accompanied the white-matter alterations: subgroup 1, deficits in sustained attention and delayed memory; subgroup 2, dysfunction in delayed memory; and subgroup 3, no significant deficits. Three subtypes of white-matter abnormality exist in individuals with major depression, those having widespread abnormalities suffering more neurocognitive impairments, which may provide evidence for parsing the heterogeneity of the disorder and help optimize type-specific treatment approaches.

Abstract

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.

Abstract

The anterior lordosis of the cervical spine is thought
to contribute to pitch (fo) production by influencing
cricoid rotation as a function of larynx height. This
study examines the matter of inter-individual
variation in cervical spine shape and whether this has
an influence on how fo is produced along increasing
or decreasing scales, using the ArtiVarK dataset,
which contains real-time MRI pitch production data.
We find that the cervical spine actively participates in
fo production, but the amount of displacement
depends on individual shape. In general, anterior
spine motion (tending toward cervical lordosis)
occurs for low fo, while posterior movement (tending
towards cervical kyphosis) occurs for high fo.

Abstract

Objective

Resting-state functional magnetic resonance imaging (fMRI) is promising for Alzheimer’s disease (AD). This study aimed to examine short-term reliability of the default-mode network (DMN), one of the main haemodynamic patterns of the brain.
Materials and methods

Using a 1.5 T Philips Achieva scanner, two consecutive resting-state fMRI runs were acquired on 69 healthy adults, 62 patients with mild cognitive impairment (MCI) due to AD, and 28 patients with AD dementia. The anterior and posterior DMN and, as control, the visual-processing network (VPN) were computed using two different methodologies: connectivity of predetermined seeds (theory-driven) and dual regression (data-driven). Divergence and convergence in network strength and topography were calculated with paired t tests, global correlation coefficients, voxel-based correlation maps, and indices of reliability.
Results

No topographical differences were found in any of the networks. High correlations and reliability were found in the posterior DMN of healthy adults and MCI patients. Lower reliability was found in the anterior DMN and in the VPN, and in the posterior DMN of dementia patients.
Discussion

Strength and topography of the posterior DMN appear relatively stable and reliable over a short-term period of acquisition but with some degree of variability across clinical samples.

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Abstract

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

Abstract

Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme–colour synaesthesia (n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index (R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging.

Abstract

Background Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms.

Objective To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach.

Methods We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African–American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted.

Results Genome-wide significant effects were observed at rs1555839 (p=4.03×10−8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer–promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule.

Conclusion This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene–brain–behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

Abstract

A commonly held assumption in cognitive neuroscience is that, because measures of human brain function are closer to underlying biology than distal indices of behavior/cognition, they hold more promise for uncovering genetic pathways. Supporting this view is an influential fMRI-based study of sentence reading/listening by Pinel et al. (2012), who reported that common DNA variants in specific candidate genes were associated with altered neural activation in language-related regions of healthy individuals that carried them. In particular, different single-nucleotide polymorphisms (SNPs) of FOXP2 correlated with variation in task-based activation in left inferior frontal and precentral gyri, whereas a SNP at the KIAA0319/TTRAP/THEM2 locus was associated with variable functional asymmetry of the superior temporal sulcus. Here, we directly test each claim using a closely matched neuroimaging genetics approach in independent cohorts comprising 427 participants, four times larger than the original study of 94 participants. Despite demonstrating power to detect associations with substantially smaller effect sizes than those of the original report, we do not replicate any of the reported associations. Moreover, formal Bayesian analyses reveal substantial to strong evidence in support of the null hypothesis (no effect). We highlight key aspects of the original investigation, common to functional neuroimaging genetics studies, which could have yielded elevated false-positive rates. Genetic accounts of individual differences in cognitive functional neuroimaging are likely to be as complex as behavioral/cognitive tests, involving many common genetic variants, each of tiny effect. Reliable identification of true biological signals requires large sample sizes, power calculations, and validation in independent cohorts with equivalent paradigms.

SIGNIFICANCE STATEMENT A pervasive idea in neuroscience is that neuroimaging-based measures of brain function, being closer to underlying neurobiology, are more amenable for uncovering links to genetics. This is a core assumption of prominent studies that associate common DNA variants with altered activations in task-based fMRI, despite using samples (10–100 people) that lack power for detecting the tiny effect sizes typical of genetically complex traits. Here, we test central findings from one of the most influential prior studies. Using matching paradigms and substantially larger samples, coupled to power calculations and formal Bayesian statistics, our data strongly refute the original findings. We demonstrate that neuroimaging genetics with task-based fMRI should be subject to the same rigorous standards as studies of other complex traits.

Abstract

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

Abstract

The Hmong Diaspora is one of the widest modern human migrations. Mainly localised in South-East Asia, the United States of America, and metropolitan France, a small community has also settled the Amazonian forest of French Guiana. We have biologically analysed 62 individuals of this unique Guianese population through three complementary genetic markers: mitochondrial DNA (HVS-I/II and coding region SNPs), Y-chromosome (SNPs and STRs), and the Gm allotypic system. All genetic systems showed a high conservation of the Asian gene pool (Asian ancestry: mtDNA = 100.0%; NRY = 99.1%; Gm = 96.6%), without a trace of founder effect. When compared across various Asian populations, the highest correlations were observed with Hmong-Mien groups still living in South-East Asia (Fst < 0.05; P-value < 0.05). Despite a long history punctuated by exodus, the French Guianese Hmong have maintained their original genetic diversity.

Abstract

We show that Atkinson’s (Reports, 15 April 2011, p. 346) intriguing proposal—that global
linguistic diversity supports a single language origin in Africa—is an artifact of using suboptimal
data, biased methodology, and unjustified assumptions. We criticize his approach using more
suitable data, and we additionally provide new results suggesting a more complex scenario for the
emergence of global linguistic diversity.

Abstract

Language is the best example of a cultural evolutionary system, able to retain a phylogenetic signal over many thousands of years. The temporal stability (conservatism) of basic vocabulary is relatively well understood, but the stability of the structural properties of language (phonology, morphology, syntax) is still unclear. Here we report an extensive Bayesian phylogenetic investigation of the structural stability of numerous features across many language families and we introduce a novel method for analyzing the relationships between the “stability profiles” of language families. We found that there is a strong universal component across language families, suggesting the existence of universal linguistic, cognitive and genetic constraints. Against this background, however, each language family has a distinct stability profile, and these profiles cluster by geographic area and likely deep genealogical relationships. These stability profiles reveal, for example, the ancient historical relationships between the Siberian and American language families, presumed to be separated by at least 12,000 years. Thus, such higher-level properties of language seen as an evolutionary system might allow the investigation of ancient connections between languages and shed light on the peopling of the world.

Abstract

Commentary on Cohen, E. (2012). The evolution of tag-based cooperation in humans: The case for accent. Current Anthropology, 53, 588-616. doi:10.1086/667654.

Abstract

Approach and avoidance are two behavioral responses that make people tend to approach positive and avoid negative situations. This study examines whether postural behavior is influenced by the affective state of pictures. While standing on the Wii™ Balance Board, participants viewed pleasant, neutral, and unpleasant pictures (passively viewing phase). Then they had to move their body to the left or the right (lateral movement phase) to make the next picture appear. We recorded movements in the anterior-posterior direction to examine approach and avoidant behavior. During passively viewing, people approached pleasant pictures. They avoided unpleasant ones while they made a lateral movement. These findings provide support for the idea that we tend to approach positive and avoid negative situations.

Abstract

Mutations in the human FOXP2 gene cause impaired speech development and linguistic deficits, which have been best characterised in a large pedigree called the KE family. The encoded protein is highly conserved in many vertebrates and is expressed in homologous brain regions required for sensorimotor integration and motor-skill learning, in particular corticostriatal circuits. Independent studies in multiple species suggest that the striatum is a key site of FOXP2 action. Here, we used in vivo recordings in awake-behaving mice to investigate the effects of the KE-family mutation on the function of striatal circuits during motor-skill learning. We uncovered abnormally high ongoing striatal activity in mice carrying an identical mutation to that of the KE family. Furthermore, there were dramatic alterations in striatal plasticity during the acquisition of a motor skill, with most neurons in mutants showing negative modulation of firing rate, starkly contrasting with the predominantly positive modulation seen in control animals. We also observed striking changes in the temporal coordination of striatal firing during motor-skill learning in mutants. Our results indicate that FOXP2 is critical for the function of striatal circuits in vivo, which are important not only for speech but also for other striatal-dependent skills.

Abstract

In principle mutational records make it possible to estimate frequencies of disease alleles (q) for autosomal recessive disorders using a novel approach based on the calculation of the Homozygosity Index (HI), i.e., the proportion of homozygous patients, which is complementary to the proportion of compound heterozygous patients P(CH). In other words, the rarer the disorder, the higher will be the HI and the lower will be the P(CH). To test this hypothesis we used mutational records of individuals affected with Familial Mediterranean Fever (FMF) and Phenylketonuria (PKU), born to either consanguineous or apparently unrelated parents from six population samples of the Mediterranean region. Despite the unavailability of precise values of the inbreeding coefficient for the general population, which are needed in the case of apparently unrelated parents, our estimates of q are very similar to those of previous descriptive epidemiological studies. Finally, we inferred from simulation studies that the minimum sample size needed to use this approach is 25 patients either with unrelated or first cousin parents. These results show that the HI can be used to produce a ranking order of allele frequencies of autosomal recessive disorders, especially in populations with high rates of consanguineous marriages.

Abstract

Many learners of a foreign language (L2) struggle to correctly pronounce newly-learned speech sounds, yet many others achieve this with apparent ease. Here we explored how a training study of learning complex consonant clusters at the very onset of the L2 acquisition can inform us about L2 learning in general and individual differences in particular. To this end, adult Dutch native speakers were trained on Slovak words with complex consonant clusters (e.g., pstruh /pstrux/‘trout’, štvrť /ʃtvrc/ ‘quarter’) using auditory and orthographic input. In the same session following training, participants were tested on a battery of L2 perception and production tasks. The battery of L2 tests was repeated twice more with one week between each session. In the first session, an additional battery of control tests was used to test participants’ native language (L1) skills. Overall, in line with some previous research, participants showed only weak learning effects across the L2 perception tasks. However, there were considerable individual differences across all L2 tasks, which remained stable across sessions. Only two participants showed overall high L2 production performance that fell within 2 standard deviations of the mean ratings obtained for an L1 speaker. The mispronunciation detection task was the only perception task which significantly predicted production performance in the final session. We conclude by discussing several recommendations for future L2 learning studies.

Abstract

CONTEXT Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES Primary data. STUDY SELECTION Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19 505) (P = .01). CONCLUSION These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Abstract

Background Reduced total brain volume is a consistent finding in children with Attention Deficit/Hyperactivity Disorder (ADHD). In order to get a better understanding of the neurobiology of ADHD, we take the first step in studying the dimensionality of current self-reported adult ADHD symptoms, by looking at its relation with total brain volume. Methodology/Principal Findings In a sample of 652 highly educated adults, the association between total brain volume, assessed with magnetic resonance imaging, and current number of self-reported ADHD symptoms was studied. The results showed an association between these self-reported ADHD symptoms and total brain volume. Post-hoc analysis revealed that the symptom domain of inattention had the strongest association with total brain volume. In addition, the threshold for impairment coincides with the threshold for brain volume reduction. Conclusions/Significance This finding improves our understanding of the biological substrates of self-reported ADHD symptoms, and suggests total brain volume as a target intermediate phenotype for future gene-finding in ADHD.

Abstract

Infectious diseases exert a constant evolutionary pressure on the innate immunity genes. TLR4, an important member of the Toll-like receptors family, specifically recognizes conserved structures of various infectious pathogens. Two functional TLR4 polymorphisms, Asp299Gly and Thr399Ile, modulate innate host defense against infections, and their prevalence between various populations has been proposed to be influenced by local infectious pressures. If this assumption is true, strong local infectious pressures would lead to a homogeneous pattern of these ancient TLR4 polymorphisms in geographically close populations, while a weak selection or genetic drift may result in a diverse pattern. We evaluated TLR4 polymorphisms in 15 ethnic groups of Iran, to assess whether infections exerted selective pressures on different haplotypes containing these variants. The Iranian subpopulations displayed a heterogeneous pattern of TLR4 polymorphisms, comprising various percentages of Asp299Gly and Thr399Ile alone or in combination. The Iranian sample as a whole showed an intermediate mixed pattern when compared with commonly found patterns in Africa, Europe, Eastern Asia and Americas. These findings suggest a weak or absent selection pressure on TLR4 polymorphisms in the Middle-East, that does not support the assumption of an important role of these polymorphisms in the host defence against local pathogens.

Abstract

Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Here, we use genetic mapping, copy-number analysis, exclusion of mutations by high-throughput sequencing, gene expression analysis and functional assays to show that HMPS is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This unusual mutation is associated with increased allele-specific GREM1 expression. Whereas GREM1 is expressed in intestinal subepithelial myofibroblasts in controls, GREM1 is predominantly expressed in the epithelium of the large bowel in individuals with HMPS. The HMPS duplication contains predicted enhancer elements; some of these interact with the GREM1 promoter and can drive gene expression in vitro. Increased GREM1 expression is predicted to cause reduced bone morphogenetic protein (BMP) pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel.

Abstract

Microarrays provide a powerful analytical tool for the simultaneous detection of multiple pathogens. We developed diagnostic suspension microarrays for sensitive and specific detection of the biothreat pathogens Bacillus anthracis, Yersinia pestis, Francisella tularensis and Coxiella burnetii. Two assay chemistries for amplification and labeling were developed, one method using direct hybridization and the other using target-specific primer extension, combined with hybridization to universal arrays. Asymmetric PCR products for both assay chemistries were produced by using a multiplex asymmetric PCR amplifying 16 DNA signatures (16-plex). The performances of both assay chemistries were compared and their advantages and disadvantages are discussed. The developed microarrays detected multiple signature sequences and an internal control which made it possible to confidently identify the targeted pathogens and assess their virulence potential. The microarrays were highly specific and detected various strains of the targeted pathogens. Detection limits for the different pathogen signatures were similar or slightly higher compared to real-time PCR. Probit analysis showed that even a few genomic copies could be detected with 95% confidence. The microarrays detected DNA from different pathogens mixed in different ratios and from spiked or naturally contaminated samples. The assays that were developed have a potential for application in surveillance and diagnostics. © 2012 Janse et al.

Abstract

Widespread minority language shift in Early Modern Europe is often ascribed to restrictive language policies and the migration of both majority- and minority-language speakers. However, without a sociohistorically credible account of the mechanisms through which these events caused a language shift, these policies lack explanatory power. Inspired by research on 'language histories from below,' we present an integrated sociohistorical and linguistic account that can shed light on the procresses taking place during a case of language shift in the 17th and 18th centuries. We present and analyze demographic data on the immigration and integration of French speakers in previously Dutch-speaking Dunkirk in this period, showing how moderate intermarriage of immigrants and locals could have represented a motive and a mechanism for language shift against a backdrop of larger language-political processes. We then discuss the modern language-shift dialect of Dunkirk in comparison with different dialects of French. The linguistic data suggests a large influence from the dialects of migrants, underlining their role in the language shift process. The combination of sociohistorical and linguistic evidence gives us a better understanding of language shift in this period, showing the value of an integrated 'from below' approach.

Abstract

Heterozygous mutations of the human FOXP2 transcription factor gene cause the best-described examples of monogenic speech and language disorders. Acquisition of proficient spoken language involves auditory-guided vocal learning, a specialized form of sensory-motor association learning. The impact of etiological Foxp2 mutations on learning of auditory-motor associations in mammals has not been determined yet. Here, we directly assess this type of learning using a newly developed conditioned avoidance paradigm in a shuttle-box for mice. We show striking deficits in mice heterozygous for either of two different Foxp2 mutations previously implicated in human speech disorders. Both mutations cause delays in acquiring new motor skills. The magnitude of impairments in association learning, however, depends on the nature of the mutation. Mice with a missense mutation in the DNA-binding domain are able to learn, but at a much slower rate than wild type animals, while mice carrying an early nonsense mutation learn very little. These results are consistent with expression of Foxp2 in distributed circuits of the cortex, striatum and cerebellum that are known to play key roles in acquisition of motor skills and sensory-motor association learning, and suggest differing in vivo effects for distinct variants of the Foxp2 protein. Given the importance of such networks for the acquisition of human spoken language, and the fact that similar mutations in human FOXP2 cause problems with speech development, this work opens up a new perspective on the use of mouse models for understanding pathways underlying speech and language disorders.

Abstract

Purpose: Classical studies of consanguinity have taken advantage of the relationship between the gene frequency for a rare autosomal recessive disorder (q) and the proportion of offspring of consanguineous couples who are affected with the same disorder. The Swedish geneticist Gunnar Dahlberg provided the first theoretical formulation of the inverse correlation between q and the increase in frequency of consanguineous marriages among parents of affected children with respect to marriages of the same degree in the general population. Today it is possible to develop a new approach for estimating q using mutation analysis of affected offspring of consanguineous couples. The rationale of this new approach is based on the possibility that the child born of consanguineous parents carries the same mutation in double copy (true homozygosity) or alternatively carries two different mutations in the same gene (compound heterozygosity). In the latter case the two mutations must have been inherited through two different ancestors of the consanguineous parents (in this case the two mutated alleles are not ‘identical by descent’). Patients and methods: Data from the offspring of consanguineous marriages affected with different autosomal recessive disorders were collected by different molecular diagnostic laboratories in Mediterranean countries and in particular in Arab countries, where the frequencies of consanguineous marriages is high, show the validity of this approach. Results: The proportion of compound heterozygotes among children affected with a given autosomal recessive disorder, born of consanguineous parents, can be taken as an indirect indicator of the frequency of the same disorder in the general population. Identification of the responsible gene (and mutations) is the necessary condition to apply this method. Conclusion: The following paper from our group relevant for the present review is being published: Alessandro Gialluisi, Tommaso Pippucci, Yair Anikster, Ugur Ozbek, Myrna Medlej-Hashim, Andre Megarbane and Giovanni Romeo: Estimating the allele frequency of autosomal recessive disorders through mutational records and consanguinity: the homozygosity index (HI) annals of human genetics (in press; acceptance date 1 November 2011) In addition, our experimental data show that the causative mutation for a rare autosomal recessive disorder can be identified by whole exome sequencing of only two affected children of first cousins parents, as described in the following recent paper: Pippucci T, Benelli M, Magi A, Martelli PL, Magini P, Torricelli F, Casadio R, Seri M, Romeo G EX-HOM (EXome HOMozygosity): A Proof of Principle. Hum Hered 2011; 72:45-53.

Abstract

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

Abstract

Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder, and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterisation of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300bp to -177bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, whilst a region -982bp to -301bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by FOXP2, a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia (DVD). Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.

Abstract

Corrigendum to CNTNAP2 variants affect early language development in the general population A. J. O. Whitehouse, D. V. M. Bishop, Q. W. Ang, C. E. Pennell and S. E. Fisher Genes Brain Behav (2011) doi: 10.1111/j.1601-183X.2011.00684.x. The authors have detected a typographical error in the Abstract of this paper. The error is in the fifth sentence, which reads: ‘‘On the basis of these findings, we performed analyses of four-marker haplotypes of rs2710102–rs759178–rs17236239–rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype GCAG,P = .0014).’’ Rather than ‘‘GCAG’’, the final haplotype should read ‘‘CGAG’’. This typographical error was made in the Abstract only and this has no bearing on the results or conclusions of the study, which remain unchanged. Reference Whitehouse, A. J. O., Bishop, D. V. M., Ang, Q. W., Pennell, C. E. & Fisher, S. E. (2011) CNTNAP2 variants affect early language development in the general population. Genes Brain Behav 10, 451–456. doi: 10.1111/j.1601-183X.2011.00684.x.

Abstract

We carried out the first study on the relationship between individual language aptitude and structural connectivity of language pathways in the adult brain. We measured four components of language aptitude (vocabulary learning, VocL; sound recognition, SndRec; sound-symbol correspondence, SndSym; and grammatical inferencing, GrInf) using the LLAMA language aptitude test (Meara, 2005). Spatial working memory (SWM), verbal working memory (VWM) and IQ were also measured as control factors. Diffusion Tensor Imaging (DTI) was employed to investigate the structural connectivity of language pathways in the perisylvian language network. Principal Component Analysis (PCA) on behavioural measures suggests that a general ability might be important to the first stages of L2 acquisition. It also suggested that VocL, SndSy and SWM are more closely related to general IQ than SndRec and VocL, and distinguished the tasks specifically designed to tap into L2 acquisition (VocL, SndRec,SndSym and GrInf) from more generic measures (IQ, SWM and VWM). Regression analysis suggested significant correlations between most of these behavioural measures and the structural connectivity of certain language pathways, i.e., VocL and BA47-Parietal pathway, SndSym and inter-hemispheric BA45 pathway, GrInf and BA45-Temporal pathway and BA6-Temporal pathway, IQ and BA44-Parietal pathway, BA47-Parietal pathway, BA47-Temporal pathway and inter-hemispheric BA45 pathway, SWM and inter-hemispheric BA6 pathway and BA47-Parietal pathway, and VWM and BA47-Temporal pathway. These results are discussed in relation to relevant findings in the literature.

Abstract

How does language comprehension interact with motor activity? We investigated the conditions under which comprehending an action sentence affects people's balance. We performed two experiments to assess whether sentences describing forward or backward movement modulate the lateral movements made by subjects who made sensibility judgments about the sentences. In one experiment subjects were standing on a balance board and in the other they were seated on a balance board that was mounted on a chair. This allowed us to investigate whether the action compatibility effect (ACE) is robust and persists in the face of salient incompatibilities between sentence content and subject movement. Growth-curve analysis of the movement trajectories produced by the subjects in response to the sentences suggests that the ACE is indeed robust. Sentence content influenced movement trajectory despite salient inconsistencies between implied and actual movement. These results are interpreted in the context of the current discussion of embodied, or grounded, language comprehension and meaning representation.