Publications

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Abstract

Processing speech in a non-native language requires listeners to cope with influences from their first language and to overcome the effects of limited exposure and experience. These factors may be particularly important when listening in adverse conditions. However,native listeners also suffer in noise, and the intelligibility of speech in noise clearly depends on factors which are independent of a listener’s first language. The current study explored the issue of language-independence by comparing the responses of eight listener groups differing in native language when confronted with the task of identifying English intervocalic consonants in three masker backgrounds, viz.stationary speech-shaped noise, temporally-modulated speech-shaped noise and competing English speech. The study analysed the effects of (i) noise type, (ii) speaker, (iii) vowel context, (iv) consonant, (v) phonetic feature classes, (vi) stress position, (vii) gender and (viii) stimulus onset relative to noise onset. A significant degree of similarity in the response to many of these factors was evident across all eight language groups, suggesting that acoustic and auditory considerations play a large role in determining intelligibility. Language- specific influences were observed in the rankings of individual consonants and in the masking effect of competing speech relative to speech-modulated noise.

Abstract

We report an investigation of the perception of American English phonemes by Dutch listeners proficient in English. Listeners identified either the consonant or the vowel in most possible English CV and VC syllables. The syllables were embedded in multispeaker babble at three signal-to-noise ratios (16 dB, 8 dB, and 0 dB). Effects of signal-to-noise ratio on vowel and consonant identification are discussed as a function of syllable position and of relationship to the native phoneme inventory. Comparison of the results with previously reported data from native listeners reveals that noise affected the responding of native and non-native listeners similarly.

Abstract

Contemporary methods of computational cognitive modeling have recently been criticized by Addyman and French (2012) on the grounds that they have not kept up with developments in computer technology and human–computer interaction. They present a manifesto for change according to which, it is argued, modelers should devote more effort to making their models accessible, both to non-modelers (with an appropriate easy-to-use user interface) and modelers alike. We agree that models, like data, should be freely available according to the normal standards of science, but caution against confusing implementations with specifications. Models may embody theories, but they generally also include implementation assumptions. Cognitive modeling methodology needs to be sensitive to this. We argue that specification, replication and experimentation are methodological approaches that can address this issue.

Abstract

Incremental comprehension of head-final constructions can reveal structural attachment preferences for ambiguous phrases. This study investigates
how temporarily ambiguous PPs are processed in Dutch verb-final constructions. In De aannemer heeft op het dakterras bespaard/gewerkt ‘The
contractor has on the roof terrace saved/worked’, the PP is locally ambiguous between attachment as argument and as adjunct. This ambiguity is
resolved by the sentence-final verb. In a self-paced reading task, we manipulated the argument/adjunct status of the PP, and its position relative to the
verb. While we found no reading-time differences between argument and
adjunct PPs, we did find that transitive verbs, for which the PP is an argument, were read more slowly than intransitive verbs, for which the PP is an adjunct. We suggest that Dutch parsers have a preference for adjunct attachment of preverbal PPs, and discuss our findings in terms of incremental
parsing models that aim to minimize costly reanalysis.

Abstract

A key challenge in understanding stories and conversations is the comprehension of ‘anaphora’, words that refer back to previously mentioned words or concepts (‘antecedents’). In psycholinguistic theories, anaphor comprehension involves the initial activation of the antecedent and its subsequent integration into the unfolding representation of the narrated event. A recent proposal suggests that these processes draw upon the brain’s recognition memory and language networks, respectively, and may be dissociable in patterns of neural oscillatory synchronization (Nieuwland & Martin, 2017). We addressed this proposal in an electroencephalogram (EEG) study with pre-registered data acquisition and analyses, using event-related potentials (ERPs) and neural oscillations. Dutch participants read two-sentence mini stories containing proper names, which were repeated or new (ease of activation) and semantically coherent or incoherent with the preceding discourse (ease of integration). Repeated names elicited lower N400 and Late Positive Component amplitude than new names, and also an increase in theta-band (4-7 Hz) synchronization, which was largest around 240-450 ms after name onset. Discourse-coherent names elicited an increase in gamma-band (60-80 Hz) synchronization compared to discourse-incoherent names. This effect was largest around 690-1000 ms after name onset and exploratory beamformer analysis suggested a left frontal source. We argue that the initial activation and subsequent discourse-level integration of referents can be dissociated with event-related EEG activity, and are associated with respectively theta- and gamma-band activity. These findings further establish the link between memory and language through neural oscillations.

Abstract

During conversation, interlocutors often produce their utterances with little overlap or gap between their turns. But what mechanism underlies this striking ability to time articulation appropriately? In 2 verbal yes/no question-answering experiments, we investigated whether listeners use the speech rate of questions to time articulation of their answers. In Experiment 1, we orthogonally manipulated the speech rate of the context (e.g., Do you have a . . .) and final word (e.g., dog?) of questions using time-compression, so that each component was spoken at the natural rate or twice as a fast. Listeners responded earlier when the context was speeded rather than natural, suggesting they used the speaker’s context rate to time answer articulation. Additionally, listeners responded earlier when the speaker’s final syllable was speeded than natural, regardless of context rate, suggesting they adjusted the timing of articulation after listening to a single syllable produced at a different rate. We replicated this final word effect in Experiment 2, which also showed that our speech rate manipulation did not influence the timing of response preparation. Together, these findings suggest listeners use speech rate information to time articulation when answering questions

Abstract

Listeners quickly learn to understand speech that has been distorted, and this process is enhanced when comprehension is constrained by higher-level knowledge. In three experiments, we investigated whether this knowledge enhances comprehension of distorted speech because it allows listeners to predict (1) the meaning of the distorted utterance, or (2) the lower-level wordforms. Participants listened to question-answer sequences, in which questions were clearly-spoken but answers were noise-vocoded. Comprehension (Experiment 1) and learning (Experiment 2) were enhanced when listeners could use the question to predict the semantics of the distorted answer, but were not enhanced by predictions of answer form. Form predictions enhanced comprehension only when questions and answers were significantly separated by time and intervening linguistic material (Experiment 3). Together, these results suggest that high-level semantic predictions enhance comprehension and learning, with form predictions playing only a minimal role.

Abstract

Past events like fluctuations in population size and post-glacial colonization processes may influence the relative importance of genetic drift, migration and selection when determining the present day patterns of genetic variation. We disentangle how drift, selection and migration shape neutral and adaptive genetic variation in 12 moor frog populations along a 1700 km latitudinal gradient. We studied genetic differentiation and variation at a MHC exon II locus and a set of 18 microsatellites.
Results

Using outlier analyses, we identified the MHC II exon 2 (corresponding to the β-2 domain) locus and one microsatellite locus (RCO8640) to be subject to diversifying selection, while five microsatellite loci showed signals of stabilizing selection among populations. STRUCTURE and DAPC analyses on the neutral microsatellites assigned populations to a northern and a southern cluster, reflecting two different post-glacial colonization routes found in previous studies. Genetic variation overall was lower in the northern cluster. The signature of selection on MHC exon II was weaker in the northern cluster, possibly as a consequence of smaller and more fragmented populations.
Conclusion

Our results show that historical demographic processes combined with selection and drift have led to a complex pattern of differentiation along the gradient where some loci are more divergent among populations than predicted from drift expectations due to diversifying selection, while other loci are more uniform among populations due to stabilizing selection. Importantly, both overall and MHC genetic variation are lower at northern latitudes. Due to lower evolutionary potential, the low genetic variation in northern populations may increase the risk of extinction when confronted with emerging pathogens and climate change.

Abstract

In three experiments, listeners detected vowel or consonant targets in lists of CV syllables constructed from five vowels and five consonants. Responses were faster in a predictable context (e.g., listening for a vowel target in a list of syllables all beginning with the same consonant) than in an unpredictable context (e.g., listening for a vowel target in a list of syllables beginning with different consonants). In Experiment 1, the listeners’ native language was Dutch, in which vowel and consonant repertoires are similar in size. The difference between predictable and unpredictable contexts was comparable for vowel and consonant targets. In Experiments 2 and 3, the listeners’ native language was Spanish, which has four times as many consonants as vowels; here effects of an unpredictable consonant context on vowel detection were significantly greater than effects of an unpredictable vowel context on consonant detection. This finding suggests that listeners’ processing of phonemes takes into account the constitution of their language’s phonemic repertoire and the implications that this has for contextual variability.

Abstract

Single nucleotide polymorphisms (SNPs) within the MIR137, TCF4, and ZNF804A genes show genome-wide association to schizophrenia. However, the biological basis for the associations is unknown. Here, we tested the effects of these genes on brain structure in 1300 healthy adults. Using volumetry and voxel-based morphometry, neither gene-wide effects—including the combined effect of the genes—nor single SNP effects—including specific psychosis risk SNPs—were found on total brain volume, grey matter, white matter, or hippocampal volume. These results suggest that the associations between these risk genes and schizophrenia are unlikely to be mediated via effects on macroscopic brain structure.

Abstract

This paper discusses some improvements in recent and planned versions of the multimodal annotation tool ELAN, which are targeted at improving the usability of annotated files. Increased support for multilingual documents is provided, by allowing for multilingual vocabularies and by specifying a language per document, annotation layer (tier) or annotation. In addition, improvements in the search possibilities and the display of the results have been implemented, which are especially relevant in the interpretation of the results of complex multi-tier searches.

Abstract

Collocations generated by concordancers are a standard instrument in the exploitation of text corpora for the analysis of language use. Multimodal corpora show similar types of patterns, activities that frequently occur together, but there is no tool that offers facilities for visualising such patterns. Examples include timing of eye contact with respect to speech, and the alignment of activities of the two hands in signed languages. This paper describes recent enhancements to the standard CLARIN tools ELAN and TROVA for multimodal annotation to address these needs: first of all the query and concordancing functions were improved, and secondly the tools now generate visualisations of multilayer collocations that allow for intuitive explorations and analyses of multimodal data. This will provide a boost to the linguistic fields of gesture and sign language studies, as it will improve the exploitation of multimodal corpora.

Abstract

A basic question for the study of the mental lexicon is whether there are morphological representations and processes that are independent of phonology and semantics. According to a prominent tradition, morphological relatedness requires semantic transparency: semantically transparent words are related in meaning to their stems, while semantically opaque words are not. This study examines the question of morphological relatedness using intra-modal auditory priming by Dutch prefixed verbs. The key conditions involve semantically transparent prefixed primes (e.g., aanbieden ‘offer’, with the stem bieden, also ‘offer’) and opaque primes (e.g., verbieden ‘forbid’). Results show robust facilitation for both transparent and opaque pairs; phonological (Experiment 1) and semantic (Experiment 2) controls rule out the possibility that these other types of relatedness are responsible for the observed priming effects. The finding of facilitation with opaque primes suggests that morphological processing is independent of semantic and phonological representations. Accordingly, the results are incompatible with theories that make semantic overlap a necessary condition for relatedness, and favor theories in which words may be related in ways that do not require shared meaning. The general discussion considers several specific proposals along these lines, and compares and contrasts questions about morphological relatedness of the type found here with the different but related question of whether there is morphological decomposition of complex forms or not.

Abstract

The present study investigated the neural correlates of infant discrimination of very similar linguistic varieties (Quebecois and Parisian French) using functional Near InfraRed Spectroscopy. In line with previous behavioral and electrophysiological data, there was no evidence that 3-month-olds discriminated the two regional accents, whereas 5-month-olds did, with the locus of discrimination in left anterior perisylvian regions. These neuroimaging results suggest that a developing language network relying crucially on left perisylvian cortices sustains infants' discrimination of similar linguistic varieties within this early period of infancy.

Abstract

The hypothesis that vocalic categories are enhanced in infant-directed speech (IDS) has received a great deal of attention and support. In contrast, work focusing on the acoustic implementation of consonantal categories has been scarce, and positive, negative, and null results have been reported. However, interpreting this mixed evidence is complicated by the facts that the definition of phonetic enhancement varies across articles, that small and heterogeneous groups have been studied across experiments, and further that the categories chosen are likely affected by other characteristics of IDS. Here, an analysis of the English sibilants /s/ and /ʃ/ in a large corpus of caregivers’ speech to another adult and to their infant suggests that consonantal categories are indeed enhanced, even after controlling for typical IDS prosodic characteristics.

Abstract

There are increasing reports that individual variation in behavioral and neurophysiological measures of infant speech processing predicts later language outcomes, and specifically concurrent or subsequent vocabulary size. If such findings are held up under scrutiny, they could both illuminate theoretical models of language development and contribute to the prediction of communicative disorders. A qualitative, systematic review of this emergent literature illustrated the variety of approaches that have been used and highlighted some conceptual problems regarding the measurements. A quantitative analysis of the same data established that the bivariate relation was significant, with correlations of similar strength to those found for well-established nonlinguistic predictors of language. Further exploration of infant speech perception predictors, particularly from a methodological perspective, is recommended.

Abstract

Typically, the point vowels [i,ɑ,u] are acoustically more peripheral in infant-directed speech (IDS) compared to adult-directed speech (ADS). If caregivers seek to highlight lexically relevant contrasts in IDS, then two sounds that are contrastive should become more distinct, whereas two sounds that are surface realizations of the same underlying sound category should not. To test this prediction, vowels that are phonemically contrastive ([i-ɪ] and [eɪ-ε]), vowels that map onto the same underlying category ([æ- ] and [ε- ]), and the point vowels [i,ɑ,u] were elicited in IDS and ADS by American English mothers of two age groups of infants (four- and eleven-month-olds). As in other work, point vowels were produced in more peripheral positions in IDS compared to ADS. However, there was little evidence of hyperarticulation per se (e.g. [i-ɪ] was hypoarticulated). We suggest that across-the-board lexically based hyperarticulation is not a necessary feature of IDS.

Abstract

Talking about odors and flavors is difficult for most people, yet experts appear to be able to convey critical information about wines in their reviews. This seems to be a contradiction, and wine expert descriptions are frequently received with criticism. Here, we propose a method for probing the language of wine reviews, and thus offer a means to enhance current vocabularies, and as a by-product question the general assumption that wine reviews are gibberish. By means of two different quantitative analyses—support vector machines for classification and Termhood analysis—on a corpus of online wine reviews, we tested whether wine reviews are written in a consistent manner, and thus may be considered informative; and whether reviews feature domain-specific language. First, a classification paradigm was trained on wine reviews from one set of authors for which the color, grape variety, and origin of a wine were known, and subsequently tested on data from a new author. This analysis revealed that, regardless of individual differences in vocabulary preferences, color and grape variety were predicted with high accuracy. Second, using Termhood as a measure of how words are used in wine reviews in a domain-specific manner compared to other genres in English, a list of 146 wine-specific terms was uncovered. These words were compared to existing lists of wine vocabulary that are currently used to train experts. Some overlap was observed, but there were also gaps revealed in the extant lists, suggesting these lists could be improved by our automatic analysis.

Abstract

In the wild, chimpanzees (Pan troglodytes) are often faced with clumped food resources that they may know how to access but abstain from doing so due to social pressures. To better understand how social settings influence resource acquisition, we tested fifteen semi-wild chimpanzees from two social groups alone and in the presence of others. We investigated how resource acquisition was affected by relative social dominance, whether collaborative problem solving or (active or passive) sharing occurred amongst any of the dyads, and whether these outcomes were related to relationship quality as determined from six months of observational data. Results indicated that chimpanzees, regardless of rank, obtained fewer rewards when tested in the presence of others compared to when they were tested alone. Chimpanzees demonstrated behavioral inhibition; chimpanzees who showed proficient skill when alone often abstained from solving the task when in the presence of others. Finally, individuals with close social relationships spent more time together in the problem solving space, but collaboration and sharing were infrequent and sessions in which collaboration or sharing did occur contained more instances of aggression. Group living provides benefits and imposes costs, and these findings highlight that one cost of group living may be diminishing productive individual behaviors.

Abstract

The cooperative breeding hypothesis posits that cooperatively breeding species are motivated to act prosocially, that is, to behave in ways that provide benefits to others, and that cooperative breeding has played a central role in the evolution of human prosociality. However, investigations of prosocial behaviour in cooperative breeders have produced varying results and the mechanisms contributing to this variation are unknown. We investigated whether reciprocity would facilitate prosocial behaviour among cottontop tamarins, a cooperatively breeding primate species likely to engage in reciprocal altruism, by comparing the number of food rewards transferred to partners who had either immediately previously provided or denied rewards to the subject. Subjects were also tested in a non-social control condition. Overall, results indicated that reciprocity increased food transfers. However, temporal analyses revealed that when the tamarins' behaviour was evaluated in relation to the non-social control, results were best explained by (i) an initial depression in the transfer of rewards to partners who recently denied rewards, and (ii) a prosocial effect that emerged late in sessions independent of reciprocity. These results support the cooperative breeding hypothesis, but suggest a minimal role for positive reciprocity, and emphasize the importance of investigating proximate temporal mechanisms underlying prosocial behaviour.

Abstract

Recent debates have questioned the extent to which culturally-transmitted norms drive behavioral variation in resource sharing across human populations. We shed new light on this discussion by examining the group-level variation in the social dynamics and resource sharing of chimpanzees, a species that is highly social and forms long-term community associations but differs from humans in the extent to which cultural norms are adopted and enforced. We rely on theory developed in primate socioecology to guide our investigation in four neighboring chimpanzee groups at a sanctuary in Zambia. We used a combination of experimental and observational approaches to assess the distribution of resource holding potential in each group. In the first assessment, we measured the proportion of the population that gathered in a resource-rich zone, in the second we assessed naturally occurring social spacing via social network analysis, and in the third we assessed the degree to which benefits were equally distributed within the group. We report significant, stable group-level variation across these multiple measures, indicating that group-level variation in resource sharing and social tolerance is not necessarily reliant upon human-like cultural norms.

Abstract

Alpha-band oscillatory activity is involved in modulating memory and attention. However, few studies have investigated individual differences in oscillatory activity during the encoding of emotional memory, particularly in sleep paradigms where sleep is thought to play an active role in memory consolidation. The current study aimed to address the question of whether individual alpha frequency (IAF) modulates the consolidation of declarative memory across periods of sleep and wake. 22 participants aged 18 – 41 years (mean age = 25.77) viewed 120 emotionally valenced images (positive, negative, neutral) and completed a baseline memory task before a 2hr afternoon sleep opportunity and an equivalent period of wake. Following the sleep and wake conditions, participants were required to distinguish between 120 learned (target) images and 120 new (distractor) images. This method allowed us to delineate the role of different oscillatory components of sleep and wake states in the emotional modulation of memory. Linear mixed-effects models revealed interactions between IAF, rapid eye movement sleep theta power, and slow-wave sleep slow oscillatory density on memory outcomes. These results highlight the importance of individual factors in the EEG in modulating oscillatory-related memory consolidation and subsequent behavioural outcomes and test predictions proposed by models of sleep-based memory consolidation.

Abstract

Language-specific differences in the size and distribution of the phonemic repertoire can have implications for the task facing listeners in recognising spoken words. A language with more phonemes will allow shorter words and reduced embedding of short words within longer ones, decreasing the potential for spurious lexical competitors to be activated by speech signals. We demonstrate that this is the case via comparative analyses of the vocabularies of English and Spanish. A language which uses suprasegmental as well as segmental contrasts, however, can substantially reduce the extent of spurious embedding.

Abstract

Native American English and non-native(Dutch)listeners identified either the consonant or the vowel in all possible American English CV and VC syllables. The syllables were embedded in multispeaker babble at three signal-to-noise ratios(0, 8, and 16 dB). The phoneme identification
performance of the non-native listeners was less accurate than that of the native listeners. All listeners were adversely affected by noise. With these isolated syllables, initial segments were harder to identify than final segments. Crucially, the effects of language background and noise did not interact; the performance asymmetry between the native and non-native groups was not significantly different across signal-to-noise ratios. It is concluded that the frequently reported disproportionate difficulty of non-native listening under disadvantageous conditions is not due to a disproportionate increase in phoneme misidentifications.

Abstract

The retiring academic may look back upon, inter alia, years of conference attendance. Speech error researchers are uniquely fortunate because they can collect data in any situation involving communication; accordingly, the retiring speech error researcher will have collected data at those conferences. We here address the issue of whether error data collected in situations involving conviviality (such as at conferences) is representative of error data in general. Our approach involved a comparison, across three levels of linguistic processing, between a specially constructed Conviviality Sample and the largest existing source of speech error data, the newly available Fromkin Speech Error Database. The results indicate that there are grounds for regarding the data in the Conviviality Sample as a better than average reflection of the true population of all errors committed. These findings encourage us to recommend further data collection in collaboration with like-minded colleagues.

Abstract

In English and Dutch, listeners entrain to prosodic contours to predict where focus will fall in an utterance. Here, we ask whether this strategy is universally available, even in languages with very different phonological systems (e.g., tone versus non-tone languages). In a phoneme detection experiment, we examined whether prosodic entrainment also occurs in Mandarin Chinese, a tone language, where the use of various suprasegmental cues to lexical identity may take precedence over their use in salience. Consistent with the results from Germanic languages, response times were facilitated when preceding intonation predicted high stress on the target-bearing word, and the lexical tone of the target word (i.e., rising versus falling) did not affect the Mandarin listeners' response. Further, the extent to which prosodic entrainment was used to detect the target phoneme was the same in both English and Mandarin listeners. Nevertheless, native Mandarin speakers did not adopt an entrainment strategy when the sentences were presented in English, consistent with the suggestion that L2 listening may be strained by additional functional load from prosodic processing. These findings have implications for how universal and language-specific mechanisms interact in the perception of focus structure in everyday discourse.

Abstract

Assimilation of place of articulation across a nasal and a following stop consonant is obligatory in Japanese, but not in Dutch. In four experiments the processing of assimilated forms by speakers of Japanese and Dutch was compared, using a task in which listeners blended pseudo-word pairs such as ranga-serupa. An assimilated blend of this pair would be rampa, an unassimilated blend rangpa. Japanese listeners produced significantly more assimilated than unassimilated forms, both with pseudo-Japanese and pseudo-Dutch materials, while Dutch listeners produced significantly more unassimilated than assimilated forms in each materials set. This suggests that Japanese listeners, whose native-language phonology involves obligatory assimilation constraints, represent the assimilated nasals in nasal-stop sequences as unmarked for place of articulation, while Dutch listeners, who are accustomed to hearing unassimilated forms, represent the same nasal segments as marked for place of articulation.

Abstract

Listeners learn from their past experience of listening to spoken words, and use this learning to maximise the efficiency of future word recognition. This paper summarises evidence that the facilitatory effects of drawing on past experience are mediated by abstraction, enabling learning to be generalised across new words and new listening situations. Phoneme category retuning, which allows adaptation to speaker-specific articulatory characteristics, is generalised on the basis of relatively brief experience to words previously unheard from that speaker. Abstract knowledge of prosodic regularities is applied to recognition even of novel words for which these regularities were violated. Prosodic word-boundary regularities drive segmentation of speech into words independently of the membership of the lexical candidate set resulting from the segmentation operation. Each of these different cases illustrates how abstraction from past listening experience has contributed to the efficiency of lexical recognition.

Abstract

The perceptual processing of speech is a constant interplay of multiple competing albeit convergent processes: acoustic input vs. higher-level representations, universal mechanisms vs. language-specific, veridical traces of speech experience vs. construction and activation of abstract representations. The present summary concerns the third of these issues. The ability to generalise across experience and to deal with resulting abstractions is the hallmark of human cognition, visible even in early infancy. In speech processing, abstract representations play a necessary role in both production and perception. New sorts of evidence are now informing our understanding of the breadth of this role.

Abstract

One of a listener’s major tasks in understanding continuous speech in segmenting the speech signal into separate words. When listening conditions are difficult, speakers can help listeners by deliberately clear speech. We found that speakers do indeed attempt to makr word boundaries; moreover, they differentiate between word boundaries in a way which suggest they are sensitive to listener needs. Application of heuristic segmentation strategies makes word boundaries before strong syllables easiest for listeners to perceive; but under difficult listening conditions speakers pay more attention to marking word boundaries before weak syllables, i.e. they mark those boundaries which are otherwise particularly hard to perceive.

Abstract

Previous research has shown that, in a phoneme detection task, vowels produce longer reaction times than consonants, suggesting that they are harder to perceive. One possible explanation for this difference is based upon their respective acoustic/articulatory characteristics. Another way of accounting for the findings would be to relate them to the differential functioning of vowels and consonants in the syllabic structure of words. In this experiment, we examined the second possibility. Targets were two pairs of phonemes, each containing a vowel and a consonant with similar phonetic characteristics. Subjects heard lists of English words had to press a response key upon detecting the occurrence of a pre-specified target. This time, the phonemes which functioned as vowels in syllabic structure yielded shorter reaction times than those which functioned as consonants. This rules out an explanation for response time difference between vowels and consonants in terms of function in syllable structure. Instead, we propose that consonantal and vocalic segments differ with respect to variability of tokens, both in the acoustic realisation of targets and in the representation of targets by listeners.

Abstract

In English and Dutch, listeners entrain to prosodic contours to predict where focus will fall in an utterance. However, is this strategy universally available, even in languages with different phonological systems? In a phoneme detection experiment, we examined whether prosodic entrainment is also found in Mandarin Chinese, a tone language, where in principle the use of pitch for lexical identity may take precedence over the use of pitch cues to salience. Consistent with the results from Germanic languages, response times were facilitated when preceding intonation predicted accent on the target-bearing word. Acoustic analyses revealed greater F0 range in the preceding intonation of the predicted-accent sentences. These findings have implications for how universal and language-specific mechanisms interact in the processing of salience.

Abstract

Languages contain tens of thousands of words, but these are constructed from a tiny handful of phonetic elements. Consequently, words resemble one another, or can be embedded within one another, a coup stick snot with standing. me process of spoken-word recognition by human listeners involves activation of multiple word candidates consistent with the input, and direct competition between activated candidate words. Further, human listeners are sensitive, at an early, prelexical, stage of speeeh processing, to constraints on what could potentially be a word of the language.

Abstract

Speech signals originate as a sequence of linguistic units selected by speakers, but these units are necessarily realised in the suprasegmental dimensions of time, frequency and amplitude. For this reason prosodic structure has been viewed as a mandatory target of language processing by both speakers and listeners. In apparent contradiction, however, prosody has also been argued to be ancillary rather than core linguistic structure, making processing of prosodic structure essentially optional. In the present tribute to one of the luminaries of prosodic research for the past quarter century, we review evidence from studies of the processing of lexical stress and focal accent which reconciles these views and shows that both claims are, each in their own way, fully true.

Abstract

Vocabularies contain hundreds of thousands of words built from only a handful of phonemes; longer words inevitably tend to contain shorter ones. Recognising speech thus requires distinguishing intended words from accidentally present ones. Acoustic information in speech is used wherever it contributes significantly to this process; but as this review shows, its contribution differs across languages, with the consequences of this including: identical and equivalently present information distinguishing the same phonemes being used in Polish but not in German, or in English but not in Italian; identical stress cues being used in Dutch but not in English; expectations about likely embedding patterns differing across English, French, Japanese.

Abstract

English and French listeners performed two tasks - click location and speeded click detection - with both English and French sentences, closely matched for syntactic and phonological structure. Clicks were located more accurately in open- than in closed-class words in both English and French; they were detected more rapidly in open- than in closed-class words in English, but not in French. The two listener groups produced the same pattern of responses, suggesting that higher-level linguistic processing was not involved in these tasks.

Abstract

The phoneme detection task is widely used in spoken word recognition research. Alphabetically literate participants, however, are more used to explicit representations of letters than of phonemes. The present study explored whether phoneme detection is sensitive to how target phonemes are, or may be, orthographically realised. Listeners detected the target sounds [b,m,t,f,s,k] in word-initial position in sequences of isolated English words. Response times were faster to the targets [b,m,t], which have consistent word-initial spelling, than to the targets [f,s,k], which are inconsistently spelled, but only when listeners’ attention was drawn to spelling by the presence in the experiment of many irregularly spelled fillers. Within the inconsistent targets [f,s,k], there was no significant difference between responses to targets in words with majority and minority spellings. We conclude that performance in the phoneme detection task is not necessarily sensitive to orthographic effects, but that salient orthographic manipulation can induce such sensitivity.

Abstract

It is a widely held belief that women talk more than men; but experimental evidence has suggested that this belief is mistaken. The present study investigated whether listener bias contributes to this mistake. Dialogues were recorded in mixed-sex and single-sex versions, and male and female listeners judged the proportions of talk contributed to the dialogues by each participant. Female contributions to mixed-sex dialogues were rated as greater than male contributions by both male and female listeners. Female contributions were more likely to be overestimated when they were speaking a dialogue part perceived as probably female than when they were speaking a dialogue part perceived as probably male. It is suggested that the misestimates are due to a complex of factors that may involve both perceptual effects such as misjudgment of rates of speech and sociological effects such as attitudes to social roles and perception of power relations.

Abstract

The phoneme detection task is widely used in spoken-word recognition research. Alphabetically literate participants, however, are more used to explicit representations of letters than of phonemes. The present study explored whether phoneme detection is sensitive to how target phonemes are, or may be, orthographically realized. Listeners detected the target sounds [b, m, t, f, s, k] in word-initial position in sequences of isolated English words. Response times were faster to the targets [b, m, t], which have consistent word-initial spelling, than to the targets [f, s, k], which are inconsistently spelled, but only when spelling was rendered salient by the presence in the experiment of many irregularly spelled filler words. Within the inconsistent targets [f, s, k], there was no significant difference between responses to targets in words with more usual (foam, seed, cattle) versus less usual (phone, cede, kettle) spellings. Phoneme detection is thus not necessarily sensitive to orthographic effects; knowledge of spelling stored in the lexical representations of words does not automatically become available as word candidates are activated. However, salient orthographic manipulations in experimental input can induce such sensitivity. We attribute this to listeners' experience of the value of spelling in everyday situations that encourage phonemic decisions (such as learning new names)

Abstract

Bisyllabic sequences which could be interpreted as one word or two were produced in sentence contexts by a trained speaker, and syllabic durations measured. Listeners judged whether the bisyllables, excised from context, were one word or two. The proportion of two-word choices correlated positively with measured duration, but only for bisyllables stressed on the second syllable. The results may suggest a limit for listener sensitivity to syllabic lengthening as a word boundary cue.

Abstract

The performance of automatic speech recognition systems is usually assessed in terms of error rate. Human speech recognition produces few errors, but relative difficulty of processing can be assessed via response time techniques. We report the construction of a measure analogous to response time in a machine recognition system. This measure may be compared directly with human response times. We conducted a trial comparison of this type at the phoneme level, including both tense and lax vowels and a variety of consonant classes. The results suggested similarities between human and machine processing in the case of consonants, but differences in the case of vowels.

Abstract

Segmentation of continuous speech into its component words is a nontrivial task for listeners. Previous work has suggested that listeners develop heuristic segmentation procedures based on experience with the structure of their language; for English, the heuristic is that strong syllables (containing full vowels) are most likely to be the initial syllables of lexical words, whereas weak syllables (containing central, or reduced, vowels) are nonword-initial, or, if word-initial, are grammatical words. This hypothesis is here tested against natural and laboratory-induced missegmentations of continuous speech. Precisely the expected pattern is found: listeners erroneously insert boundaries before strong syllables but delete them before weak syllables; boundaries inserted before strong syllables produce lexical words, while boundaries inserted before weak syllables produce grammatical words.

Abstract

Adverse listening conditions always make the perception of speech harder, but their deleterious effect is far greater if the speech we are trying to understand is in a non-native language. An imperfect signal can be coped with by recourse to the extensive knowledge one has of a native language, and imperfect knowledge of a non-native language can still support useful communication when speech signals are high-quality. But the combination of imperfect signal and imperfect knowledge leads rapidly to communication breakdown. This phenomenon is undoubtedly well known to every reader of Speech Communication from personal experience. Many readers will also have a professional interest in explaining, or remedying, the problems it produces. The journal’s readership being a decidedly interdisciplinary one, this interest will involve quite varied scientific approaches, including (but not limited to) modelling the interaction of first and second language vocabularies and phonemic repertoires, developing targeted listening training for language learners, and redesigning the acoustics of classrooms and conference halls. In other words, the phenomenon that this special issue deals with is a well-known one, that raises important scientific and practical questions across a range of speech communication disciplines, and Speech Communication is arguably the ideal vehicle for presentation of such a breadth of approaches in a single volume. The call for papers for this issue elicited a large number of submissions from across the full range of the journal’s interdisciplinary scope, requiring the guest editors to apply very strict criteria to the final selection. Perhaps unique in the history of treatments of this topic is the combination represented by the guest editors for this issue: a phonetician whose primary research interest is in second-language speech (MLGL), an engineer whose primary research field is the acoustics of masking in speech processing (MC), and a psychologist whose primary research topic is the recognition of spoken words (AC). In the opening article of the issue, these three authors together review the existing literature on listening to second-language speech under adverse conditions, bringing together these differing perspectives for the first time in a single contribution. The introductory review is followed by 13 new experimental reports of phonetic, acoustic and psychological studies of the topic. The guest editors thank Speech Communication editor Marc Swerts and the journal’s team at Elsevier, as well as all the reviewers who devoted time and expert efforts to perfecting the contributions to this issue.

Abstract

Monolingual French speakers employ a syllable-based procedure in speech segmentation; monolingual English speakers use a stress-based segmentation procedure and do not use the syllable-based procedure. In the present study French-English bilinguals participated in segmentation experiments with English and French materials. Their results as a group did not simply mimic the performance of English monolinguals with English language materials and of French monolinguals with French language materials. Instead, the bilinguals formed two groups, defined by forced choice of a dominant language. Only the French-dominant group showed syllabic segmentation and only with French language materials. The English-dominant group showed no syllabic segmentation in either language. However, the English-dominant group showed stress-based segmentation with English language materials; the French-dominant group did not. We argue that rhythmically based segmentation procedures are mutually exclusive, as a consequence of which speech segmentation by bilinguals is, in one respect at least, functionally monolingual.

Abstract

Phoneme detection is a psycholinguistic task in which listeners' response time to detect the presence of a pre-specified phoneme target is measured. Typically, detection tasks have used consonant targets. This paper reports two experiments in which subjects responded to vowels as phoneme detection targets. In the first experiment, targets occurred in real words, in the second in nonsense words. Response times were long by comparison with consonantal targets. Targets in initial syllables were responded to much more slowly than targets in second syllables. Strong vowels were responded to faster than reduced vowels in real words but not in nonwords. These results suggest that the process of phoneme detection produces different results for vowels and for consonants. We discuss possible explanations for this difference, in particular the possibility of language-specificity.

Abstract

Recognising continuous speech in a second language is often unexpectedly difficult, as the operation of segmenting speech is so attuned to native-language structure. We report the initial steps in development of a novel training method for second-language listening, focusing on speech segmentation and employing a task designed for studying this: word-spotting. Listeners detect real words in sequences consisting of a word plus a minimal context. The present validation study shows that learners from varying non-English backgrounds successfully perform a version of this task in English, and display appropriate sensitivity to structural factors that also affect segmentation by native English listeners.

Abstract

We investigated whether readers use the low-level cue of proper noun capitalization in the parafovea to infer syntactic category, and whether this results in an early update of the representation of a sentence’s syntactic structure. Participants read sentences containing either a subject relative or object relative clause, in which the relative clause’s overt argument was a proper noun (e.g., The tall lanky guard who alerted Charlie/Charlie alerted to the danger was young) across three experiments. In Experiment 1 these sentences were presented in normal sentence casing or entirely in upper case. In Experiment 2 participants received either valid or invalid parafoveal previews of the relative clause. In Experiment 3 participants viewed relative clauses in only normal conditions. We hypothesized that we would observe relative clause effects (i.e., inflated fixation times for object relative clauses) while readers were still fixated on the word who, if readers use capitalization to infer a parafoveal word’s syntactic class. This would constitute a syntactic parafoveal-on-foveal effect. Furthermore, we hypothesised that this effect should be influenced by sentence casing in Experiment 1 (with no cue for syntactic category being available in upper case sentences) but not by parafoveal preview validity of the target words. We observed syntactic parafoveal-on-foveal effects in Experiment 1 and 3, and a Bayesian analysis of the combined data from all three experiments. These effects seemed to be influenced more by noun capitalization than lexical processing. We discuss our findings in relation to models of eye movement control and sentence processing theories.

Abstract

In two eye-tracking studies we investigated whether readers can detect a violation of the phonological-grammatical convention for the indefinite article an to be followed by a word beginning with a vowel when these two words appear in the parafovea. Across two experiments participants read sentences in which the word an was followed by a parafoveal preview that was either correct (e.g. Icelandic), incorrect and represented a phonological violation (e.g. Mongolian), or incorrect without representing a phonological violation (e.g. Ethiopian), with this parafoveal preview changing to the target word as participants made a saccade into the space preceding an. Our data suggests that participants detected the phonological violation while the target word was still two words to the right of fixation, with participants making more regressions from the previewed word and having longer go-past times on this word when they received a violation preview as opposed to a non-violation preview. We argue that participants were attempting to perform aspects of sentence integration on the basis of low-level orthographic information from the previewed word.

Abstract

We present an eye-tracking study testing a hypothesis emerging from several theories of prediction during language processing, whereby predictable words should be skipped more than unpredictable words even in syntactically illegal positions. Participants read sentences in which a target word became predictable by a certain point (e.g., “bone” is 92% predictable given, “The dog buried his. . .”), with the next word actually being an intensifier (e.g., “really”), which a noun cannot follow. The target noun remained predictable to appear later in the sentence. We used the boundary paradigm to present the predictable noun or an alternative unpredictable noun (e.g., “food”) directly after the intensifier, until participants moved beyond the intensifier, at which point the noun changed to a syntactically legal word. Participants also read sentences in which predictable or unpredictable nouns appeared in syntactically legal positions. A Bayesian linear-mixed model suggested a 5.7% predictability effect on skipping of nouns in syntactically legal positions, and a 3.1% predictability effect on skipping of nouns in illegal positions. We discuss our findings in relation to theories of lexical prediction during reading.

Abstract

Recent advances in large-scale data storage and processing offer unprecedented opportunities for behavioral scientists to collect and analyze naturalistic data, including from under-represented groups. Audio data, particularly real-world audio recordings, are of particular interest to behavioral scientists because they provide high-fidelity access to subtle aspects of daily life and social interactions. However, these methodological advances pose novel risks to research participants and communities. In this article, we outline the benefits and challenges associated with collecting, analyzing, and sharing multi-hour audio recording data. Guided by the principles of autonomy, privacy, beneficence, and justice, we propose a set of ethical guidelines for the use of longform audio recordings in behavioral research. This article is also accompanied by an Open Science Framework Ethics Repository that includes informed consent resources such as frequent participant concerns and sample consent forms.

Abstract

The authors used 2 “visual-world” eye-tracking experiments to examine lexical access using Dutch constructions in which the verb did or did not place semantic constraints on its subsequent subject noun phrase. In Experiment 1, fixations to the picture of a cohort competitor (overlapping with the onset of the referent’s name, the subject) did not differ from fixations to a distractor in the constraining-verb condition. In Experiment 2, cross-splicing introduced phonetic information that temporarily biased the input toward the cohort competitor. Fixations to the cohort competitor temporarily increased in both the neutral and constraining conditions. These results favor models in which mapping from the input onto meaning is continuous over models in which contextual effects follow access of an initial form-based competitor set.

Abstract

Speech-in-speech perception can be challenging because the processing of competing acoustic and linguistic information leads to informational masking. Here, a method is proposed to isolate the linguistic component of informational masking while keeping the distractor's acoustic information unchanged. Participants performed a dichotic listening cocktail-party task before and after training on 4-band noise-vocoded sentences that became intelligible through the training. Distracting noise-vocoded speech interfered more with target speech comprehension after training (i.e., when intelligible) than before training (i.e., when unintelligible) at −3 dB SNR. These findings confirm that linguistic and acoustic information have distinct masking effects during speech-in‐speech comprehension

Abstract

Aims Circulating microRNAs (miRNAs) may represent a novel class of biomarkers; therefore, we examined whether acute myocardial infarction (MI) modulates miRNAs plasma levels in humans and mice. Methods and results Healthy donors (n = 17) and patients (n = 33) with acute ST-segment elevation MI (STEMI) were evaluated. In one cohort (n = 25), the first plasma sample was obtained 517 ± 309 min after the onset of MI symptoms and after coronary reperfusion with percutaneous coronary intervention (PCI); miR-1, -133a, -133b, and -499-5p were ∼15- to 140-fold control, whereas miR-122 and -375 were ∼87–90% lower than control; 5 days later, miR-1, -133a, -133b, -499-5p, and -375 were back to baseline, whereas miR-122 remained lower than control through Day 30. In additional patients (n = 8; four treated with thrombolysis and four with PCI), miRNAs and troponin I (TnI) were quantified simultaneously starting 156 ± 72 min after the onset of symptoms and at different times thereafter. Peak miR-1, -133a, and -133b expression and TnI level occurred at a similar time, whereas miR-499-5p exhibited a slower time course. In mice, miRNAs plasma levels and TnI were measured 15 min after coronary ligation and at different times thereafter. The behaviour of miR-1, -133a, -133b, and -499-5p was similar to STEMI patients; further, reciprocal changes in the expression levels of these miRNAs were found in cardiac tissue 3–6 h after coronary ligation. In contrast, miR-122 and -375 exhibited minor changes and no significant modulation. In mice with acute hind-limb ischaemia, there was no increase in the plasma level of the above miRNAs. Conclusion Acute MI up-regulated miR-1, -133a, -133b, and -499-5p plasma levels, both in humans and mice, whereas miR-122 and -375 were lower than control only in STEMI patients. These miRNAs represent novel biomarkers of cardiac damage.

Abstract

The Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA) is a new tool for the systematic assessment of perceptual and sensorimotor timing skills. It spans a broad range of timing skills aimed at differentiating individual timing profiles. BAASTA consists of sensitive time perception and production tasks. Perceptual tasks include duration discrimination, anisochrony detection (with tones and music), and a version of the Beat Alignment Task. Perceptual thresholds for duration discrimination and anisochrony detection are estimated with a maximum likelihood procedure (MLP) algorithm. Production tasks use finger tapping and include unpaced and paced tapping (with tones and music), synchronization-continuation, and adaptive tapping to a sequence with a tempo change. BAASTA was tested in a proof-of-concept study with 20 non-musicians (Experiment 1). To validate the results of the MLP procedure, less widespread than standard staircase methods, three perceptual tasks of the battery (duration discrimination, anisochrony detection with tones, and with music) were further tested in a second group of non-musicians using 2 down / 1 up and 3 down / 1 up staircase paradigms (n = 24) (Experiment 2). The results show that the timing profiles provided by BAASTA allow to detect cases of timing/rhythm disorders. In addition, perceptual thresholds yielded by the MLP algorithm, although generally comparable to the results provided by standard staircase, tend to be slightly lower. In sum, BAASTA provides a comprehensive battery to test perceptual and sensorimotor timing skills, and to detect timing/rhythm deficits.

Abstract

This work was supported by grants from the French Agence Nationale de la Recherche (ANR-2010-BLAN-1901) and from French Fondation de France to Anne Christophe, from the National Institute of Child Health and Human Development (HD054448) to Cynthia Fisher, Fondation Fyssen and Ecole de Neurosciences de Paris to Alex Cristia, and a PhD fellowship from the Direction Générale de l'Armement (DGA, France) supported by the PhD program FdV (Frontières du Vivant) to Isabelle Dautriche. We thank Isabelle Brunet for the recruitment, Michel Dutat for the technical support, and Hernan Anllo for his puppet mastery skill. We are grateful to the families that participated in this study. We also thank two anonymous reviewers for their comments on an earlier draft of this manuscript.

Abstract

The ability to make inferences is essential for effective language comprehension. While inferencing training benefits reading comprehension in school-aged children (see Elleman, 2017, for a review), we do not yet know whether it is beneficial to support the development of these skills prior to school entry. In a pre-registered randomised controlled trial, we evaluated the efficacy of a parent-delivered intervention intended to promote four-year-olds’ oral inferencing skills during shared book-reading. One hundred children from socioeconomically diverse backgrounds were randomly assigned to inferencing training or an active control condition of daily maths activities. The training was found to have no effect on inferencing. However, inferencing measures were highly correlated with children's baseline language ability. This suggests that a more effective approach to scaffolding inferencing in the preschool years might be to focus on promoting vocabulary to develop richer and stronger semantic networks.

Abstract

This article surveys what is currently known about the complex interplay between genetics and the language sciences. It focuses not only on the genetic architecture of language and speech, but also on their interactions on the cultural and evolutionary timescales. Given the complexity of these issues and their current state of flux and high dynamism, this article surveys the main findings and topics of interest while also briefly introducing the main relevant methods, thus allowing the interested reader to fully appreciate and understand them in their proper context. Of course, not all the relevant publications and resources are mentioned, but this article aims to select the most relevant, promising, or accessible for nonspecialists.

Abstract

Language is not a purely cultural phenomenon somehow isolated from its wider environment, and we may only understand its origins and evolution by seriously considering its embedding in this environment as well as its multimodal nature. By environment here we understand other aspects of culture (such as communication technology, attitudes towards language contact, etc.), of the physical environment (ultraviolet light incidence, air humidity, etc.), and of the biological infrastructure for language and speech. We are specifically concerned in this paper with the latter, in the form of the biases, constraints and affordances that the anatomy and physiology of the vocal tract create on speech and language. In a nutshell, our argument is that (a) there is an under-appreciated amount of inter-individual variation in vocal tract (VT) anatomy and physiology, (b) variation that is non-randomly distributed across populations, and that (c) results in systematic differences in phonetics and phonology between languages. Relevant differences in VT anatomy include the overall shape of the hard palate, the shape of the alveolar ridge, the relationship between the lower and upper jaw, to mention just a few, and our data offer a new way to systematically explore such differences and their potential impact on speech. These differences generate very small biases that nevertheless can be amplified by the repeated use and transmission of language, affecting language diachrony and resulting in cross-linguistic synchronic differences. Moreover, the same type of biases and processes might have played an essential role in the emergence and evolution of language, and might allow us a glimpse into the speech and language of extinct humans by, for example, reconstructing the anatomy of parts of their vocal tract from the fossil record and extrapolating the biases we find in present-day humans.

Abstract

There are some 6000 languages spoken today, classfied in approximately 90 linguistic families and many isolates, and also differing across structural, typological, dimensions. Genetically, the human species is remarkably homogeneous, with the existant genetic diversity mostly explain by intra-population differences between individuals, but the remaining inter-population differences have a non-trivial structure. Populations splits and contacts influence both languages and genes, in principle allowing them to evolve in parallel ways. The farming/language co-dispersal hypothesis is a well-known such theory, whereby farmers spreading agriculture from its places of origin also spread their genes and languages. A different type of relationship was recently proposed, involving a genetic bias which influences the structural properties of language as it is transmitted across generations. Such a bias was proposed to explain the correlations between the distribution of tone languages and two brain development-related human genes and, if confirmed by experimental studies, it could represent a new factor explaining the distrbution of diversity. The present chapter overviews these related topics in the hope that a truly interdisciplinary approach could allow a better understanding of our complex (recent as well as evolutionary) history.

Abstract

There is an ongoing debate about whether discourse biases can constrain sentence
processing. Previous work has shown comprehension question accuracy to decrease
for temporarily ambiguous sentences preceded by a context biasing towards an initial
misinterpretation, suggesting a role of context for modulating comprehension.
However, this creates limited modulation of reading times at the disambiguating word,
suggesting initial syntactic processing may be unaffected by context [Christianson &
Luke, 2011. Context strengthens initial misinterpretations of text. Scientific Studies of
Reading, 15(2), 136–166]. The current experiments examine whether propositional and
structural content from preceding comprehension questions can cue readers to expect
certain structures in temporarily ambiguous garden-path sentences. The central finding
is that syntactic repair processes remain unaffected while reading times in other
regions are modulated by preceding questions. This suggests that reading strategies
can be superficially influenced by preceding comprehension questions without
impacting the fidelity of ultimate (mis)representations.

Abstract

Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

Abstract

Assays based on Bioluminescence Resonance Energy Transfer (BRET) provide a sensitive and reliable means to monitor protein-protein interactions in live cells. BRET is the non-radiative transfer of energy from a ‘donor’ luciferase enzyme to an ‘acceptor’ fluorescent protein. In the most common configuration of this assay, the donor is Renilla reniformis luciferase and the acceptor is Yellow Fluorescent Protein (YFP). Because the efficiency of energy transfer is strongly distance-dependent, observation of the BRET phenomenon requires that the donor and acceptor be in close proximity. To test for an interaction between two proteins of interest in cultured mammalian cells, one protein is expressed as a fusion with luciferase and the second as a fusion with YFP. An interaction between the two proteins of interest may bring the donor and acceptor sufficiently close for energy transfer to occur. Compared to other techniques for investigating protein-protein interactions, the BRET assay is sensitive, requires little hands-on time and few reagents, and is able to detect interactions which are weak, transient, or dependent on the biochemical environment found within a live cell. It is therefore an ideal approach for confirming putative interactions suggested by yeast two-hybrid or mass spectrometry proteomics studies, and in addition it is well-suited for mapping interacting regions, assessing the effect of post-translational modifications on protein-protein interactions, and evaluating the impact of mutations identified in patient DNA.

Abstract

Investigation of the biological basis of human speech and language is being transformed by developments in molecular technologies, including high-throughput genotyping and next-generation sequencing of whole genomes. These advances are shedding new light on the genetic architecture underlying language-related disorders (speech apraxia, specific language impairment, developmental dyslexia) as well as that contributing to variation in relevant skills in the general population. We discuss how state-of-the-art methods are uncovering a range of genetic mechanisms, from rare mutations of large effect to common polymorphisms that increase risk in a subtle way, while converging on neurogenetic pathways that are shared between distinct disorders. We consider the future of the field, highlighting the unusual challenges and opportunities associated with studying genomics of language-related traits.