Quantifying the dark data in museum fossil collections as palaeontology undergoes a second digital revolution.

Large-scale analysis of the fossil record requires aggregation of palaeontological data from individual fossil localities. Prior to computers, these synoptic datasets were compiled by hand, a laborious undertaking that took years of effort and forced palaeontologists to make difficult choices about what types of data to tabulate. The advent of desktop computers ushered in palaeontology's first digital revolution-online literature-based databases, such as the Paleobiology Database (PBDB). However, the published literature represents only a small proportion of the palaeontological data housed in museum collections. Although this issue has long been appreciated, the magnitude, and thus potential significance, of these so-called 'dark data' has been difficult to determine. Here, in the early phases of a second digital revolution in palaeontology--the digitization of museum collections-we provide an estimate of the magnitude of palaeontology's dark data. Digitization of our nine institutions' holdings of Cenozoic marine invertebrate collections from California, Oregon and Washington in the USA reveals that they represent 23 times the number of unique localities than are currently available in the PBDB. These data, and the vast quantity of similarly untapped dark data in other museum collections, will, when digitally mobilized, enhance palaeontologists' ability to make inferences about the patterns and processes of past evolutionary and ecological changes.

Semantic fluency in deaf children who use spoken and signed language in comparison with hearing peers.

BACKGROUND: Deafness has an adverse impact on children's ability to acquire spoken languages. Signed languages offer a more accessible input for deaf children, but because the vast majority are born to hearing parents who do not sign, their early exposure to sign language is limited. Deaf children as a whole are therefore at high risk of language delays. AIMS: We compared deaf and hearing children's performance on a semantic fluency task. Optimal performance on this task requires a systematic search of the mental lexicon, the retrieval of words within a subcategory and, when that subcategory is exhausted, switching to a new subcategory. We compared retrieval patterns between groups, and also compared the responses of deaf children who used British Sign Language (BSL) with those who used spoken English. We investigated how semantic fluency performance related to children's expressive vocabulary and executive function skills, and also retested semantic fluency in the majority of the children nearly 2 years later, in order to investigate how much progress they had made in that time. METHODS & PROCEDURES: Participants were deaf children aged 6-11 years (N = 106, comprising 69 users of spoken English, 29 users of BSL and eight users of Sign Supported English-SSE) compared with hearing children (N = 120) of the same age who used spoken English. Semantic fluency was tested for the category 'animals'. We coded for errors, clusters (e.g., 'pets', 'farm animals') and switches. Participants also completed the Expressive One-Word Picture Vocabulary Test and a battery of six non-verbal executive function tasks. In addition, we collected follow-up semantic fluency data for 70 deaf and 74 hearing children, nearly 2 years after they were first tested. OUTCOMES & RESULTS: Deaf children, whether using spoken or signed language, produced fewer items in the semantic fluency task than hearing children, but they showed similar patterns of responses for items most commonly produced, clustering of items into subcategories and switching between subcategories. Both vocabulary and executive function scores predicted the number of correct items produced. Follow-up data from deaf participants showed continuing delays relative to hearing children 2 years later. CONCLUSIONS & IMPLICATIONS: We conclude that semantic fluency can be used experimentally to investigate lexical organization in deaf children, and that it potentially has clinical utility across the heterogeneous deaf population. We present normative data to aid clinicians who wish to use this task with deaf children.

Compound heterozygous mutations in the IFT140 gene cause Opitz trigonocephaly C syndrome in a patient with typical features of a ciliopathy.

〈 We report on an infant with Opitz trigonocephaly C syndrome (OTCS), who also had manifestations of ciliopathy, including short ribs (non-asphyxiating), trident acetabular roofs, postaxial polydactyly cone-shaped epiphyses, and dysplasia of the renal, hepatic and pancreatic tissues. To investigate the molecular cause, we used an exome sequencing strategy followed by Sanger sequencing. Two rare variants, both predicted to result in loss of functional protein, were identified in the IFT140 gene; a substitution at the splice donor site of exon 24 (c.723 + 1 G > T) and a 17 bp deletion, impacting the first coding exon (c.-11_6del). The variants were confirmed as being biallelic using Sanger sequencing, showing that the splice variant was inherited from the propositus mother and the deletion from the father. To date, Mainzer-Saldino syndrome, Jeune syndrome, and a form of nonsyndromic retinal dystrophy, have been identified as ciliopathies caused by IFT140 mutations. We provide the first description of an OTCS phenotype that appears to result from IFT140 mutations. The presentation of this patient is consistent with previous reports showing that OTCS already exhibited skeleletal and nonskeletal features of a ciliopathy.

Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder.

We describe the identification and clinical presentation of four individuals from three unrelated families with hemizygous deletions involving the DPYD gene at chromosome 1p21.3. DPYD encodes dihydropyrimidine dehydrogenase, which is the initial and rate-limiting enzyme in the catabolism of pyrimidine bases. All four individuals described met diagnostic criteria for autism spectrum disorder with severe speech delay. Patient 1's deletion was originally reported in 2008, and more detailed clinical information is provided. Subsequently, this male individual was found to have a missense mutation in the X-linked PTCHD1 autism susceptibility gene, which may also contribute to the phenotype. Patients 2 and 3 are siblings with a novel deletion encompassing the DPYD gene. In their mother, the genomic region deleted from chromosome 1p21.3 was inserted into chromosome 10. A fourth proband had a novel 10-kb intragenic deletion of exon 6 of the DPYD gene detected on a higher resolution microarray. Our study suggests that hemizygous deletions involving the DPYD locus present with variable phenotypes which can include speech delay and autistic features, and may also be influenced by additional mutations in other genes, issues which need to be considered in genetic counseling.

Mapping of three novel loci for non-syndromic autosomal recessive mental retardation (NS-ARMR) in consanguineous families from Pakistan.

To date, of 13 loci with linkage to non-syndromic autosomal recessive mental retardation (NS-ARMR), only six genes have been established with associated mutations. Here we present our study on NS-ARMR among the Pakistani population, where people are traditionally bound to marry within the family or the wider clan. In an exceptional, far-reaching genetic survey we have collected more than 50 consanguineous families exhibiting clinical symptoms/phenotypes of NS-ARMR. In the first step, nine families (MR2-9 and MR11) with multiple affected individuals were selected for molecular genetic studies. Two families (MR3, MR4) showed linkage to already know NS-ARMR loci. Fifteen affected and 10 unaffected individuals from six (MR2, MR6, MR7, MR8, MR9 and MR11) families were genotyped by using Affymetrix 5.0 or 6.0 single-nucleotide polymorphism (SNP) microarrays. SNP microarray data was visually inspected by dChip and genome-wide homozygosity analysis was performed by HomozygosityMapper. Additional mapping was performed (to exclude false-positive regions of homozygosity called by HomozygosityMapper and dChip) on all available affected and unaffected members in seven NS-ARMR families, using microsatellite markers. In this manner we were able to map three novel loci in seven different families originating from different areas of Pakistan. Two families (MR2, MR5) showed linkage on chromosome 2p25.3-p25.2. Three families (MR7, MR8, and MR9) that have been collected from the same village and belong to the same clan were mapped on chromosome 9q34.3. MR11 maps to a locus on 9p23-p13.3. Analysis of MR6 showed two positive loci, on chromosome 1q23.2-q23.3 and 8q24.21-q24.23. Genotyping in additional family members has so far narrowed, but not excluded the 1q locus. In summary, through this study we have identified three new loci for NS-ARMR, namely MRT14, 15 and 16.

The link between prosody and language skills in children with specific language impairment (SLI) and/or dyslexia.

BACKGROUND: Children with specific language impairment (SLI) and dyslexia are known to have impairments in various aspects of phonology, which have been claimed to cause their language and literacy impairments. However, 'phonology' encompasses a wide range of skills, and little is known about whether these phonological impairments extend to prosody. AIMS: To investigate certain prosodic abilities of children with SLI and/or dyslexia, to determine whether such children have prosodic impairments, whether they have the same pattern of impairments, and whether prosodic impairments are related to language and literacy deficits. METHODS & PROCEDURES: Six subtests of the Profiling Elements of Prosodic Systems - Child version (PEPS-C) were used to investigate discrimination/comprehension and imitation/production of prosodic forms that were either independent of language or that had one of two linguistic functions: chunking (prosodic boundaries) and focus (contrastive stress). The performance of three groups of 10-14-year-old children with SLI plus dyslexia, SLI, and dyslexia were compared with an age-matched control group and two younger control groups matched for various aspects of language and reading. OUTCOMES & RESULTS: The majority of children with SLI and/or dyslexia performed well on the tasks that tested auditory discrimination and imitation of prosodic forms. However, their ability to use prosody to disambiguate certain linguistic structures was impaired relative to age-matched controls, although these differences disappeared in comparison with language-matched controls. No, or only very weak, links were found between prosody and language and literacy skills in children with SLI and/or dyslexia. CONCLUSIONS & IMPLICATIONS: Children with SLI and/or dyslexia aged 10-14 years show an impaired ability to disambiguate linguistic structures for which prosody is required. However, they are able on the whole to discriminate and imitate the actual prosodic structures themselves, without reference to linguistic meaning. While the interaction between prosody and other components of language such as syntax and pragmatics is problematic for children with SLI and/or dyslexia, prosody itself does not appear to be a core impairment.

Molecular and clinical characterization of de novo and familial cases with microduplication 3q29: guidelines for copy number variation case reporting.

Microdeletions of 3q29 have previously been reported, but the postulated reciprocal microduplication has only recently been observed. Here, cases from four families, two ascertained in Toronto (Canada) and one each from Edinburgh (UK) and Leiden (Netherlands), carrying microduplications of 3q29 are presented. These families have been characterized by cytogenetic and molecular techniques, and all individuals have been further characterized with genome-wide, high density single nucleotide polymorphism (SNP) arrays run at a single centre (The Centre for Applied Genomics, Toronto). In addition to polymorphic copy-number variants (CNV), all carry duplications of 3q29 ranging in size from 1.9 to 2.4 Mb, encompassing multiple genes and defining a minimum region of overlap of about 1.6 Mb bounded by clusters of segmental duplications that is remarkably similar in location to previously reported 3q29 microdeletions. Consistent with other reports, the phenotype is variable, although developmental delay and significant ophthalmological findings were recurrent, suggesting that dosage sensitivity of genes located within 3q29 is important for eye and CNS development. We also consider CNVs found elsewhere in the genome for their contribution to the phenotype. We conclude by providing preliminary guidelines for management and anticipatory care of families with this microduplication, thereby establishing a standard for CNV reporting.

Narrative skills in deaf children who use spoken English: Dissociations between macro and microstructural devices.

Previous research has highlighted that deaf children acquiring spoken English have difficulties in narrative development relative to their hearing peers both in terms of macro-structure and with micro-structural devices. The majority of previous research focused on narrative tasks designed for hearing children that depend on good receptive language skills. The current study compared narratives of 6 to 11-year-old deaf children who use spoken English (N=59) with matched for age and non-verbal intelligence hearing peers. To examine the role of general language abilities, single word vocabulary was also assessed. Narratives were elicited by the retelling of a story presented non-verbally in video format. Results showed that deaf and hearing children had equivalent macro-structure skills, but the deaf group showed poorer performance on micro-structural components. Furthermore, the deaf group gave less detailed responses to inferencing probe questions indicating poorer understanding of the story's underlying message. For deaf children, micro-level devices most strongly correlated with the vocabulary measure. These findings suggest that deaf children, despite spoken language delays, are able to convey the main elements of content and structure in narrative but have greater difficulty in using grammatical devices more dependent on finer linguistic and pragmatic skills.

Mutations of c-kit JM domain are found in a minority of human gastrointestinal stromal tumors.

The c-kit gene encodes a transmembrane receptor kinase (KIT) which is expressed in the majority of human gastrointestinal stromal tumors (GISTs), a subtype of gastrointestinal mesenchymal neoplasms. A previous study identified mutations in the juxtamembrane (JM) domain of c-kit in five of six GISTs (Science 279: 577, 1998). To better define the frequency and spectrum of c-kit gene mutations in mesenchymal neoplasms of the GI tract that had been characterized for KIT protein expression, we examined archived tissue samples for mutations in the JM domain by PCR amplification and DNA sequencing. c-kit JM domain mutations were found in nine of 56 mesenchymal tumors (46 GISTs, eight leiomyomas, two leiomyosarcomas) and occurred exclusively in GISTs (21%). Seven of the nine mutations consisted of intragenic deletions of one to 19 codons. There was one insertion mutation that added 12 codons and one missense mutation (Val560Asp). None of the mutations disrupted the downstream reading frame of the gene. The single missense mutation (Val560Asp) is very similar to the only other missense mutation reported in GISTs (Val599Asp). Of the 46 GISTs, 43 were strongly positive for KIT protein expression and negative for diffuse expression of desmin. Neither KIT expression nor gene mutations were found in gastrointestinal leiomyomas or leiomyosarcomas. We conclude that mutation of the c-kit JM domain does not occur in gastrointestinal mesenchymal neoplasms with well developed-smooth muscle differentiation, and is restricted to GISTs. However, since these mutations are only found in a minority of GISTs, further investigation into the mechanisms of c-kit gene activation in this group of neoplasms is warranted.

Recent synchronous radiation of a living fossil.

Modern survivors of previously more diverse lineages are regarded as living fossils, particularly when characterized by morphological stasis. Cycads are often cited as a classic example, reaching their greatest diversity during the Jurassic-Cretaceous (199.6 to 65.5 million years ago) then dwindling to their present diversity of ~300 species as flowering plants rose to dominance. Using fossil-calibrated molecular phylogenies, we show that cycads underwent a near synchronous global rediversification beginning in the late Miocene, followed by a slowdown toward the Recent. Although the cycad lineage is ancient, our timetrees indicate that living cycad species are not much older than ~12 million years. These data reject the hypothesized role of dinosaurs in generating extant diversity and the designation of today's cycad species as living fossils.

Derivational morphology in children with grammatical-specific language impairment.

Although it is well-established that children with Specific Language Impairment characteristically optionally inflect forms that require tense and agreement marking, their abilities with regards to derivational suffixation are less well understood. In this paper we provide evidence from children with Grammatical-Specific Language Impairment (G-SLI) that derivational suffixes, unlike tense and agreement suffixes, are not omitted in elicitation tasks. We investigate two types of derivation - comparative/superlative formation and adjective-from-noun formation - and reveal that G-SLI children supply these suffixes at high rates, equivalent to their language matched peers. Moreover, increasing the phonological or morphological complexity of the stimulus does not trigger suffix omission, although it results in non-target forms that are not characteristic of typically developing children. We discuss what these results reveal about the nature of the deficit in G-SLI within the context of three hypotheses of SLI: the Extended Optional Infinitive, Implicit Rule and Computational Grammatical Complexity Hypotheses.

The fossil record and estimating divergence times between lineages: maximum divergence times and the importance of reliable phylogenies.

Bounded estimates on divergence times between lineages are crucial to the calculation of absolute rates of molecular evolution. Upper (minimum) bounds on divergence times are easily estimated based on earliest fossil finds. Lower (maximum) bounds are more difficult to estimate; the age of putative ancestors may be used, though in practice it is virtually impossible to distinguish ancestors from primitive sister groups, which do not, of logical necessity, constitute lower bounds on divergence times. Two relatively new approaches to estimating lower bounds directly assess the incompleteness of the fossil record. The first uses taphonomic control groups to distinguish real absences from nonpreservation, while the second, and probably more powerful, uses the quality of the fossil record to estimate confidence intervals on the bases of stratigraphic ranges. For some groups, especially vertebrates, the inclusion or exclusion of problematic fossils can dramatically affect estimated lower bounds on divergence times, often swamping the uncertainties due to the incompleteness of the fossil record and/or correlation and dating errors. When datable paleogeographic events reflect ancient divisions of faunas, a lower bound on the divergence time of species within a fauna can be established based on the geologic, rather than fossil, record. The fossil records of hominids, eutherian mammals, echinoids, and geese are used as examples.

Character analysis and the integration of molecular and morphological data in an understanding of sand dollar phylogeny.

Reconciling discordant morphological and molecular phylogenies remains a problem in modern systematics. By examining conflicting DNA-hybridization and morphological phylogenies of sand dollars, I show that morphological criteria may be used to help evaluate the reliability of molecular phylogenies where they differ from morphological trees. All available criteria for assessing the reliability of DNA-hybridization phylogenies suggest that the sand dollar DNA-hybridization phylogeny is robust. Standard homology-recognition criteria are used to assess the a priori reliabilities of the morphological attributes associated with the node drawn into question by the DNA data, and it is shown that these attributes are among the least phylogenetically informative of all the morphological characters. Moreover, the questioned node has the smallest number of supporting characters, and most of these characters are associated with the food grooves, which suggests that they may be functionally correlated. Thus, on the basis of the analysis of the morphological data and given the robustness of the DNA tree, the DNA phylogeny is preferred. Further, paleobiogeographic data support the DNA tree rather than the morphological tree, and a plausible heterochronic mechanism has been proposed that may account for the homoplasious morphological evolution that must have occurred if the DNA tree is correct.

DNA-DNA hybridization phylogeny of sand dollars and highly reproducible extent of hybridization values.

A DNA hybridization phylogeny of four sand dollars using a sea biscuit as an outgroup is presented. The study is unusual in that the normalized percent hybridization (NPH) values were all less than 50%, yet the same topology was obtained regardless of which distance metric was used, i.e., whether reciprocal distances were averaged or not, or whether or not a molecular clock was assumed. The tree also appears robust under jackknifing and bootstrapping. The extent of hybridization between homologous hybrids was measured with a five- to sevenfold higher precision than is typical, and by implication NPH was also measured with a higher than normal precision. The ability to measure highly reproducible NPH values offers the possibility of examining the phylogeny of more widely divergent species than typically studied using DNA hybridization techniques, using 1/NPH as a distance metric. The hypothesis of a molecular clock within the sand dollars was rejected, adding sand dollars to the growing list of groups where significant rate variation is known. A small fraction of the sand dollar genomes hybridized with the distantly related regular sea urchin Lytechinus. These slowly evolving sequences probably represent conserved exonic components of the genome.

Vestibular stimulation for supranuclear gaze palsy: case report.

Gaze palsies following severe destruction or irritative lesions of the cerebral hemispheres are rare. This report describes a patient with supranuclear ophthalmoplegia secondary to stroke which was rapidly resolved by cold caloric vestibular stimulation. The patient had a severe infarction of the right cerebral hemisphere and had a fixed deviated gaze to the right 3 months after onset. Cold caloric vestibular stimulation was used in an attempt to evaluate brain stem integrity. Following three successive injections of cold water at OC-5C into the external auditory canal, the patient regained full voluntary extraocular eye movements. The improvement continued for more than 12 months after the last treatment. A literature review of the neuroanatomy and neurophysiology of voluntary and reflex ocular movements is presented. A possible explanation for the improvement in this case is that vestibular input inhibits the tonic phase of antagonistic extraocular muscles while facilitating agonistic extraocular muscles.

Dollo's law and the death and resurrection of genes.

Dollo's law, the concept that evolution is not substantively reversible, implies that the degradation of genetic information is sufficiently fast that genes or developmental pathways released from selective pressure will rapidly become nonfunctional. Using empirical data to assess the rate of loss of coding information in genes for proteins with varying degrees of tolerance to mutational change, we show that, in fact, there is a significant probability over evolutionary time scales of 0.5-6 million years for successful reactivation of silenced genes or "lost" developmental programs. Conversely, the reactivation of long (> 10 million years)-unexpressed genes and dormant developmental pathways is not possible unless function is maintained by other selective constraints; the classic example of the resurrection of "hen's teeth" is most likely an experimental artifact, and the experimental reactivation of the Archaeopteryx limb developmental program has been shown to be a misinterpretation. For groups undergoing adaptive radiations, lost features may "flicker" on and off, resulting in a distribution of character states that does not reflect the phylogeny of the group.

Morphological innovation and developmental genetics.

How do the actions of individual genes contribute to the complex morphologies of animals and plants? How widespread are these genes taxonomically? How many genes are involved in the morphological differences observed between species, and can we identify them? To what extent can empirical data and theory be reconciled? We provide an overview of some recent attempts to answer these questions, answers that have taken us to the threshold of understanding the mechanistic basis and evolutionary factors that underlie morphological innovation.