Revealing uncertainty in the status of biodiversity change.

Biodiversity faces unprecedented threats from rapid global change1. Signals of biodiversity change come from time-series abundance datasets for thousands of species over large geographic and temporal scales. Analyses of these biodiversity datasets have pointed to varied trends in abundance, including increases and decreases. However, these analyses have not fully accounted for spatial, temporal and phylogenetic structures in the data. Here, using a new statistical framework, we show across ten high-profile biodiversity datasets2-11 that increases and decreases under existing approaches vanish once spatial, temporal and phylogenetic structures are accounted for. This is a consequence of existing approaches severely underestimating trend uncertainty and sometimes misestimating the trend direction. Under our revised average abundance trends that appropriately recognize uncertainty, we failed to observe a single increasing or decreasing trend at 95% credible intervals in our ten datasets. This emphasizes how little is known about biodiversity change across vast spatial and taxonomic scales. Despite this uncertainty at vast scales, we reveal improved local-scale prediction accuracy by accounting for spatial, temporal and phylogenetic structures. Improved prediction offers hope of estimating biodiversity change at policy-relevant scales, guiding adaptive conservation responses.

Butterfly richness and abundance along a gradient of imperviousness and the importance of matrix quality.

Heterogeneity in quantity and quality of resources provided in the urban matrix may mitigate adverse effects of urbanization intensity on the structure of biotic communities. To assess this we quantified the spatial variation in butterfly richness and abundance along an impervious surface gradient using three measures of urban matrix quality: floral resource availability and origin (native vs. exotic plants), tree cover, and the occurrence of remnant habitat patches. Butterfly richness and abundance were surveyed in 100 cells (500 × 500 m), selected using a random-stratified sampling design, across a continuous gradient of imperviousness in Melbourne, Australia. Sampling occurred twice during the butterfly flight season. Occurrence data were analyzed using generalized linear models at local and mesoscales. Despite high sampling completeness, we did not detect 75% of species from the regional species pool in the urban area, suggesting that urbanization has caused a large proportion of the region's butterflies to become absent or extremely rare within Melbourne's metro-area. Those species that do remain are largely very generalist in their choice of larval host plants. Butterfly species richness and abundance declined with increasing impervious surface cover and, contrary to evidence for other taxa, there was no evidence that richness peaked at intermediate levels of urbanization. Declines in abundance appeared to be more noticeable when impervious surface cover exceeded 25%, while richness declined linearly with increasing impervious surface cover. We find evidence that the quality of the urban matrix (floral resources and remnant vegetation) influenced butterfly richness and abundance although the effects were small. Total butterfly abundance responded negatively to exotic floral abundance early in the sampling season and positively to total floral abundance later in the sampling season. Butterfly species richness increased with tree cover. Negative impacts of increased urbanization intensity on butterfly species richness and abundance may be mitigated to some extent by improving the quality of the urban matrix by enhancing tree cover and the provision of floral resources, with some evidence that native plants are more effective.

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia.

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.

A global assessment of the social and conservation outcomes of protected areas.

Protected areas (PAs) are a key strategy for protecting biological resources, but they vary considerably in their effectiveness and are frequently reported as having negative impacts on local people. This has contributed to a divisive and unresolved debate concerning the compatibility of environmental and socioeconomic development goals. Elucidating the relationship between positive and negative social impacts and conservation outcomes of PAs is key for the development of more effective and socially just conservation. We conducted a global meta-analysis on 165 PAs using data from 171 published studies. We assessed how PAs affect the well-being of local people, the factors associated with these impacts, and crucially the relationship between PAs' conservation and socioeconomic outcomes. Protected areas associated with positive socioeconomic outcomes were more likely to report positive conservation outcomes. Positive conservation and socioeconomic outcomes were more likely to occur when PAs adopted comanagement regimes, empowered local people, reduced economic inequalities, and maintained cultural and livelihood benefits. Whereas the strictest regimes of PA management attempted to exclude anthropogenic influences to achieve biological conservation objectives, PAs that explicitly integrated local people as stakeholders tended to be more effective at achieving joint biological conservation and socioeconomic development outcomes. Strict protection may be needed in some circumstances, yet our results demonstrate that conservation and development objectives can be synergistic and highlight management strategies that increase the probability of maximizing both conservation performance and development outcomes of PAs.

708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits.

A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10(-5), OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.

Candidate gene polymorphisms for behavioural adaptations during urbanization in blackbirds.

Successful urban colonization by formerly rural species represents an ideal situation in which to study adaptation to novel environments. We address this issue using candidate genes for behavioural traits that are expected to play a role in such colonization events. We identified and genotyped 16 polymorphisms in candidate genes for circadian rhythms, harm avoidance and migratory and exploratory behaviour in 12 paired urban and rural populations of the blackbird Turdus merula across the Western Palaearctic. An exonic microsatellite in the SERT gene, a candidate gene for harm avoidance behaviour, exhibited a highly significant association with habitat type in an analysis conducted across all populations. Genetic divergence at this locus was consistent in 10 of the 12 population pairs; this contrasts with previously reported stochastic genetic divergence between these populations at random markers. Our results indicate that behavioural traits related to harm avoidance and associated with the SERT polymorphism experience selection pressures during most blackbird urbanization events. These events thus appear to be influenced by homogeneous adaptive processes in addition to previously reported demographic founder events.

Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder.

The neuronal PAS domain 3 (NPAS3) gene encodes a neuronal transcription factor that is implicated in psychiatric disorders by the identification of a human chromosomal translocation associated with schizophrenia and a mouse knockout model with behavioural and hippocampal neurogenesis defects. To determine its contribution to the risk of psychiatric illness in the general population, we genotyped 70 single-nucleotide polymorphisms across the NPAS3 gene in 368 individuals with bipolar disorder, 386 individuals with schizophrenia and 455 controls. Modestly significant single-marker and global and individual haplotypes were identified in four discrete regions of the gene. The presence of both risk and protective haplotypes at each of these four regions indicated locus and allelic heterogeneity within NPAS3 and suggested a model whereby interactions between variants across the gene might contribute to susceptibility to illness. This was supported by predicting the most likely haplotype for each individual at each associated region and then calculating an NPAS3-mediated 'net genetic load' value. This value differed significantly from controls for both bipolar disorder (P=0.0000010) and schizophrenia (P=0.0000012). Logistic regression analysis also confirmed the combinatorial action of the four associated regions on disease risk. In addition, sensitivity/specificity plots showed that the extremes of the genetic loading distribution possess the greatest predictive power-a feature suggesting multiplicative allele interaction. These data add to recent evidence that the combinatorial analysis of a number of relatively small effect size haplotypes may have significant power to predict an individual's risk of a complex genetic disorder such as psychiatric illness.

The effects of a neuregulin 1 variant on white matter density and integrity.

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T(1)-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

Outcome of Newborn Hearing Screening Programme delivered by health visitors.

BACKGROUND: The Newborn Hearing Screening Programme (NHSP) was introduced in England in 2001 to detect congenital hearing loss in the newborn. The screen is either hospital- or community-based. OBJECTIVES: This is the first large-scale study of community-based NHSP published in the United Kingdom which aims to evaluate the performance of the community-based screen and compare it against national targets for NHSP and the outcome of national pilot projects. METHOD: Hearing screening data recorded for 10,074 well babies between March 2004 and December 2005 were analysed. Babies who were admitted to the Special Care Baby Unit were excluded. The case notes of all children who failed the initial hearing screen, either unilateral or bilateral, were reviewed retrospectively. Specific performance measures include coverage rate, referral rate and yield. Reasons for failure to complete the screen were identified. RESULTS: The community programme met all the standards set by the NHSP and the results are comparable with the average of the pilot sites reported in 2004. CONCLUSION: The data demonstrate that a community-based hearing screening programme conducted by Health Visitors meets all the current national standards and could be implemented across wider areas in this country. Its advantages include a low false positive rate and convenience for parents living in rural areas. The babies identified can be diagnosed and rehabilitated in a time which meets national standards.

Nuts and bolts of psychiatric genetics: building on the Human Genome Project.

Schizophrenia and bipolar affective disorder are chronic, disabling illnesses that together affect 2% of the population. Genetic factors are known to be important in their development, but there are, as yet, no confirmed susceptibility genes. Here we discuss important issues in terms of alternative genetic strategies (linkage, association and/or cytogenetics) in the identification of candidate genes for the major psychoses. We discuss the impact of the Human Genome Project, the role of comparative genetics in finding and testing positional candidates, and the prospects for rational drug design and personalized medicine.

Placement and refined mapping of established and new markers on human chromosome 11q using a small panel of somatic cell hybrids.

Constructing detailed chromosome maps relies on the ability to place new markers rapidly and accurately. Here we map two new anonymous DNA markers precisely on chromosome 11q and refine the location of established markers using a panel of just six fragmentation hybrids, with reference to four translocation chromosomes. As several of the hybrids retain multiple segments of chromosome 11, it is possible to quickly assign new markers to subintervals using this modest set of hybrid DNAs.

Recognition and management of sinusitis.

Acute sinusitis frequently follows upper respiratory tract infections. Patients complain of headache, facial pain, fever and purulent rhinorrhoea. Diagnosis is based upon the symptoms, and treatment comprises symptomatic relief with analgesics, topical or systemic decongestants and steam inhalation. If indicated, antibiotics should be given for an adequate period of time. Patients with chronic sinusitis complain of a combination of nasal obstruction, rhinorrhoea and postnasal drip associated with intermittent facial pain, with symptoms persisting for 3 months or more. Predisposition to the condition may be caused by rhinitis (allergic or nonallergic) and anatomical variants. Failure of mucociliary transport and sinus ostial obstruction leads to mucosal oedema, mucous hypersecretion and chronic infection. Current treatment aims are to control rhinitis and improve ventilation and function of the sinuses. Rhinitis may be controlled with the long term use of topical corticosteroids, mast cell stabilisers or antihistamines, either alone or in combination. Secretions may be cleared with steam inhalation and/or saline nasal douching. Failure to control chronic sinusitis with medical treatment may indicate surgery. The aim of surgery is to improve ventilation and facilitate drainage of the sinuses, allowing the restoration of normal function. Removal of nasal polyps, reduction of inferior turbinates or septal straightening may be all that is required. Some patients will need endoscopic ethmoidectomy and middle meatal antrostomy. Improved ventilation in the ethmoid infundibulum may help to resolve disease in maxillary and frontal sinuses. Medical treatment of underlying rhinitis will need to be continued postoperatively, often in the long term, while special consideration needs to be paid to sinusitis in children, in relation to dental disease and in the immunosuppressed. Complications of acute and chronic sinusitis include intraorbital and intracranial sepsis. These potentially lethal complications need urgent evaluation with high resolution computerised tomography (CT) scanning, intravenous administration of broad spectrum antibiotics (including anaerobic and microaerophilic cover) and urgent surgical drainage as appropriate.

Mutational analysis of the Wolfram syndrome gene in two families with chromosome 4p-linked bipolar affective disorder.

Bipolar affective disorder (BPAD) is a complex disease with a significant genetic component. Heterozygous carriers of Wolfram syndrome (WFS) are at increased risk of psychiatric illness. A gene for WFS (WFS1) has recently been cloned and mapped to chromosome 4p, in the general region we previously reported as showing linkage to BPAD. Here we present sequence analysis of the WFS1 coding sequence in five affected individuals from two chromosome 4p-linked families. This resulted in the identification of six polymorphisms, two of which are predicted to change the amino acid sequence of the WFS1 protein, however none of the changes segregated with disease status. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:158-160, 2000.