Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways

Fanconi anemia (FA) and ataxia telangiectasia (AT) are clinically distinct autosomal recessive disorders characterized by spontaneous chromosome breakage and hematological cancers. FA cells are hypersensitive to mitomycin C (MMC), while AT cells are hypersensitive to ionizing radiation (IR). Here, we identify the Fanconi anemia protein, FANCD2, as a link between the FA and ATM damage response pathways. ATM phosphorylates FANCD2 on serine 222 in vitro. This site is also phosphorylated in vivo in an ATM-dependent manner following IR. Phosphorylation of FANCD2 is required for activation of an S phase checkpoint. The ATM-dependent phosphorylation of FANCD2 on S222 and the FA pathway-dependent monoubiquitination of FANCD2 on K561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 results in both MMC and IR hypersensitivity.     

Linkage-disequilibrium-based binning affects the interpretation of GWASs

Genome-wide association studies (GWASs) are critically dependent on detailed knowledge of the pattern of linkage disequilibrium (LD) in the human genome. GWASs generate lists of variants, usually SNPs, ranked according to the significance of their association to a trait. Downstream analyses generally focus on the gene or genes that are physically closest to these SNPs and ignore their LD profile with other SNPs. We have developed a flexible R package (LDsnpR) that efficiently assigns SNPs to genes on the basis of both their physical position and their pairwise LD with other SNPs. We used the positional-binning and LD-based-binning approaches to investigate whether including these "LD-based" SNPs would affect the interpretation of three published GWASs on bipolar affective disorder (BP) and of the imputed versions of two of these GWASs. We show how including LD can be important for interpreting and comparing GWASs. In the published, unimputed GWASs, LD-based binning effectively "recovered" 6.1%-8.3% of Ensembl-defined genes. It altered the ranks of the genes and resulted in nonnegligible differences between the lists of the top 2,000 genes emerging from the two binning approaches. It also improved the overall gene-based concordance between independent BP studies. In the imputed datasets, although the increases in coverage (>0.4%) and rank changes were more modest, even greater concordance between the studies was observed, attesting to the potential of LD-based binning on imputed data as well. Thus, ignoring LD can result in the misinterpretation of the GWAS findings and have an impact on subsequent genetic and functional studies.     

Host range testing of a prospective classical biological control agent against cabbage maggot,Delia radicum,in Canada

The introduction of a European natural enemy, Aleochara bipustulata L. (Coleoptera: Staphylinidae), is being considered for control of cabbage maggot, Delia radicum (L.) (Diptera: Anthomyiidae) in canola in Canada, and the host specificity of this pupal parasitoid must first be studied. Contemporary guidelines were used to select 18 species of Diptera to represent non-target species taxonomically related or ecologically similar to reported hosts of A. bipustulata, or beneficial species. No-choice tests were used to determine which of the 18 species are within A. bipustulata’s fundamental host range, and whether puparial structure or mass or duration of pupal development influence their acceptability and suitability as hosts. Five species were consistently suitable as hosts, and these were either relatively small or were taxonomically closely related to the target host. The probability that a puparium would be entered by a parasitoid larva was greatest for small puparia, but was unaffected by pupal duration. The probability of completing parasitoid development once a puparium was entered was influenced by both puparial mass and duration of pupal development. Pitfall traps to assess habitat associations caught A. bipustulata adults in a variety of crop habitats but none were caught in forests. Host range and habitat data are used to argue that there is little risk of parasitism to beneficial taxa. Non-target species taxonomically closely related to the target D. radicum or with small puparia may fall within the fundamental host range of A. bipustulata. However, risk to many of these species may be minimal because of the habitat preferences of the parasitoid and its cues for host-finding and recognition.     

The genetic structure of the Swedish population

Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise F(st)) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions.     

Relationships between native small mammals and native and introduced large herbivores

Australia has a range of native and introduced large herbivores that could affect the abundance of small mammals through direct and indirect effects. Here we study the relationship between occurrence of the introduced rusa deer (Rusa timorensis) and the native swamp wallaby (Wallabia bicolor), and the abundance of four species of native small mammals in coastal heath vegetation with varying fire history. The abundance of two species, the brown antechinus (Antechinus stuartii) and bush rat (Rattus fuscipes), was related to occurrence of large herbivores and was dependent also on fire history. Abundance of swamp rats (R. lutreolus) and New Holland mice (Pseudomys novaehollandiae) was not related to the occurrence of any of the large herbivores, and did not depend on fire history. At sites burned within the last 9 years, captures of brown antechinus were negatively related to both deer and wallaby occurrence, and captures of bush rats were negatively related to deer occurrence. However, at sites that burned more than 15 years ago, captures of brown antechinus and bush rats were not related to large herbivore occurrence. Overall there was either no relationship, or a negative one, between small mammals and the large herbivores. This mensurative study has demonstrated relationships between deer and wallabies and small mammals, with fire as an additional important factor. From the results of the current study we put forward a series of hypotheses that need to be tested by future experiments.     

2,3-Dideoxy-3-Phthalimidopentoses in the Synthesis of 3′-Amino-2′,3′-Dideoxynucleosides

Abstract

3′-Amino-3′deoxythymidine is a very effective drug in vivo against L 1210 leukemia. It mives 1441 increase in lifespan with very little drug-induced toricitylil. Therefore, it was attractive to synthesize a large series of cuialogues, but unfortunately, such compounds are only achievable through a 1inear synthesis via the corresponding nucleoside which typically is transformed into the 3′-azido derivative and finally reduced.     

Behavioural responses to dimethyl disulphide by Aleochara bilineata and Aleochara bipustulata

Adult Aleochara bipustulata L. and Aleochara bilineata Gyllenhal (Coleoptera: Staphylinidae) are predatory on immature stages of cabbage root fly Delia radicum (L.) (Diptera: Anthomyiidae). Larvae of the two Aleochara are parasitoids of D. radicum pupae. Female Aleochara lay eggs near D. radicum puparia; the newly‐hatched Aleochara larvae enter puparia and consume the contents. Delia radicum‐infested roots of brassicas give off dimethyl disulphide (DMDS). In the field, DMDS attracts adult Aleochara to pitfall traps but does not enhance the biological control of D. radicum. In the present study, we investigate the behavioural responses of the Aleochara to DMDS in still air, as well as in moving air in a Y‐tube olfactometer, and also investigate the influence of DMDS on host selection. In larvae of both Aleochara species, DMDS induces a restricted‐area search in still air, resulting in elevated frequencies of attack of D. radicum puparia close to a source of DMDS. In the olfactometer, newly‐emerged virgin adults of both sexes of both Aleochara species choose alternatives to DMDS, older recently‐mated females are attracted to DMDS, and older males and older mate‐deprived females show no preference. Mating status of males determines the switch of their response to DMDS from avoidance to indifference. We conclude that DMDS is an important cue for host‐finding, although other cues are involved in mate‐finding. We discuss the implications for use of DMDS to enhance D. radicum mortality and for parasitism of nontarget species if A. bipustulata is introduced to Canada for biological control of D. radicum.     

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it functions in a network of proteins encoded by tumor suppressors. Notably, many of these tumor suppressors are related to the cellular response to DNA damage. The recruitment of PALB2 to DNA double-strand breaks at the head of this network is via a ubiquitin-dependent signaling pathway that involves the RAP80, Abraxas and BRCA1 tumor suppressors. Next, PALB2 interacts with BRCA2, which is a tumor suppressor, and with the RAD51 recombinase. These interactions promote DNA repair by homologous recombination (HR). More recently, PALB2 has been found to bind the RAD51 paralog, RAD51C, as well as the translesion polymerase pol η, both of which are tumor suppressors with functions in HR. Further, an interaction with MRG15, which is related to chromatin regulation, may facilitate DNA repair in damaged chromatin. Finally, PALB2 interacts with KEAP1, a regulator of the response to oxidative stress. The PALB2 network appears to mediate the maintenance of genome stability, may explain the association of many of the corresponding genes with similar spectra of tumors, and could present novel therapeutic opportunities.     

Genome-Wide Analysis of Attention Deficit Hyperactivity Disorder in Norway

Background

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric condition, but it has been difficult to identify genes underlying this disorder. This study aimed to explore genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci.

Materials and Methods

Participants were recruited through Norwegian medical and birth registries as well as the general population. Presence of ADHD was defined according to DSM-IV criteria. Genotyping was performed using Illumina Human OmniExpress-12v1 microarrays. Statistical analyses were divided into several steps: (1) genome-wide association in the form of logistic regression in PLINK and follow-up pathway analyses performed in DAPPLE and INRICH softwares, (2) SNP-heritability calculated using genome-wide complex trait analysis (GCTA) tool, (3) gene-based association tests carried out in JAG software, and (4) evaluation of previously reported genome-wide signals and candidate genes of ADHD.

Results

In total, 1.358 individuals (478 cases and 880 controls) and 598.384 autosomal SNPs were subjected to GWA analysis. No single polymorphism reached genome-wide significance. The strongest signal was observed at rs9949006 in the ENSG00000263745 gene (OR=1.51, 95% CI 1.28–1.79, p=1.38E-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs1393072, OR=1.46, 95% CI = 1.21–1.77, p=9.95E-05) and TPH2 (rs17110690, OR = 1.38, 95% CI = 1.14–1.66, p=8.31E-04).

Conclusion

This study confirms the complexity and heterogeneity of ADHD etiology. Taken together with previous findings, our results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder.     

New insights from the last decade of research in psychiatric genetics: discoveries,challenges and clinical implications

Psychiatric genetics has made substantial progress in the last decade, providing new insights into the genetic etiology of psychiatric disorders, and paving the way for precision psychiatry, in which individual genetic profiles may be used to personalize risk assessment and inform clinical decision-making. Long recognized to be heritable, recent evidence shows that psychiatric disorders are influenced by thousands of genetic variants acting together. Most of these variants are commonly occurring, meaning that every individual has a genetic risk to each psychiatric disorder, from low to high. A series of large-scale genetic studies have discovered an increasing number of common and rare genetic variants robustly associated with major psychiatric disorders. The most convincing biological interpretation of the genetic findings implicates altered synaptic function in autism spectrum disorder and schizophrenia. However, the mechanistic understanding is still incomplete. In line with their extensive clinical and epidemiological overlap, psychiatric disorders appear to exist on genetic continua and share a large degree of genetic risk with one another. This provides further support to the notion that current psychiatric diagnoses do not represent distinct pathogenic entities, which may inform ongoing attempts to reconceptualize psychiatric nosology. Psychiatric disorders also share genetic influences with a range of behavioral and somatic traits and diseases, including brain structures, cognitive function, immunological phenotypes and cardiovascular disease, suggesting shared genetic etiology of potential clinical importance. Current polygenic risk score tools, which predict individual genetic susceptibility to illness, do not yet provide clinically actionable information. However, their precision is likely to improve in the coming years, and they may eventually become part of clinical practice, stressing the need to educate clinicians and patients about their potential use and misuse. This review discusses key recent insights from psychiatric genetics and their possible clinical applications, and suggests future directions.