* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Conference Report - IGB-CNR
Genomic imprinting wikipedia , lookup
Protein moonlighting wikipedia , lookup
Human genetic variation wikipedia , lookup
Human genome wikipedia , lookup
Gene desert wikipedia , lookup
Gene nomenclature wikipedia , lookup
Non-coding DNA wikipedia , lookup
Epigenetics of diabetes Type 2 wikipedia , lookup
Medical genetics wikipedia , lookup
Oncogenomics wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Gene therapy wikipedia , lookup
Genetic engineering wikipedia , lookup
Frameshift mutation wikipedia , lookup
Long non-coding RNA wikipedia , lookup
Gene expression profiling wikipedia , lookup
History of genetic engineering wikipedia , lookup
Gene expression programming wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
Helitron (biology) wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
Point mutation wikipedia , lookup
Genome evolution wikipedia , lookup
Neuronal ceroid lipofuscinosis wikipedia , lookup
Mir-92 microRNA precursor family wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Microevolution wikipedia , lookup
Genome (book) wikipedia , lookup
Designer baby wikipedia , lookup
Public health genomics wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
EUROPEAN HUMAN GENETICS CONFERENCE 2010 REPORT By Sabrina Carrella, Ph.D. Student The EUROPEAN HUMAN GENETICS CONFERENCE in Gothenburg (Sweden, June 12-15, 2010) examined several different topics: there were numerous opportunities to glean new information and to learn about new devices and approaches to detect and treat different human genetic diseases. In particular, one of the most interesting arguments concerned the massive potential of technologies such as next generation sequencing to identify the genetic basis of rare disorders using samples from only a handful of patients. Society President Dian Donnai believes that the during last 10 years there has been considerable progress and the changes have been enormous. She said that the next generation sequencing technology will provide many more discoveries that will help us to understand the predisposition to complex diseases and the biological pathways involved in disease. "Patients have to be prepared for genetic testing and genetic-based therapy, and there is a big deficit in the genetic knowledge of doctors and nurses in, perhaps, the majority of European countries", she said. "We need to address things like the educational needs of medical and nursing training, but also to involve the public more in what's going on in genetics. This is a big challenge, and it's important to find the right way to do it." Professor Sir Alec Jeffreys FRS (Royal Society Wolfson Research professor in the Department of Genetics at the University of Leicester, England, UK) argued that these technologies are not going to be the answer to everything and that a new approach is needed. He said: "To go further we need to start off with whole genome sequences on very large cohorts of people and couple this with a lot of bioinformatics linking with information about tissue-specific expression profiling, epigenetic, epigenome scans, etc..”. Attending the different oral presentations given at the congress it was possible to observe how useful these new technologies can be in different fields of human genetic research. The Scientific Programme Committee analyzed the 1718 abstracts submitted and selected a group of abstracts for the oral presentations that could give us the opportunity to gain interesting information on different aspects of all the topics examined during the congress. This series of reports is based on some of the presentations by scientists and scientist/clinicians at the ESHG congress. On the first day, June 12th 2010, during the Opening Plenary Session 1, there was the first example of how the new technologies can have an impact on our lives and patients’ lives. • Genetics of cancer predisposition (L. A. Aaltonen) Many of the early molecular studies on cancer predisposition focused on large pedigrees segregating syndromic cancer susceptibility phenotypes. The advances of the human genome project have brought in new resources year after year, such as better genetic markers and maps, and finally the full human genomic sequence and the technologies to analyze it at an acceptable cost. The speaker focused the attention on the latest developments that have led to the unraveling of the underlying genetic components of most high penetrance cancer syndromes. In fact, genome wide association studies have taken the work forward, towards population level cancer susceptibility. However, such disease phenotypes have been resistant to research by traditional methods such as linkage and top GWAS approaches. The speaker stated that next generation sequencing will unravel this key component of the genetics of cancer predisposition in the near future and concluded saying that this task will require considerable effort from the many health care professionals dealing with these issues. Particularly exciting new findings were presented in a “what’s new?” session: • The Effect of Translocation-Induced Nuclear Re-organization on Gene Expression (L. Harewood) Translocations are known to affect the expression of genes at the breakpoints and, in the case of unbalanced translocations, to alter the gene copy number. Dr. Louise Harewood showed us her work in which she has studied the effect of balanced chromosomal rearrangements on gene expression by comparing transcriptomes of cell lines from controls and individuals with the t (11; 22) (q23; q11) translocation. The number of differentially expressed transcripts between translocation carrying and control cohorts was significantly higher than that observed between control samples alone, suggesting that balanced rearrangements have a greater effect on gene expression than normal variations. Many of the affected genes are located on the derivative chromosome 11. They show that this chromosome is concomitantly altered in its spatial organization, occupying a more central position in the nucleus than its non-rearranged counterpart. She said that their results are consistent with recent studies that indicate that nuclear position plays a functional role in regulating the expression of some genes. Their study suggests that chromosomal translocations can result in large-scale changes in gene expression that are the consequence of alterations in normal chromosome territory positioning. • PDZD7 is a modifier of and digenic contributor to retinal disease in Usher syndrome (H. J. Bolz) Usher syndrome (USH), an inherited condition involving both hearing loss and retinitis pigmentosa (RP), is not simply a recessively inherited disease; in fact there is often an unexplained variability of the visual characteristics of the condition, even between close family members. Dr. Hanno Bolz (Associate Medical Director of the Bioscientia Centre for Human Genetics, Ingelheim, Germany, and active in teaching and research at the University Hospital of Cologne) said that his team’s research challenges the traditional view that USH was inherited as a single gene disorder, and showed that it may result from at least two different genetic mutations. Using a genome-wide database search they identified PDZD7, encoding a homolog of proteins mutated in Usher subtypes 1C and 2D (USH1C, USH2D). They demonstrated the interaction between PDZD7 and two Usher disease proteins, GPR98 (USH2C) and USH2A, and their colocalization in the photoreceptor’s connecting cilium region. Moreover on a homozygous USH2A mutation background, they showed that PDZD7 aggravates RP. In this work they were able to validate these findings in transgenic zebrafish, because visual defects are typically not evident in mouse models of Usher syndrome, and to show that PDZD7 localizes to the cilia, thus providing further confirmation that USH is a retinal ciliopathy. Their data in zebrafish were consistent with the digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in USH2A patients. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and significantly reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Dr. Bolz said “With advances in new sequencing techniques that permit simultaneous analysis of several genes, we will need to interpret variants in all Usher genes in a patient, not only in one. Two hits in a single Usher gene may explain the disease in one patient, but not its variability. Our research is a step on the road to understanding that variability and to being able to provide an accurate prognosis of disease progression”. This could lead to a more accurate diagnosis of this condition, which is responsible for up to 10% of all cases of childhood deafness and 50% of all deafness/blindness in adults. • De novo mutations of SETBP1 cause Schinzel-Giedion syndrome (Hoischen,B) Schinzel-Giedion syndrome is characterized by severe mental retardation and characteristic facial features. Most patients die before the age of 10 years. The exomes of four affected individuals with Schinzel-Giedion syndrome were sequenced to a mean coverage of 43-fold. On average 21,800 genetic variants were identified per patient. After filtering against known variants and selecting variants affecting the same gene in all patients, only a single candidate gene remained, SETBP1 which encodes SET binding protein 1. Sequencing confirmed the presence of SETBP1 mutations in these 4 individuals as well as in 8 additional Schinzel-Giedion syndrome patients. All mutations occurred de novo and all mutations were missense, and clustered to an ultra highly conserved 11bp exonic region of SETBP1. In conclusion, their study shows the potential of exome sequencing for disease gene identification by unraveling the first dominant Mendelian disorder. Exome sequencing is particularly useful for identifying these types of mutations for which no other genome wide approach is applicable. • Complete genome sequencing and analysis of diploid African-American and MexicanAmerican genomes: implications for personal ancestry reconstruction and multi-ethnic medical genomics (F. M. De La Vega) Understanding the genetic ancestry of mixed populations, such as those found in North America, can not only help to detect their origins but also to understand the genetic basis of complex diseases. “It is the first time that the genomes of individuals of admixed ancestry have been sequenced in such detail”, said Dr. Francisco De La Vega (Life Technologies, Foster City, California, USA). At the congress he presented results from the sequencing, assembly, and genomic analysis of two genomes using the SOLiD System, a greatly increasing the resolution of the analyses and achieving a very much clearer picture of the ancestry of genome sequences for the individuals studied. The donor individuals were of Mexican and African ancestry and represented the first "admixed" genomes to be sequenced to high coverage. They demonstrated that genomic sequencing provides a finer resolution of "admixture breakpoints" based on allele frequency estimates from HapMap and the 1000 Genomes Project. Finally, using the SOLiD comparative personal genomic data sets and 1000 Genomes data they quantified the relative proportions of private, rare, and common functional and neutral genetic variations. “We believe that our work will help move forward genetic disease association studies in these admixed populations”, said Dr. De La Vega, and he concluded “the decreasing costs of sequencing genomes through new sequencing instruments such as those developed by Life Technologies, is making it possible for the first time to compare on a large scale genetic variants among and within populations”. • A mutation in the 3'UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia (B. Arveiler) A family with dominant X-linked chondrodysplasia had previously beendescribed. The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1. The speaker presented the data in which they have identified a variant *281A>T in the 3’UTR of the HDAC6 gene that totally segregates with the disease. The variant is located in the seed sequence of hsa-miR-433. They demonstrated that hsa-miR-433 (miR433) down-regulated both the expression of endogenous HDAC6 and that of an eGFP-reporter mRNA bearing the wild-type 3’UTR of HDAC6. This effect was totally abrogated when the reporter mRNA presents the mutated HDAC6 3’UTR. The HDAC6 protein was found to be over-expressed in the thymus from an affected male fetus. Concomitantly, the level of total alpha-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alphatubulin was found to be profoundly decreased. These results strongly suggest that this HDAC6 3’UTR variant suppressed the hsa-miR-433-mediated post-transcriptional regulation causing the over expression of HDAC6. This variant is likely to constitute the molecular cause of this new form of Xlinked chondrodysplasia. In fact their working hypothesis is that this over expression can lead to RUNX over expression and to IHH expression repression, which finally result in chondrogenesis abnormality. This represents the first example of a skeletal disease caused by the loss of a miRNAmediated post-transcriptional regulation on its target mRNA, even if he specified that more experiment will be performed to demonstrate their hypothesis using different animal model systems ( Danio rerio, Xenopus laevis..). On the second day, June 13th 2010, I presented our work titled “The microRNA miR-204 is required for vertebrate eye development” during the Concurrent Sessions C04: Sensory Disorders and Neurobiology. • Identification of novel deafness genes by homozygosity mapping in Dutch families (H. Kremer) Novel autosomal recessive nonsyndromic hearing loss (arNSHI) loci are generally determined in large consanguineous families and are often large (10-30 Mb). In this work the authors followed a strategy of homozygosity mapping with high density SNP arrays in 125 patients with putative arNSHI from 77 families to delimit the critical region of known deafness loci and/or identify novel loci. They identified two different regions and performed mutation analysis of all the exons in these regions revealing putatively pathogenic mutations in GRXCR1 and PTPRQ. Vestibular dysfunction can be associated with hearing loss for both genes. • Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutation in C20orf54 (D. J. Josifova) Brown-Vialetto-Van Laere syndrome is a rare neurological disorder characterized by amyotrophic lateral sclerosis with onset in infancy. The disease usually presents with VII, IX, X, XI and XII cranial nerve palsies, which develop in a previously healthy individual. A complex neurological phenotype evolves with disease progression. The course is invariably progressive, but the rate of decline is variable within and between families. Here this group identified a candidate gene, C20orf54 by studying a consanguineous family with multiple affected individuals and subsequently demonstrated that mutations in this gene were the cause of disease in other, unrelated families. • Phenotypic modifiers of DJ1 (S. Jain) Parkinson’s disease (PD) is a slow progressing neurodegenerative disease with devastating clinical symptoms. The authors conducted a high content screening for interactors of DJ1, a gene mutated in PD to determine if any of them is capable of affecting DJ1 function. They have been able to identify several genes which are able to rescue DJ1 deficits in cell viability such as PPP2R2C, PSF, 4E-BP and other genes which are able to enhance the loss of DJ1. 4E-BP is a translational inhibitor for which many drugs are available. Therefore the administration of 4E-BP activators, such as rapamycin, may protect cells from apoptosis and thus may be an effective treatment to prevent or delay the onset of the disease. Using this approach they have been able to construct a detailed molecular pathway of the proteins that are involved in the function of DJ1 and to identify additional therapeutic targets. • MiR-135b regulates two transcriptional cofactors, PC4 and Psip1, in the mammalian inner ear, identified using an integrative transcriptomic and proteomic approach (K. B. Avraham) The relevance of micro-RNAs to the inner ear has recently been emphasized by the discovery of miRNA mutations leading to deafness in humans and mice. In this work the authors integrated a comparative transcriptomic and proteomic analysis and a miRNA screen of early post-natal cochlear and vestibular sensory epithelia derived from mice, with sequence-based predictions, to efficiently identify functional miRNAs and their targets. Using FAME, a bioinformatic tool developed by Ron Shamir, they identified PC4 and Psip1, two transcriptional cofactors that interact with one another, as targets for miR-135b in the inner ear hair cells. PC4 mediates functional interactions between upstream activators and general transcriptional machinery. Psip1 is involved in the transcriptional regulation of stress related genes, mRNA splicing, and cell survival. In order to prove the interaction between the miRNA and its target proteins, the miRNA was silenced or over-expressed in the cell line and the protein levels were studied using semi-quantitative western blot analysis. Their attention focuses on miR-135b regulation and its effects on downstream pathways in the inner ear. • Olfactory Expression of Mutant A30P alpha-Synuclein in Conditional Mouse Brain: Implications for Early Stage of Parkinson’s Disease (S. Nuber) Cognitive and psychiatric deficits precede motor impairment in Parkinson’s disease (PD). In this premotor stage the neuropathology is detectable in the olfactory bulb and a smell deficiency is found in about 90% of PD patients. A fast, simple and non invasive test of the ability to smell may be an important tool to screen people who are likely to develop Parkinson’s disease (PD), in which motor symptoms only become evident at a later stage of the disease. Dr. Silke Nuber, from the Department of Medical Genetics, University of Tübingen, Germany, said that her team’s research could help in the development of treatments for the early stages of the disease. They have generated and characterized a tet-off conditional mouse model expressing human [A30P] alpha-synuclein in the olfactory bulb. Alpha-synuclein can be turned off in these animals by the administration of an antibiotic, allowing scientists to look at the reversibility of the neuropathological alterations. “The mice expressed alpha-synuclein primarily in the neurons of the olfactory bulb”, said Dr. Nuber, “and we therefore expected to find alterations in smell-related behaviour in these animals. Since one of the earliest symptoms in PD patients is a reduction in the sense of smell, we felt that these mice could mimic the early stages of the disease.” They found that over expressing the mutated [A30P] alpha-synuclein led to a down regulation of dopamine neurotransmission in the olfactory bulb. In this way they have developed one of the first models to show this olfactory dopamine deficit without additional abnormalities in the nigrostriatal pathway. They have further detected an up regulation of neurotransmitter content in the striatum and substantia nigra and mitochondrial dysfunction in the non-olfactory brain regions, both of which could be reversed in old-aged mice. Using this transgenic mouse model, it is possible to model and explore in detail the impact of olfactory alpha-synucleinopathy on other brain regions; this model is also a useful tool to study early intervention strategies, which may halt or even reverse the massive dopaminergic neurodegeneration that takes place in human PD patients. Session S06 - Long Distance Regulation • Disruption of long-distance highly conserved non coding sequences at the SOX9 locus (S. Lyonnet) Two thirds of non-coding elements that have remained evolutionarily conserved, named conserved non-coding sequences (CNCs) do not correspond to transcribed sequences. Enrichment for CNCs has been demonstrated within gene deserts nearest to physically isolated genes known or suspected to be important developmental regulators. It has been suggested that in these cases CNCs may represent regulatory elements (enhancers or suppressors) necessary for the correct spatiotemporal expression of these genes needed for vertebrate development. Here the speaker discussed recent findings from his group: - A common non-coding enhancer genomic variant in a highly conserved sequence located in a noncoding region of the RET gene - The discovery of a long-distance disruption of enhancer CNCs on both sides of the SOX9 gene coding sequences in Pierre Robin sequence (PRS), a common orofacial cleft anomaly with mandibular hypoplasia. Their data, combined with existing evidence from human and animal phenotypes, strongly suggests that the disruption of distant, tissue-specific regulatory elements, required for the normal development of the mandibula, perturbs the embryonic expression of SOX9 and accounts for the PRS phenotype. From these and other data that he showed us during his presentation, we gained information about the genomic alteration of highly conserved non-coding elements, located near to, or at a long distance from, the coding sequences of a gene that might alter gene expression in a tissue-specific and timespecific manner. • Clustered gene co-regulation and enhancer sharing can be modulated by developmentally regulated chromatin loops (J. L. Gomez-Skarmeta) The authors presented a general map of enhancer distribution in the IrxA and IrxB clusters analyzed using transgenic Xenopus, zebrafish and mouse embryos. Using Chromatin Conformation Capture, they demonstrated that enhancer sharing is widespread within the cluster, which explains the common expression domains of IrxA genes in particular tissues and the evolutionarily conserved architecture of the cluster. They also identified an insulator and two chromatin loops within the cluster that may help partition it in two independent regulatory domains in certain cell types. The speaker also showed us different examples of cluster gene regulation (e.g. six6-six1-six4), suggesting the presence of developmentally regulated loops that facilitate the formation of genespecific regulatory landscapes for the clustered genes. • Far reaching consequences - mechanisms and problems of long range control (S. Mundlos) Conserved non-coding elements (CNEs) are particularly abundant in “gene deserts” surrounding genes that have important functions during development and may be as far as 1 Mb away from the gene they regulate. The binding of transcription factors to the element and the subsequent loop formation between the CNE and the gene’s promoter leads to the gene regulation. Mutations that interfere with the cis regulatory capacity of these elements can thus be expected to result in an altered gene expression in a certain cell type at a given time point. The speaker showed us their work in which they investigated the consequences of CNE-controlled gene regulation and the effect of mutations using cytogenetic and high-resolution array CGH in mouse models and patients. They identified several molecular mechanisms that cause abnormalities in long range control. All abnormalities were detected in patients or mice with congenital malformations. These include the disconnection of control elements from their target gene by translocations, changes in presumed transcription factor binding sites by point mutations, and altered gene regulation by deletions, and duplications of CNEs. These data suggest that the congenital malformations are caused by alterations of the fine tuning of gene expression which in consequence disturbs dosage-dependent signaling pathways. 14 June 2010: Concurrent Session C09 – Mouse Genetics and Therapy • Kidney-specific inactivation of Ofd1 leads to renal cystic disease associated to an up regulation of the mTOR pathway (D. Iaconis) The Oral-Facial-Digital type I syndrome (OFDI; MIM 311200) is a rare syndromic form of inherited renal cystic disease caused by mutations in the OFD1 gene. Dr. Iaconis and her colleagues generated a conditional inactivation of the mouse Ofd1 gene using the Ksp-cre transgenic line, which resulted in a viable model characterized by renal cystic disease and a progressive impairment of renal function. Studying this model they demonstrated that primary cilia initially form and then disappear after the development of cysts, suggesting that the dysfunction of primary cilia is a consequence of renal cystic disease. They demonstrated an upregulation of the mTOR pathway in the renal structures and that treatment with rapamycin, a specific inhibitor of the mTOR pathway, resulted in a significant reduction in the number and size of the renal cysts and a decrease in the cystic index compared with untreated mutant animals, suggesting that dysregulation of this pathway in the model is mTOR-dependent. This animal model could allow the understanding of the molecular link between mTOR and cyst development, and eventually the identification of novel drug targets for renal cystic disease. • Lack of Mid1, the mouse ortholog of the Opitz Syndrome gene, causes abnormal development of the anterior cerebellar vermis. (G. Meroni) The X-linked form of Opitz G/BBB Syndrome (OS) is a genetic disorder characterized by midline developmental defects caused by loss-of-function mutations in the MID1 gene. MID1 encodes an ubiquitin ligase that controls Phosphatase 2A but its role in the pathogenesis of the disease is still unclear. Mid1 null mice show the brain anatomical defect observed in patients, i.e. hypoplasia of the anterior portion of the medial cerebellum, the vermis. The authors showed that lack of Mid1 causes the shortening of the posterior dorsal midbrain; the rostralization of the midbrain/cerebellum boundary; and the down-regulation of Fgf17, a key player in the development of this region. Thus, lack of Mid1 causes a mis-specification of the midbrain/cerebellar boundary that results in an abnormal development of the most anterior cerebellar lobes. For these reasons this animal model provides a tool for further in vivo studies of the physiological and pathological role of the Mid1 gene. • The forkhead transcription factor FOXL2 is sumoylated in both human and mouse: Sumoylation affects its stability, localization, and activity (M. Marongiu) Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome (BPES) is caused by mutations in the FOXL2 forkhead transcription factor. Inactivation of Foxl2 in mice demonstrated its indispensability for female gonad sex determination and ovary development and revealed its antagonism of Sox9, the effector of male testis development. In this work the authors looked for FOXL2 interacting proteins and using yeast-two-hybrid screening, they found that FOXL2 interacts with PIAS1 and UBC9, both parts of the sumoylation machinery. They confirmed the interactions by co-immunoprecipitation and demonstrated that human FOXL2 is sumoylated in both in vitro and in vivo systems. They demonstrated that FOXL2 co-localizes with SUMO-1, identified 7 putative sumoylation sites (using Abgent SUMOplot™software) and created FOXL2 mutants in which the lysines (higher score putative sumoylation sites: K25, K87, K114, K150) were changed to arginine. Their results indicate that K114 and K150 are involved in FOXL2 sumoylation, and nuclear localization and that all mutations influence FOXL2 transcriptional activity. • SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy (B. Wirth) SMA is a common autosomal recessively inherited neuromuscular disorder determined by a functional impairment of the α-motor neurons within the spinal cord. SMA is caused by a functional loss of the survival motor neuron gene 1 (SMN1), whereas the disease severity is mainly influenced by the number of SMN2 copies. The authors analyzed two severe SMA mouse models each carrying two SMN2 transgenes and showed that treatment with 25 mg/kg/2x/day SAHA increased the lifespan of SMA mice by 30%, significantly improved motor function abilities, reduced degeneration of the motor neurons within the spinal cord and increased the size of the neuromuscular junctions and muscle fibers compared to vehicle-treated SMA mice. For these reasons SAHA might be suitable for SMA therapy. Session S11 - RNA Molecules: Nature, Expression and Sense • Mechanisms of miRNA-mediated gene silencing (E.Izaurralde) MicroRNAs (miRNAs) are able to silence gene expression post-transcriptionally and to exert their function they associate with Argonaute proteins (AGOs) in miRNA-induced silencing complexes (miRISCs). The AGO proteins are not sufficient to mediate silencing and require interaction with proteins of the GW182 family. The speaker showed with different examples that AGO-GW182 complexes mediate silencing by promoting translational repression and mRNA deadenylation catalyzed by CAF1-CCR4-NOT, the major cytoplasmic deadenylase complex. Deadenylation decreases translation efficiency and commits the mRNA to decapping and 5’-to-3’ exonucleolytic degradation. Using a new strategy (with a reporter gene that carries 5 BoxB) they analyzed GW182 protein function in an independent way from the AGO protein function, and identified two domains critical for silencing: an N-terminal GW-repeat-containing region conferring binding to the AGOs, and a bipartite silencing domain, consisting of Mid and C-terminal regions, which elicits the translational repression and degradation of miRNA targets. This domain interacts with the cytoplasmic poly (A)-binding protein 1 (PABPC1) that is needed for the mRNA stability. This suggests that GW182 proteins are PABP-interacting proteins (Paips) that interfere with the function of PABPC1 in mRNA stabilization and translation. • The hidden layer of noncoding RNA in the epigenetic control of human development and cognition (J.S.Mattick) The extent of non-protein-coding DNA increases with increasing complexity, reaching 98.8% in humans, suggesting that much of the information required for programming development may reside in these sequences. Moreover it is now evident that the majority of the mammalian genome is transcribed into non-protein-coding RNAs (ncRNAs), and that there are a lot of long and short RNAs in mammals that show specific expression patterns and subcellular locations. These studies indicate that these RNAs form a massive network of regulatory information that regulates different processes and directs a precise pattern of gene expression during growth and development. It also appears that RNAs are important for brain development, learning and memory, and that primates have developed sophisticated RNA editing systems to modify hardwired genetic information in response to experience, that in turn can modulate epigenetic memory, some of which may be inherited. RNAs may hold the key to understanding human evolution, development and cognition, as well as our individual differences and susceptibilities to complex diseases. • System genetics of non-coding RNA (L. Steinmetz) By profiling genome-wide transcription at a high resolution of the complete yeast genome, the speaker and collaborators have found hundreds of novel intergenic and antisense non-coding RNA transcripts. By comparing transcriptome profiles across multiple conditions and strains, they have defined an annotated set of differentially expressed non-coding transcripts. Hundreds of non-coding RNAs appear to arise from an inherent bi-directional transcription from eukaryotic promoters. Many others originate from 3’ nucleosome depleted regions of genes and are transcribed antisense to the open reading frame. The regulatory patterns of these transcripts suggest the mechanisms by which they could be regulated and by which they could regulate the expression of other genes. 15 June 2010: Session S15 – Molecular Processes in Neurodegenerative Diseases • Using Simple Cells to Model Complex Diseases (S.L.Lindquist) A surprising number of human diseases, especially neurodegenerative diseases, result from basic problems in protein folding. One feature these diseases share is the occurrence of complexes of misfolded, aggregated proteins in the affected neurons. In this work Dr. Lindquist and collaborators, have developed simple cellular models of these protein folding disorders by over-expressing human disease-associated proteins in yeast. They presented models for the misfolding of α-syn and Aβ using yeast cells as “living test tubes” to investigate the mechanisms of toxicity associated with problems in protein folding, trafficking, and degradation and complemented these basic studies with a transcriptional analysis and high-throughput chemical and genetic screens for toxicity modifiers. • C. elegans models for neurodegenerative diseases (E. Nollen) Some neurodegenerative diseases are associated with the accumulation of misfolded proteins in aggregates in the brain. Using the nematode worm Caenorhabditis elegans to model these diseases and high-throughput genetic screens, Dr. Nollen and her group have identified genes that modify aggregation of the disease proteins and their toxicity. They have recently identified an evolutionarily highly conserved (52% of similarity with SERF-2) modifier of aggregation, moag-4, as a positive regulator of aggregate formation in C. elegans models for misfolding diseases. They have shown, using mutants carrying the moag-4 deletion, that this gene drives the formation of compact misfolding intermediates that are required for aggregate formation and that a loss of moag-4 promotes longevity in parallel to the core IGF/insulin (IIS) longevity pathway. Thus, moag-4 has a dual function as a regulator of protein aggregation and of lifespan in C. elegans. • The prion-like aspect of Alzheimer´s disease (M.Jucker) To understand the mechanisms by which abnormal protein processing and aggregation leads to cerebral amyloidosis, cellular dysfunction, and dementia, several transgenic mouse models have been generated. These mouse models have been instrumental in the study of the induction and spread of the Alzheimer’s Disease (AD) lesions and a mechanism reminescent of prions has been suggested. The observation that Aβ structural variants can be induced in vivo in these mouse models intensifies the search for the agent that drives the corruptive protein templating in AD pathogenesis. AD lesions and neurodegeneration likely occur many years before the clinical signs of the disease. Jucker's work could lead to the identification of amyloid-inducing factors as pre-synthomatic tools for a diagnosis and early mechanism-based intervention. Concurrent Session C14 – Mutation Mechanism • Mutation in SHOC2 promotes aberrant protein N-myristoylation and underlies Noonanlike syndrome with loose anagen hair (V. Cordeddu) In this work the authors showed that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat-containing protein that positively modulates RAS-MAPK signal flow, underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with Noonan-like syndrome shared the 4A>G missense change (Ser2Gly) in SHOC2 that introduces an Nmyristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Induction of SHOC2S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling, suggesting that, as already demonstrated in vitro, this mutation enhanced MAPK activation. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease. • Another gene for autosomal recessive ALX-related frontonasal dysplasias: Disruption in ALX1 (CART1) causes anophthalmia and severe facial clefting (E. Uz) The authors presented a new autosomal recessive frontonasal dysplasia in two families characterized by bilateral anophthalmia/microphthalmia, a bilateral oblique facial cleft, a complete cleft palate, hypertelorism, a wide nasal bridge and low set and posteriorly rotated ears. Using Affymetrix SNP Array genotyping and homozygosity mapping, they mapped this clinical entity to chromosome 12q21. In one of the families with three affected individuals, they detected a homozygous 3.7 Mb deletion containing the ALX1 (aristales-related homeobox transcription factor 1 or CART1) gene. In the second family, they identified a homozygous donor splice site mutation (c.537+1 G>A), which is predicted to disrupt the functionally essential homeodomain structure of the ALX1 protein. These results provide evidence that loss of ALX1 function causes a severe impairment of early craniofacial development. This study further expands the spectrum of the recently recognized autosomal recessive “ALX-related FND” phenotypes in humans. Before the conclusion of the congress there was the prize giving of the ESHG awards for outstanding research by young scientists presented as a spoken contribution at the conference. Additionally Professor Sir. Alec Jeffreys was awarded with the ESHG Lecture AWARD speaking in Plenary Session 5. 2010 Winners Young Investigator Awards for Outstanding Science Louise The Effect of Translocation-Induced Nuclear Re-organization on Gene Harewood Expression (Lausanne) Silke Nuber Expression of Mutant A30P alpha-Synuclein in Conditional Mouse Brain: (Tübingen) Implications for Early Stage of Parkinson's Disease Sabrina Carrella The microRNA miR-204 is required for vertebrate eye development (Naples) Olli Pietiläinen Inverse mapping approach implies the role of large CNVs in intellectual (Helsinki) deficits and learning difficulties in a population cohort Shushant Jain Phenotypic modifiers of DJ1 (Amsterdam) Isabelle Oberlé Award Suleyman Targeted next generation sequencing identifies a mutation associated with Gulsuner cerebellar hypoplasia and mental retardation with quadrupedal locomotion (Ankara) Lodewijk Sandkuijl Award Gosia Trynka Multiple common genetic variants for coeliac disease influencing immune (Groningen) gene expression Session: C03 Complex Diseases ESHG Poster Awards Emma Burkitt SHOC2 mutations in patients with cardio-facio-cutaneous syndrome Wright P02.036 (Manchester) Alev Erogullari A functional link of DYT1 and DYT6 dystonia: Repression of TOR1A (Lükeck) (DYT1) gene expression by the transcription factor activity of THAP1 (DYT6) PL5.1 - ESHG Award Lecture • DNA fingerprinting and the turbulent genome (Jeffreys) University of Leicester, Department of Genetics, Leicester, United Kingdom. Sir. A. Jeffreys discussed the origins and evolution of DNA testing, the creation of major national DNA databases and the extraordinary impact that DNA has had on forensic and legal medicine. The presentation also focused the attention on how DNA fingerprinting has identified some of the most unstable regions in the human genome, allowing us to study human DNA evolution in real time and to explore the fundamental processes of mutation and recombination that are the ultimate source of all human DNA variations.