Finishing the finished human chromosome 22 sequence

A combination of approaches was used to close 8 of the 11 gaps in the original sequence of human chromosome 22, and to generate a total 1.018 Mb of new sequence

Auditory Function in the Tc1 Mouse Model of Down Syndrome Suggests a Limited Region of Human Chromosome 21 Involved in Otitis Media

Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K+ currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca2+ activated K+ current (IK,f), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Entretiens autoadministrés sur ordinateur et mesure des comportements sensibles

Rogers Susan M., Gribble James N., Turner Charles F., Miller Heather G.- Computerized self-interviewing and the measurement of sensitive behaviors Surveys that rely on respondents to provide information on sensitive, stigmatized, or illicit behaviors may be subject to reporting bias. Audio computer-assisted self-interview (audio-CASI) technology has been developed by researchers at the Research Triangle Institute, USA to overcome the limitations of traditional paper and pencil self-administered questionnaires (SAQs) and in-person interviewer-administered questionnaires (IAQs). The development of audio-CASI technology has fundamentally altered the interview context for measuring sexual and other sensitive behaviors by providing privacy without requiring literacy. This paper reviews the scientific development of audio-CASI and describes the results of methodological experiments comparing audio-CASI with other survey interview modes. In 1995, RTI's audio-CASI technology was field tested in two major U.S. national surveys: The National Survey of Adolescent Males (NSAM) and the National Survey of Family Growth (NSFG). These surveys found substantially higher levels of reporting of drug use, same gender sexual contact and induced abortion with audio-CASI than IAQs or SAQs.Rogers Susan M., Gribble James N., Turner Charles F., Miller Heather G.- Computerized self-interviewing and the measurement of sensitive behaviors Surveys that rely on respondents to provide information on sensitive, stigmatized, or illicit behaviors may be subject to reporting bias. Audio computer-assisted self-interview (audio-CASI) technology has been developed by researchers at the Research Triangle Institute, USA to overcome the limitations of traditional paper and pencil self-administered questionnaires (SAQs) and in-person interviewer-administered questionnaires (IAQs). The development of audio-CASI technology has fundamentally altered the interview context for measuring sexual and other sensitive behaviors by providing privacy without requiring literacy. This paper reviews the scientific development of audio-CASI and describes the results of methodological experiments comparing audio-CASI with other survey interview modes. In 1995, RTI's audio-CASI technology was field tested in two major U.S. national surveys: The National Survey of Adolescent Males (NSAM) and the National Survey of Family Growth (NSFG). These surveys found substantially higher levels of reporting of drug use, same gender sexual contact and induced abortion with audio-CASI than IAQs or SAQs.Rogers Susan M., Gribble James N., Turner Charles F., Miller Heather G.- Encuestas auto-administradas a través de ordenador y medición de cuestiones delicadas Las encuestas que confian en las respuestas de los individuos sobre comportamientos controvertidos, estigmatizados о ilegales pueden contener sesgos. Investigadores del Research Triangle Institute, de Estados Unidos, han desarrollado una técnica audio de auto- encuesta asistida por ordenador (audio-CASI) para superar las limitaciones de los cuestionarios auto-administrados de forma tradicional, «con lápiz y papel » (SAQs) o reali- zados por un entrevistador (IAQs). El desarrollo de la técnica audio-CASI ha alterado de forma significativa el contexto de las entrevistas para medir comportamientos sexuales y otras cuestiones delicadas, ya que respeta la privacidad pero no requière que el individuo sepa leer y escribir. Este articulo analiza el desarrollo cientifico de audio-CASI y describe los resultados de experimentos metodológicos que se han realizado con el objetivo de comparar este méto- do a otras formas de entrevista. En 1995 se probó audio-CASI en dos encuestas norteameri- canas de gran envergadura: la Encuesta Nacionál de Hombres Adolescentes (NSAM) y la Encuesta Nacionál de Crecimiento de la Familia (NSFG). Las encuestas hallaron nivelés si- gnificativamente más elevados en la declaración del uso de drogas, contactos sexuales con individuos del mismo sexo y recurso al aborto provocado cuando se utilizó audio-CASI que a través de IAQs y SAQs.Rogers Susan M., Gribble James N., Turner Charles F., Miller Heather G. Entretiens autoadministrés sur ordinateur et mesure des comportements sensibles. In: Population, 54ᵉ année, n°2, 1999. pp. 231-250