Nigel P Carter

Publications of Nigel P Carter

• Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

  Authors: Elizabeth P Murchison, Ole B Schulz-Trieglaff, Zemin Ning, Ludmil B Alexandrov, Markus J Bauer, Beiyuan Fu, Matthew Hims, Zhihao Ding, Sergii Ivakhno, Caitlin Stewart [......] Kevin Hall, Stephen M J Searle, Nigel P Carter, Anthony T Papenfuss, P Andrew Futreal, Peter J Campbell, Fengtang Yang, David R Bentley, Dirk J Evers, Michael R Stratton

  Cell. 02/2012; 148(4):780-91.

  The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. HereThe Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.

• Diagnostic interpretation of array data using public databases and internet sources.

  Authors: Nicole de Leeuw, Trijnie Dijkhuizen, Jayne Y Hehir-Kwa, Nigel P Carter, Lars Feuk, Helen V Firth, Robert M Kuhn, David H Ledbetter, Christa Lese Martin, Conny M A van Ravenswaaij-Arts, Steven W Scherer, Soheil Shams, Steven Van Vooren, Rolf Sijmons, Morris Swertz, Ros Hastings

  Human mutation. 02/2012;

  The range of commercially available array platforms and analysis software packages is expanding and their utility is improving, making reliable detection of copy number variation (CNV) relativelyThe range of commercially available array platforms and analysis software packages is expanding and their utility is improving, making reliable detection of copy number variation (CNV) relatively straightforward. Reliable interpretation of CNV data, however, is often difficult and requires expertise. With our knowledge of the human genome growing rapidly, applications for array testing continuously broadening, and the resolution of CNV detection increasing, this leads to great complexity in interpreting what can be daunting data. Correct CNV interpretation and optimal use of the genotype information provided by SNP probes on an array depends largely on knowledge present in various resources. In addition to the availability of host laboratories' own datasets and national registries, there are several public databases and Internet resources with genotype and phenotype information that can be used for array data interpretation. With so many resources now available, it is important to know which are fit-for-purpose in a diagnostic setting. We summarise the characteristics of the most commonly used Internet databases and resources, and propose a general data interpretation strategy that can be used for comparative hybridisation, comparative intensity and genotype-based array data.

• Maternally inherited partial monosomy 9p (pter → p24.1) and partial trisomy 20p (pter → p12.1) characterized by microarray comparative genomic hybridization.

  Authors: Érika L Freitas, Susan M Gribble, Milena Simioni, Társis P Vieira, Roseane L Silva-Grecco, Marly A S Balarin, Elena Prigmore, Ana C Krepischi-Santos, Carla Rosenberg, Karoly Szuhai, Arie van Haeringen, Nigel P Carter, Vera Lúcia Gil-da-Silva-Lopes

  American journal of medical genetics. Part A. 09/2011; 155A(11):2754-61.

  We report on a 17-year-old patient with midline defects, ocular hypertelorism, neuropsychomotor development delay, neonatal macrosomy, and dental anomalies. DNA copy number investigations using aWe report on a 17-year-old patient with midline defects, ocular hypertelorism, neuropsychomotor development delay, neonatal macrosomy, and dental anomalies. DNA copy number investigations using a Whole Genome TilePath array consisting, of 30K BAC/PAC clones showed a 6.36 Mb deletion in the 9p24.1-p24.3 region and a 14.83 Mb duplication in the 20p12.1-p13 region, which derived from a maternal balanced t(9;20)(p24.1;p12.1) as shown by FISH studies. Monosomy 9p is a well-delineated chromosomal syndrome with characteristic clinical features, while chromosome 20p duplication is a rare genetic condition. Only a handful of cases of monosomy 9/trisomy 20 have been previously described. In this report, we compare the phenotype of our patient with those already reported in the literature, and discuss the role of DMRT, DOCK8, FOXD4, VLDLR, RSPO4, AVP, RASSF2, PROKR2, BMP2, MKKS, and JAG1, all genes mapping to the deleted and duplicated regions.

• High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia.

  Authors: Serena Nik-Zainal, Reiner Strick, Mekayla Storer, Ni Huang, Roland Rad, Lionel Willatt, Tomas Fitzgerald, Vicki Martin, Richard Sandford, Nigel P Carter, Andreas R Janecke, Stefan P Renner, Patricia G Oppelt, Peter Oppelt, Christine Schulze, Sara Brucker, Matthew Hurles, Matthias W Beckmann, Pamela L Strissel, Charles Shaw-Smith

  Journal of medical genetics. 03/2011; 48(3):197-204.

  Congenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia orCongenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci. In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Müllerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated. A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Müllerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Müllerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Müllerian aplasia. The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Müllerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Müllerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it.

• Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21.

  Authors: Elisavet A Papageorgiou, Alex Karagrigoriou, Evdokia Tsaliki, Voula Velissariou, Nigel P Carter, Philippos C Patsalis

  Nature medicine. 03/2011; 17(4):510-3.

  The trials performed worldwide toward noninvasive prenatal diagnosis (NIPD) of Down's syndrome (or trisomy 21) have shown the commercial and medical potential of NIPD compared to the currently usedThe trials performed worldwide toward noninvasive prenatal diagnosis (NIPD) of Down's syndrome (or trisomy 21) have shown the commercial and medical potential of NIPD compared to the currently used invasive prenatal diagnostic procedures. Extensive investigation of methylation differences between the mother and the fetus has led to the identification of differentially methylated regions (DMRs). In this study, we present a strategy using the methylated DNA immunoprecipitation (MeDiP) methodology in combination with real-time quantitative PCR (qPCR) to achieve fetal chromosome dosage assessment, which can be performed noninvasively through the analysis of fetal-specific DMRs. We achieved noninvasive prenatal detection of trisomy 21 by determining the methylation ratio of normal and trisomy 21 cases for each tested fetal-specific DMR present in maternal peripheral blood, followed by further statistical analysis. The application of this fetal-specific methylation ratio approach provided correct diagnosis of 14 trisomy 21 and 26 normal cases.

• FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation.

  Authors: George Koumbaris, Hariklia Hatzisevastou-Loukidou, Angelos Alexandrou, Marios Ioannides, Christodoulos Christodoulou, Tomas Fitzgerald, Diana Rajan, Stephen Clayton, Sophia Kitsiou-Tzeli, Joris R Vermeesch, Nicos Skordis, Pavlos Antoniou, Ants Kurg, Ioannis Georgiou, Nigel P Carter, Philippos C Patsalis

  Human molecular genetics. 02/2011; 20(10):1925-36.

  The recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyzeThe recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyze complex exonic, genic and genomic rearrangements. By analyzing a large number of isochromosomes of the long arm of chromosome X (i(Xq)), using whole-genome tiling path array comparative genomic hybridization (aCGH), ultra-high resolution targeted aCGH and sequencing, we provide evidence that the FoSTeS and MMBIR mechanisms can generate large-scale gross chromosomal rearrangements leading to the deletion and duplication of entire chromosome arms, thus suggesting an important role for DNA replication-based mechanisms in both the development of genomic disorders and cancer. Furthermore, we elucidate the mechanisms of dicentric i(Xq) (idic(Xq)) formation and show that most idic(Xq) chromosomes result from non-allelic homologous recombination between palindromic low copy repeats and highly homologous palindromic LINE elements. We also show that non-recurrent-breakpoint idic(Xq) chromosomes have microhomology-associated breakpoint junctions and are likely catalyzed by microhomology-mediated replication-dependent recombination mechanisms such as FoSTeS and MMBIR. Finally, we stress the role of the proximal Xp region as a chromosomal rearrangement hotspot.

• aCGH.Spline--an R package for aCGH dye bias normalization.

  Authors: Tomas W Fitzgerald, Lee D Larcombe, Solena Le Scouarnec, Stephen Clayton, Diana Rajan, Nigel P Carter, Richard Redon

  Bioinformatics (Oxford, England). 02/2011; 27(9):1195-200.

  MOTIVATION: The careful normalization of array-based comparative genomic hybridization (aCGH) data is of critical importance for the accurate detection of copy number changes. The difference inMOTIVATION: The careful normalization of array-based comparative genomic hybridization (aCGH) data is of critical importance for the accurate detection of copy number changes. The difference in labelling affinity between the two fluorophores used in aCGH-usually Cy5 and Cy3-can be observed as a bias within the intensity distributions. If left unchecked, this bias is likely to skew data interpretation during downstream analysis and lead to an increased number of false discoveries. RESULTS: In this study, we have developed aCGH.Spline, a natural cubic spline interpolation method followed by linear interpolation of outlier values, which is able to remove a large portion of the dye bias from large aCGH datasets in a quick and efficient manner. Conclusions: We have shown that removing this bias and reducing the experimental noise has a strong positive impact on the ability to detect accurately both copy number variation (CNV) and copy number alterations (CNA).

• aCGH.Spline - an R package for aCGH dye bias normalization.

  Authors: Tomas W. Fitzgerald, Lee D. Larcombe, Solena Le Scouarnec, Stephen Clayton, Diana Rajan, Nigel P. Carter, Richard Redon

  Bioinformatics. 01/2011; 27:1195-1200.

• Massive genomic rearrangement acquired in a single catastrophic event during cancer development.

  Authors: Philip J Stephens, Chris D Greenman, Beiyuan Fu, Fengtang Yang, Graham R Bignell, Laura J Mudie, Erin D Pleasance, King Wai Lau, David Beare, Lucy A Stebbings [......] Harold Swerdlow, Nigel P Carter, Laura A Morsberger, Christine Iacobuzio-Donahue, George A Follows, Anthony R Green, Adrienne M Flanagan, Michael R Stratton, P Andrew Futreal, Peter J Campbell

  Cell. 01/2011; 144(1):27-40.

  Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize aCancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%-3% of all cancers, across many subtypes, and is present in ∼25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer.

• Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants.

  Authors: Dalila Pinto, Katayoon Darvishi, Xinghua Shi, Diana Rajan, Diane Rigler, Tom Fitzgerald, Anath C Lionel, Bhooma Thiruvahindrapuram, Jeffrey R Macdonald, Ryan Mills [......] Susan Gribble, Elena Prigmore, Patricia K Donahoe, Richard S Smith, Ji Hyeon Park, Matthew E Hurles, Nigel P Carter, Charles Lee, Stephen W Scherer, Lars Feuk

  Nature biotechnology. 01/2011; 29(6):512-20.

  We have systematically compared copy number variant (CNV) detection on eleven microarrays to evaluate data quality and CNV calling, reproducibility, concordance across array platforms and laboratoryWe have systematically compared copy number variant (CNV) detection on eleven microarrays to evaluate data quality and CNV calling, reproducibility, concordance across array platforms and laboratory sites, breakpoint accuracy and analysis tool variability. Different analytic tools applied to the same raw data typically yield CNV calls with <50% concordance. Moreover, reproducibility in replicate experiments is <70% for most platforms. Nevertheless, these findings should not preclude detection of large CNVs for clinical diagnostic purposes because large CNVs with poor reproducibility are found primarily in complex genomic regions and would typically be removed by standard clinical data curation. The striking differences between CNV calls from different platforms and analytic tools highlight the importance of careful assessment of experimental design in discovery and association studies and of strict data curation and filtering in diagnostics. The CNV resource presented here allows independent data evaluation and provides a means to benchmark new algorithms.

• Differential DNA methylation as a tool for noninvasive prenatal diagnosis (NIPD) of X chromosome aneuploidies.

  Authors: Floriana Della Ragione, Paola Mastrovito, Ciro Campanile, Anna Conti, Elisavet A Papageorgiou, Maj A Hultén, Philippos C Patsalis, Nigel P Carter, Maurizio D'Esposito

  The Journal of molecular diagnostics : JMD. 11/2010; 12(6):797-807.

  The demographic tendency in industrial countries to delay childbearing, coupled with the maternal age effect in common chromosomal aneuploidies and the risk to the fetus of invasive prenatalThe demographic tendency in industrial countries to delay childbearing, coupled with the maternal age effect in common chromosomal aneuploidies and the risk to the fetus of invasive prenatal diagnosis, are potent drivers for the development of strategies for noninvasive prenatal diagnosis. One breakthrough has been the discovery of differentially methylated cell-free fetal DNA in the maternal circulation. We describe novel bisulfite conversion- and methylation-sensitive enzyme digestion DNA methylation-related approaches that we used to diagnose Turner syndrome from first trimester samples. We used an X-linked marker, EF3, and an autosomal marker, RASSF1A, to discriminate between placental and maternal blood cell DNA using real-time methylation-specific PCR after bisulfite conversion and real-time PCR after methylation-sensitive restriction digestion. By normalizing EF3 amplifications versus RASSF1A outputs, we were able to calculate sex chromosome/autosome ratios in chorionic villus samples, thus permitting us to correctly diagnose Turner syndrome. The identification of this new marker coupled with the strategy outlined here may be instrumental in the development of an efficient, noninvasive method of diagnosis of sex chromosome aneuploidies in plasma samples.

• Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome.

  Authors: Valérie Malan, Diana Rajan, Sophie Thomas, Adam C Shaw, Hélène Louis Dit Picard, Valérie Layet, Marianne Till, Arie van Haeringen, Geert Mortier, Sheela Nampoothiri, Silvija Puseljić, Laurence Legeai-Mallet, Nigel P Carter, Michel Vekemans, Arnold Munnich, Raoul C Hennekam, Laurence Colleaux, Valérie Cormier-Daire

  American journal of human genetics. 08/2010; 87(2):189-98.

  By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (NFIX) deletions or nonsense mutation in three sporadic cases of aBy using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (NFIX) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, Nfix-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider NFIX as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice NFIX mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that NFIX is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic NFIX mutations trigger distinct phenotypes, depending specifically on their impact on NMD.

• Laser excitation power and the flow cytometric resolution of complex karyotypes.

  Authors: Bee L Ng, Nigel P Carter

  Cytometry. Part A : the journal of the International Society for Analytical Cytology. 06/2010; 77(6):585-8.

  The analytical resolution of individual chromosome peaks in the flow karyotype of cell lines is dependent on sample preparation and the detection sensitivity of the flow cytometer. We haveThe analytical resolution of individual chromosome peaks in the flow karyotype of cell lines is dependent on sample preparation and the detection sensitivity of the flow cytometer. We have investigated the effect of laser power on the resolution of chromosome peaks in cell lines with complex karyotypes. Chromosomes were prepared from a human gastric cancer cell line and a cell line from a patient with an abnormal phenotype using a modified polyamine isolation buffer. The stained chromosome suspensions were analyzed on a MoFlo sorter (Beckman Coulter) equipped with two water-cooled lasers (Coherent). A bivariate flow karyotype was obtained from each of the cell lines at various laser power settings and compared to a karyotype generated using laser power settings of 300 mW. The best separation of chromosome peaks was obtained with laser powers of 300 mW. This study demonstrates the requirement for high-laser powers for the accurate detection and purification of chromosomes, particularly from complex karyotypes, using a conventional flow cytometer.

• Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies.

  Authors: David T Miller, Margaret P Adam, Swaroop Aradhya, Leslie G Biesecker, Arthur R Brothman, Nigel P Carter, Deanna M Church, John A Crolla, Evan E Eichler, Charles J Epstein [......] Stephen W Scherer, Nancy B Spinner, Dimitri J Stavropoulos, James H Tepperberg, Erik C Thorland, Joris R Vermeesch, Darrel J Waggoner, Michael S Watson, Christa Lese Martin, David H Ledbetter

  American journal of human genetics. 05/2010; 86(5):749-64.

  Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), orChromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype ( approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.

• Confirmed rare copy number variants implicate novel genes in schizophrenia.

  Authors: Gloria W C Tam, Louie N van de Lagemaat, Richard Redon, Karen E Strathdee, Mike D R Croning, Mary P Malloy, Walter J Muir, Ben S Pickard, Ian J Deary, Douglas H R Blackwood, Nigel P Carter, Seth G N Grant

  Biochemical Society transactions. 04/2010; 38(2):445-51.

  Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying humanUnderstanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from >3000 schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K(+) channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge.

• Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing.

  Authors: Hansoo Park, Jong-Il Kim, Young Seok Ju, Omer Gokcumen, Ryan E Mills, Sheehyun Kim, Seungbok Lee, Dongwhan Suh, Dongwan Hong, Hyunseok Peter Kang [......] Hyeran Kim, Song Ju Yang, Kap-Seok Yang, Hyungtae Kim, Matthew E Hurles, Stephen W Scherer, Nigel P Carter, Chris Tyler-Smith, Charles Lee, Jeong-Sun Seo

  Nature genetics. 04/2010; 42(5):400-5.

  Copy number variants (CNVs) account for the majority of human genomic diversity in terms of base coverage. Here, we have developed and applied a new method to combine high-resolution arrayCopy number variants (CNVs) account for the majority of human genomic diversity in terms of base coverage. Here, we have developed and applied a new method to combine high-resolution array comparative genomic hybridization (CGH) data with whole-genome DNA sequencing data to obtain a comprehensive catalog of common CNVs in Asian individuals. The genomes of 30 individuals from three Asian populations (Korean, Chinese and Japanese) were interrogated with an ultra-high-resolution array CGH platform containing 24 million probes. Whole-genome sequencing data from a reference genome (NA10851, with 28.3x coverage) and two Asian genomes (AK1, with 27.8x coverage and AK2, with 32.0x coverage) were used to transform the relative copy number information obtained from array CGH experiments into absolute copy number values. We discovered 5,177 CNVs, of which 3,547 were putative Asian-specific CNVs. These common CNVs in Asian populations will be a useful resource for subsequent genetic studies in these populations, and the new method of calling absolute CNVs will be essential for applying CNV data to personalized medicine.

• Prepublication data sharing.

  Authors: Ewan Birney, Thomas J Hudson, Eric D Green, Chris Gunter, Sean Eddy, Jane Rogers, Jennifer R Harris, S Dusko Ehrlich, Rolf Apweiler, Christopher P Austin [......] David Valle, Eero I Vuorio, Neil M Walker, Susan Wallace, George Weinstock, William B Whitman, Kim C Worley, Cathy Wu, Jiayan Wu, Jun Yu

  Nature. 10/2009; 461(7261):168-70.

  Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets.

• Origins and functional impact of copy number variation in the human genome.

  Authors: Donald F Conrad, Dalila Pinto, Richard Redon, Lars Feuk, Omer Gokcumen, Yujun Zhang, Jan Aerts, T Daniel Andrews, Chris Barnes, Peter Campbell [......] Sam Robson, Kathy Stirrups, Armand Valsesia, Klaudia Walter, John Wei, Chris Tyler-Smith, Nigel P Carter, Charles Lee, Stephen W Scherer, Matthew E Hurles

  Nature. 10/2009;

  Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotideStructural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.

• The Role of DNA Copy Number Variation in Schizophrenia.

  Authors: Gloria W C Tam, Richard Redon, Nigel P Carter, Seth G N Grant

  Biological psychiatry. 09/2009;

  Schizophrenia is a major psychiatric disease with strong evidence of genetic risk factors. Recent studies based on genome-wide study of copy number variations (CNVs) have detected novel recurrentSchizophrenia is a major psychiatric disease with strong evidence of genetic risk factors. Recent studies based on genome-wide study of copy number variations (CNVs) have detected novel recurrent submicroscopic copy number changes, including recurrent deletions at 1q21.11, 15q11.3, 15q13.3, and the recurrent CNV at the 2p16.3 neurexin 1 locus. These schizophrenia susceptibility CNV loci demonstrate that schizophrenia is, at least in part, genetic in origin and provide the basis for further investigation of mutations associated with the disease. The studies combined have also established the role of rare and-in sporadic cases-de novo variants in schizophrenia. Furthermore, neuronal-related genes and genetic pathways are starting to emerge from the CNV loci associated with schizophrenia. Here, we review the major findings in the recent literature, which begin to unravel the genetic and biological architecture of this complex human neuropsychiatric disorder.

• Human Y Chromosome Base-Substitution Mutation Rate Measured by Direct Sequencing in a Deep-Rooting Pedigree.

  Authors: Yali Xue, Qiuju Wang, Quan Long, Bee Ling Ng, Harold Swerdlow, John Burton, Carl Skuce, Ruth Taylor, Zahra Abdellah, Yali Zhao, Daniel G Macarthur, Michael A Quail, Nigel P Carter, Huanming Yang, Chris Tyler-Smith

  Current biology : CB. 09/2009;

  Understanding the key process of human mutation is important for many aspects of medical genetics and human evolution. In the past, estimates of mutation rates have generally been inferred fromUnderstanding the key process of human mutation is important for many aspects of medical genetics and human evolution. In the past, estimates of mutation rates have generally been inferred from phenotypic observations or comparisons of homologous sequences among closely related species [1-3]. Here, we apply new sequencing technology to measure directly one mutation rate, that of base substitutions on the human Y chromosome. The Y chromosomes of two individuals separated by 13 generations were flow sorted and sequenced by Illumina (Solexa) paired-end sequencing to an average depth of 11x or 20x, respectively [4]. Candidate mutations were further examined by capillary sequencing in cell-line and blood DNA from the donors and additional family members. Twelve mutations were confirmed in approximately 10.15 Mb; eight of these had occurred in vitro and four in vivo. The latter could be placed in different positions on the pedigree and led to a mutation-rate measurement of 3.0 x 10(-8) mutations/nucleotide/generation (95% CI: 8.9 x 10(-9)-7.0 x 10(-8)), consistent with estimates of 2.3 x 10(-8)-6.3 x 10(-8) mutations/nucleotide/generation for the same Y-chromosomal region from published human-chimpanzee comparisons [5] depending on the generation and split times assumed.