Dosage Changes of a Segment at 17p13

Slides:



Advertisements
Similar presentations
Paul J. Norman, Jill A. Hollenbach, Neda Nemat-Gorgani, Wesley M
Advertisements

Recurrent Reciprocal Genomic Rearrangements of 17q12 Are Associated with Renal Disease, Diabetes, and Epilepsy  Heather C. Mefford, Séverine Clauin, Andrew.
A Genome-Wide High-Resolution Array-CGH Analysis of Cutaneous Melanoma and Comparison of Array-CGH to FISH in Diagnostic Evaluation  Lu Wang, Mamta Rao,
Mosaic Uniparental Disomies and Aneuploidies as Large Structural Variants of the Human Genome  Benjamín Rodríguez-Santiago, Núria Malats, Nathaniel Rothman,
Frequency of Nonallelic Homologous Recombination Is Correlated with Length of Homology: Evidence that Ectopic Synapsis Precedes Ectopic Crossing-Over 
Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome  Bo.
Kendy K. Wong, Ronald J. deLeeuw, Nirpjit S. Dosanjh, Lindsey R
Microarray-Based Comparative Genomic Hybridization Using Sex-Matched Reference DNA Provides Greater Sensitivity for Detection of Sex Chromosome Imbalances.
Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease  Yi-An Ko, Huiguang Yi, Chengxiang Qiu, Shizheng.
Angela Leo, Andrew M. Walker, Matthew S
Volume 88, Issue 2, Pages (October 2015)
Volume 8, Issue 5, Pages (September 2014)
Copy Number Variation Sequencing for Comprehensive Diagnosis of Chromosome Disease Syndromes  Desheng Liang, Ying Peng, Weigang Lv, Linbei Deng, Yanghui.
Customized Oligonucleotide Array-Based Comparative Genomic Hybridization as a Clinical Assay for Genomic Profiling of Chronic Lymphocytic Leukemia  Rachel.
Volume 44, Issue 3, Pages (November 2011)
Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation Profiles  Carl E.G. Bruder, Arkadiusz Piotrowski,
Volume 24, Issue 10, Pages (October 2016)
High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans  Winston Lau, Toby Andrew,
Volume 26, Issue 24, Pages (December 2016)
Volume 7, Issue 5, Pages (November 2016)
Laura J. Dumas, Majesta S. O’Bleness, Jonathan M. Davis, C
Transcriptional Memory in the Drosophila Embryo
Eric Samorodnitsky, Jharna Datta, Benjamin M
The Fine-Scale and Complex Architecture of Human Copy-Number Variation
A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies  Xingyi Guo,
Autosomal-Dominant Microtia Linked to Five Tandem Copies of a Copy-Number- Variable Region at Chromosome 4p16  Irina Balikova, Kevin Martens, Cindy Melotte,
Volume 168, Issue 5, Pages e7 (February 2017)
Volume 35, Issue 2, Pages (July 2009)
Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development 
Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders  Rui Luo, Stephan J.
A Genome-Wide High-Resolution Array-CGH Analysis of Cutaneous Melanoma and Comparison of Array-CGH to FISH in Diagnostic Evaluation  Lu Wang, Mamta Rao,
Claudia M. B. Carvalho, Rolph Pfundt, Daniel A. King, Sarah J
Volume 40, Issue 4, Pages (November 2010)
Arpita Ghosh, Fei Zou, Fred A. Wright 
Cascade Models of Synaptically Stored Memories
A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence  Haiyi Lou, Yan Lu,
Maximizing the Power of Principal-Component Analysis of Correlated Phenotypes in Genome-wide Association Studies  Hugues Aschard, Bjarni J. Vilhjálmsson,
Laura J. Dumas, Majesta S. O’Bleness, Jonathan M. Davis, C
Volume 16, Issue 8, Pages (August 2016)
Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome  Bo.
Sherlock: Detecting Gene-Disease Associations by Matching Patterns of Expression QTL and GWAS  Xin He, Chris K. Fuller, Yi Song, Qingying Meng, Bin Zhang,
Recurrent Reciprocal Genomic Rearrangements of 17q12 Are Associated with Renal Disease, Diabetes, and Epilepsy  Heather C. Mefford, Séverine Clauin, Andrew.
Defining Ploidy-Specific Thresholds in Array Comparative Genomic Hybridization to Improve the Sensitivity of Detection of Single Copy Alterations in Cell.
Anna Lindstrand, Erica E. Davis, Claudia M. B
Array Comparative Genomic Hybridization Detects Chromosomal Abnormalities in Hematological Cancers That Are Not Detected by Conventional Cytogenetics 
Volume 44, Issue 3, Pages (November 2011)
High-Resolution Molecular Characterization of 15q11-q13 Rearrangements by Array Comparative Genomic Hybridization (Array CGH) with Detection of Gene Dosage 
A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders  Jennifer A. Lee, Claudia M.B. Carvalho, James.
Avoiding Pitfalls in Molecular Genetic Testing
Highly Punctuated Patterns of Population Structure on the X Chromosome and Implications for African Evolutionary History  Charla A. Lambert, Caitlin F.
Volume 6, Issue 1, Pages (July 2002)
Volume 132, Issue 6, Pages (March 2008)
A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence  Haiyi Lou, Yan Lu,
Volume 21, Issue 9, Pages (November 2017)
Volume 50, Issue 2, Pages (April 2013)
Complete Haplotype Sequence of the Human Immunoglobulin Heavy-Chain Variable, Diversity, and Joining Genes and Characterization of Allelic and Copy-Number.
Pei-Lung Chen, Dimitrios Avramopoulos, Virginia K. Lasseter, John A
Clustering of Cyclic-Nucleotide-Gated Channels in Olfactory Cilia
A Tunable Genetic Switch Based on RNAi and Repressor Proteins for Regulating Gene Expression in Mammalian Cells  Tara L. Deans, Charles R. Cantor, James.
Volume 9, Issue 3, Pages (November 2014)
Mechanisms for Nonrecurrent Genomic Rearrangements Associated with CMT1A or HNPP: Rare CNVs as a Cause for Missing Heritability  Feng Zhang, Pavel Seeman,
A Tunable Genetic Switch Based on RNAi and Repressor Proteins for Regulating Gene Expression in Mammalian Cells  Tara L. Deans, Charles R. Cantor, James.
Molecular Analysis of a Deletion Hotspot in the NRXN1 Region Reveals the Involvement of Short Inverted Repeats in Deletion CNVs  Xiaoli Chen, Yiping Shen,
Dosage-Dependent Severity of the Phenotype in Patients with Mental Retardation Due to a Recurrent Copy-Number Gain at Xq28 Mediated by an Unusual Recombination 
A Novel Test for Recessive Contributions to Complex Diseases Implicates Bardet-Biedl Syndrome Gene BBS10 in Idiopathic Type 2 Diabetes and Obesity  Elaine T.
Cosuppression of Nonhomologous Transgenes in Drosophila Involves Mutually Related Endogenous Sequences  Manika Pal-Bhadra, Utpal Bhadra, James A. Birchler 
Chromothripsis in Healthy Individuals Affects Multiple Protein-Coding Genes and Can Result in Severe Congenital Abnormalities in Offspring  Mirjam S.
A Definitive Haplotype Map as Determined by Genotyping Duplicated Haploid Genomes Finds a Predominant Haplotype Preference at Copy-Number Variation Events 
Harrison Brand, Ryan L. Collins, Carrie Hanscom, Jill A
Anna Lindstrand, Stephan Frangakis, Claudia M. B. Carvalho, Ellen B
Presentation transcript:

Dosage Changes of a Segment at 17p13 Dosage Changes of a Segment at 17p13.1 Lead to Intellectual Disability and Microcephaly as a Result of Complex Genetic Interaction of Multiple Genes  Claudia M.B. Carvalho, Shivakumar Vasanth, Marwan Shinawi, Chad Russell, Melissa B. Ramocki, Chester W. Brown, Jesper Graakjaer, Anne-Bine Skytte, Angela M. Vianna-Morgante, Ana C.V. Krepischi, Gayle S. Patel, LaDonna Immken, Kyrieckos Aleck, Cynthia Lim, Sau Wai Cheung, Carla Rosenberg, Nicholas Katsanis, James R. Lupski  The American Journal of Human Genetics  Volume 95, Issue 5, Pages 565-578 (November 2014) DOI: 10.1016/j.ajhg.2014.10.006 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 High-Resolution aCGH Plot for Individuals BAB3036, BAB3277, and BAB3045 (A) Individuals with small deletions of 17p13.1 region. Black box delimits the smallest region of overlap deleted in subjects with microcephaly. (B) Individual with triplication involving 17p13.1 region. CNVs were detected by oligonucleotide probes for which the mean normalized log2 (Cy5/Cy3) ratio of the CGH signal reached mean thresholds of −1 (indicating a heterozygous deletion [CN = 1]), 0.6 (indicating a duplication [CN = 3]), or 1.0 (indicating a triplication [CN = 4]). The American Journal of Human Genetics 2014 95, 565-578DOI: (10.1016/j.ajhg.2014.10.006) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Representative Summary of CNVs Involving 17p13.1 (A) Top: Individuals with deletions are represented by green rectangles and the individual with a triplication is represented by blue rectangle. The graphical normalized data for each individual was obtained by applying the most distal and proximal oligonucleotide genomic probe coordinates to the custom track at UCSC Genome Browser website. Positions are given relative to build hg18. Vertical blue rectangle delimits the smallest region of overlap (SRO) for the microcephaly phenotype in this cohort. Plus sign indicates presence of absolute microcephaly; minus sign indicates absence of absolute microcephaly (refer to Table 2 for Z score values). N/A indicates information not available. Bottom: Dosage-sensitive region associated with small head size (157 kb) chr17: 6,996,378–7,152,828 (hg18). (B) Graph of Z scores of head circumferences in subjects with 17p13.1 deletions. Black dots: individual Z score of subjects who harbor CNVs encompassing entirely predefined SRO of 157 kb. Black squares: individual Z scores of subjects who harbor CNVs that do not encompass predefined SRO or encompass it partially. All measurements are plotted as age- and sex-matched Z scores. Bars indicate mean and 95% confidence intervals. The American Journal of Human Genetics 2014 95, 565-578DOI: (10.1016/j.ajhg.2014.10.006) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Delimited 17p13.1 Region Harbors Dosage-Sensitive Genes as Experimentally Assayed in Zebrafish (A) Overexpression of capped human mRNA corresponding to nine loci in the 17p13.1 region in zebrafish embryos leads to microcephaly at 4 dpf. Representative dorsal images of zebrafish embryos injected with the indicated human mRNA scored for microcephaly at 4 dpf. (B) Graph represents the probability distribution curve of distance between eyes in zebrafish embryos upon overexpression injection of individual mRNAs. (C) List of individual capped human mRNAs and corresponding Z score measured as distance between eyes in zebrafish at 4 dpf (B). (D) Graph represents the probability distribution curve of distance between eyes in zebrafish embryos injected with splice blocker morpholinos of the indicated genes and scored for microcephaly at 4 dpf. (E) The corresponding Z scores of the probability distribution curves in (D). The American Journal of Human Genetics 2014 95, 565-578DOI: (10.1016/j.ajhg.2014.10.006) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 4 Loss of the Primary Drivers of Microcephaly Lead to Reduced Cell Division in Zebrafish (A) Zebrafish embryos were injected with the morpholinos as indicated and stained for phospho-histone H3 at 2 dpf. Representative images are shown for control and morpholino suppression. The dashed lines in the controls indicate the regions used for calculating the number of histone-positive cells. (B) Graph represents average and standard error of histone-positive cells in each sample from 20 embryos. (C) Representative images of TUNEL staining of 3 dpf zebrafish embryos either uninjected or injected with 3 ng of acadvl, dvl2, or gabarap MO. (D) Graph represents the average number of TUNEL-positive cells and standard error for each condition. The American Journal of Human Genetics 2014 95, 565-578DOI: (10.1016/j.ajhg.2014.10.006) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 5 Loss of the Primary Drivers Result in Decreased S/G2/M Population Neuro2A Cells Neuro2A cells were transfected with a pool of four different siRNAs targeting Asgr1 and compared with cells transfected with scrambled siRNA (Scr si). The remaining seven genes were suppressed with a combination of five shRNAs in pLKO.1 vector for each gene and compared against the control cells transfected with scrambled shRNA (pLKO.1 scr). Three days after transfection, cells were harvested, fixed, permeabilized, and stained with propidium iodide (PI). Cell cycle analysis was carried by flow cytometry and the average percentage of G0/G1 and S/G2/M population of each condition from three experiments is represented and the error bars indicate the standard deviation. ∗∗p < 0.005. The American Journal of Human Genetics 2014 95, 565-578DOI: (10.1016/j.ajhg.2014.10.006) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 6 Schematic Model for Dosage-Sensitive Region at 17p13.1 Associated with Small Head Size in Human Top: Model representing loci that leads to severe (red), moderate (yellow), and no scored phenotype (green). Bottom: Summary of the binary genetic interactions tested between loci for microcephaly in zebrafish embryos. The American Journal of Human Genetics 2014 95, 565-578DOI: (10.1016/j.ajhg.2014.10.006) Copyright © 2014 The American Society of Human Genetics Terms and Conditions