Identification of genetic variation using Next-Generation Sequencing:
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| Format: | Thesis Book |
| Language: | English |
| Published: |
2014
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| Subjects: | |
| Online Access: | Volltext https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20140327-1169718-0-3 Inhaltsverzeichnis |
| Item Description: | Enth. Zeitschriftenaufsätze |
| Physical Description: | 165 S. Ill., graph. Darst. |
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Record in the Search Index
| _version_ | 1804152142008680448 |
|---|---|
| adam_text | TECHNISCHE
UNIVERSITAT
MUNCHEN
LEHRSTUHL FIIR BIOINFORMATIK
IDENTIFICATION OF GENETIC
VARIATION USING
NEXT-GENERATION SEQUENCING
SEBASTIAN HUBERT ECK
VOLLSTANDIGER ABDRUCK DER VON DER FAKULTAT WISSENSCHAFTSZENTRUM WEIHEN-
STEPHAN FIIR ERNAHRUNG. LANDNUTZUNG UND UMWELT DER TECHNISCHEN UNIVER
SITAT MUNCHEN ZUR ERLANGUNG DES AKADEMISCHEN GRADES EINES
DOKTORS DER NATURWISSENSCHAFTEN
GENEHMIGTEN DISSERTATION.
VORSITZENDER:
UNIV.-PROF. DR. H.-R. FRIES
PRIIFER DER DISSERTATION:
1. UNIV.-PROF. DR. H-W. MEWES
2. UNIV.-PROF. DR. R. ZIMMER. LUDWIG-MAXIMILIANS UNIVERSITAT MUNCHEN
3. PRIV.-DOZ. DR. T. M. STROM
DIE DISSERTATION WURDE AM 30.07.2013 BEI DER TECHNISCHEN UNIVERSITAT
MUNCHEN
EINGEREICHT UND AM 27.01.2014 DURCH DIE FAKULTAT WISSENSCHAFTSZENTRUM
WEI-
HENSTEPHAN FIIR ERNAHRUNG, LANDNUTZUNG UND UMWELT ANGENOMMEN.
HTTP://D-NB.INFO/1053670532
CONTENTS
1 INTRODUCTION 12
1.1 HUMAN GENETIC DISORDERS 12
1.2 IDENTIFICATION OF CAUSATIVE MUTATIONS IN GENETIC DISORDERS . . 14
1.3 COMMON AND RARE VARIANTS IN GENETIC DISORDERS 16
1.4 DNA SEQUENCING 19
1.5 NEXT-GENERATION SEQUENCING 23
1.6 ROCHE/454 SEQUENCING 24
1.7 SOLID - SEQUENCING BY LIGATION 25
1.8 SOLEXA TECHNOLOGY 28
1.8.1 SEQUENCING-
BY-SYNTHESIS 28
1.8.2 ILLUMINA DATA ANALYSIS PIPELINE 32
1.8.3 GENOME ANALYZER IIX 34
1.8.4 HISEQ2000 35
1.9 SHORT-READ ALIGNMENT ALGORITHMS 36
1.9.1 HASH TABLE BASED ALGORITHMS 36
1.9.1.1 MAQ 37
1.9.2 SUFFIX-ARRAY-BASED ALGORITHMS 39
1.9.2.1 BURROWS-WHEELER TRANSFORMATION 39
1.9.2.2 BWA 40
1.9.2.3 SAMTOOLS 41
1.10 EXOME SEQUENCING 42
1.10.1 IN-SOLUTION ENRICHMENT 43
1.10.2 APPLICATIONS 45
2 RESULTS 47
2.1 ANALYSIS PIPELINE FOR NEXT-GENERATION SEQUENCING DATA .... 47
2.2 COMPONENTS 48
2.2.1 ALIGNMENT 49
6
2.2.2 VARIANT CALLING 50
2.2.2.1 SNV CALLING 50
2.2.2.2 VARIANT FILTERING 51
2.2.3 RUN STATISTICS 52
2.3 EXOME VARIANT DATABASE 53
2.3.1 CANDIDATE GENE IDENTIFICATION 54
2.3.2 QUERY PARAMETERS 54
2.3.3 QUERY TYPES 56
2.4 IDENTIFICATION OF DISEASE CAUSING AND DISEASE ASSOCIATED FILI
ATIONS 59
2.5 SOMATIC MUTATIONS - IDENTIFICATION OF RECURRING TUMOR-SPECIFIC
SOMATIC MUTATIONS IN ACUTE MYELOID LEUKEMIA BY TRANSCRIPTOME
SEQUENCING 59
2.6 MONOGENIC DISORDERS - IDENTIFICATION OF MUTATIONS IN ADAPTOR
PROTEIN COMPLEX 4 PROTEINS AS CAUSE OF INTELLECTUAL DISABILITY . 64
2.7 COMMON DISEASE I - IDENTIFICATION OF A MUTATION IN VPS35
CAUSING LATE-ONSET PARKINSON 66
2.8 COMMON DISEASE II - DYSFUNCTIONAL NITRIC OXIDE SIGNALING IN
CREASES RISK OF MYOCARDIAL INFARCTION 69
3 DISCUSSION 73
3.1 GENERAL MUTATION IDENTIFICATION STRATEGIES FOR EXOME SEQUENC
ING 73
3.2 ACCURACY OF VARIANT CALLS 76
3.2.1 SEQUENCING ARTIFACTS 76
3.3 ENRICHMENT BIAS 79
3.3.1 COVERAGE DISTRIBUTION 79
3.3.2 INCOMPLETE ENRICHMENT 80
3.4 STATISTICAL ANALYSIS OF 732 EXOMES 81
3.4.1 AVERAGE EXOME STATISTICS 81
3.4.2 VARIANT DISTRIBUTION PER GENE 84
3.4.3 COMPARISON WITH GENE MUTATION DATABASE HGMD . . 85
3.4.3.1 CARRIER BURDEN AND IDENTIFICATION OF LITERA
TURE MISANNOTATIONS 87
4 OUTLOOK 89
4.1 THIRD-GENERATION SEQUENCING 89
4.1.1 SINGLE-MOLECULE REAL-TIME SEQUENCING 90
7
4.1.2 NANOPORE SEQUENCING
4.1.3 SEQUENCING BY MICROSCOPY TECHNIQUES
4.1.4 COMPLETE GENOMICS
4.1.5 ION TORRENT
94
97
98
100
4.1.6 CLINICAL DIAGNOSTICS AND PERSONALIZED MEDICINE .... 102
4.1.7 SUMMARY AND CONCLUSION OF NEXT-
GENERATION SEQUENC-
4.2.1 IDENTIFICATION OF RECURRING TUMOR-SPECIFIC SOMATIC MU
TATIONS IN ACUTE MYELOID LEUKEMIA BY TRANSCRIPTOME SE-
4.2.2 ADAPTOR PROTEIN COMPLEX 4 DEFICIENCY CAUSES SEVERE
AUTOSOMAL-RECESSIVE INTELLECTUAL DISABILITY. PROGRES
SIVE SPASTIC PARAPLEGIA, SHY CHARACTER, AND SHORT STATURE 114
4.2.3 A MUTATION IN VPS35, ENCODING A SUBUNIT OF THE RETROMER
COMPLEX. CAUSES LATE-ONSET PARKINSON DISEASE .... 123
4.2.4 COMPLETE LIST OF PUBLICATIONS 132
ING INSTRUMENTS
APPENDIX - MANUSCRIPTS
103
106
QUENCING.
106
8
|
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| discipline | Biologie Informatik Medizin |
| format | Thesis Book |
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| spelling | Eck, Sebastian Verfasser aut Identification of genetic variation using Next-Generation Sequencing Sebastian Hubert Eck 2014 165 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Enth. Zeitschriftenaufsätze München, Techn. Univ., Diss., 2014 (DE-588)4113937-9 Hochschulschrift gnd-content Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:91-diss-20140327-1169718-0-3 http://mediatum.ub.tum.de/node?id=1169718 Verlag kostenfrei Volltext https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20140327-1169718-0-3 Resolving-System DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027259931&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Eck, Sebastian Identification of genetic variation using Next-Generation Sequencing |
| subject_GND | (DE-588)4113937-9 |
| title | Identification of genetic variation using Next-Generation Sequencing |
| title_auth | Identification of genetic variation using Next-Generation Sequencing |
| title_exact_search | Identification of genetic variation using Next-Generation Sequencing |
| title_full | Identification of genetic variation using Next-Generation Sequencing Sebastian Hubert Eck |
| title_fullStr | Identification of genetic variation using Next-Generation Sequencing Sebastian Hubert Eck |
| title_full_unstemmed | Identification of genetic variation using Next-Generation Sequencing Sebastian Hubert Eck |
| title_short | Identification of genetic variation using Next-Generation Sequencing |
| title_sort | identification of genetic variation using next generation sequencing |
| topic_facet | Hochschulschrift |
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