Bioinformatics for Geneticists: A Bioinformatics Primer for the Analysis of Genetic Data

Bioinformatics for Geneticists......Page 3
Contents......Page 7
Foreword......Page 13
Preface......Page 17
Contributors......Page 19
Glossary......Page 21
Section I
An Introduction to
Bioinformatics for
the Geneticist......Page 25
1.1 Introduction......Page 27
1.2 The Role of Bioinformatics in Genetics Research......Page 28
1.3 Genetics in the Post-Genome Era......Page 29
1.4 Conclusions......Page 36
References......Page 39
2.1 Introduction......Page 41
2.2 Basic Principles......Page 42
2.3 Data Entry and Storage......Page 44
2.4 Data Manipulation......Page 45
2.5 Examples of Code......Page 46
2.6 Resources......Page 54
References......Page 55
Section II
Mastering Genes, Genomes and
Genetic Variation Data......Page 57
3.1 Introduction......Page 59
3.2 Accessing the Data......Page 62
3.3 Application of HapMap Data in Association Studies......Page 66
References......Page 78
4.1 Introduction......Page 83
4.2 Genomic Sequence Assembly......Page 84
4.3 Annotation from a Distance: The Generalities......Page 88
4.4 Annotation up close and Personal: The Specifics......Page 94
4.5 Annotation: The next Generation......Page 102
References......Page 104
5.1 Introduction......Page 109
5.2 Why Learn to Predict and Analyse Genes in the Complete Genome Era?......Page 110
5.3 The Evidence Cascade for Gene Products......Page 112
5.4 Dealing with the Complexities of Gene Models......Page 119
5.5 Locating known Genes in the Human Genome......Page 121
5.6 Genome Portal Inspection......Page 124
5.7 Analysing Novel Genes......Page 125
5.8 Conclusions and Prospects......Page 126
References......Page 127
6.1 Introduction......Page 129
6.2 The Genomic Landscape......Page 130
6.3 Concepts......Page 133
6.4 Practicalities......Page 137
6.5 Technology......Page 142
6.6 Applications......Page 156
6.7 Challenges and Future Directions......Page 161
6.8 Conclusion......Page 162
References......Page 163
Section III
Bioinformatics for Genetic
Study Design and Analysis......Page 169
7.2 Clinical Ascertainment......Page 171
7.3 Genome-Wide Mapping of Monogenic Diseases......Page 172
7.4 The Nature of Mutation in Monogenic Diseases......Page 176
7.5 Considering Epigenetic Effects in Mendelian Traits......Page 184
References......Page 186
8.1 Introduction......Page 189
8.2 Theoretical and Practical Considerations......Page 190
8.3 A Stepwise Approach to Locus Refinement and Candidate Gene Identification......Page 200
8.4 Conclusion......Page 204
8.5 A List of the Software Tools and Web LInks Mentioned in this Chapter......Page 205
References......Page 206
9.1 Introduction......Page 209
9.2 Dealing with the (Draft) Human Genome Sequence......Page 210
9.3 Progressing Loci of Interest with Genomic Information......Page 211
9.4 In Silico Characterization of the IBD5 Locus – A Case Study......Page 215
9.5 Drawing Together Biological Rationale – Hypothesis Building......Page 233
9.6 Identification of Potentially Functional Polymorphisms......Page 235
9.7 Conclusions......Page 236
References......Page 237
10.2 Linkage Analysis......Page 241
10.3 Association Analysis......Page 247
10.4 Linkage disequilibrium......Page 253
10.5 Quantitative Trait Locus (QTL) Rapping in Experimental Crosses......Page 259
10.6 Closing Remarks......Page 263
References......Page 265
Section IV
Moving from Associated Genes
to Disease Alleles......Page 271
11.1 Introduction......Page 273
11.2 Principles of Predictive Functional Analysis of Polymorphisms......Page 276
11.3 The Anatomy of Promoter Regions and Regulatory Elements......Page 280
11.4 The Anatomy of Genes......Page 282
11.6 Analysis of Novel Regulatory Elements and Motifs in Nucleotide Sequences......Page 290
11.7 Functional Analysis of Non-Synonymous Coding Polymorphisms......Page 292
11.8 Integrated Tools for Functional Analysis of Genetic Variation......Page 298
References......Page 300
12.1 Introduction......Page 305
12.2 Predicting Regulatory Regions......Page 308
12.3 Modelling and Predicting Transcription Factor-Binding Sites......Page 312
12.4 Predicting Regulatory Elements for Splicing Regulation......Page 319
12.5 Evaluating the Functional Importance of Regulatory Polymorphisms......Page 324
References......Page 326
13.1 Introduction......Page 335
13.2 Protein Features Relevant to Amino-Acid Behaviour......Page 336
13.3 Amino-Acid Classifications......Page 340
13.4 Properties of the Amino Acids......Page 342
13.5 Amino-Acid Quick Reference......Page 345
13.6 Studies of how Mutations Affect Function......Page 358
13.7 A Summary of the Thought Process......Page 363
References......Page 364
14.1 Introduction......Page 367
14.2 The Non-Coding (nc) RNA Universe......Page 368
14.3 Computational Analysis of ncRNA......Page 373
14.4 ncRNA Variation in Disease......Page 380
14.5 Assessing the Impact of Variation in ncRNA......Page 386
14.7 Conclusions......Page 387
References......Page 388
Section V
Analysis at the Genetic and
Genomic Data Interface......Page 393
15.1 Introduction......Page 395
15.2 Principles of The Application of Microarray Technology......Page 397
15.5 Descriptions of Freely Available Research Database Packages......Page 401
References......Page 409
16.1 Introduction: The Genetic Regulation of Endophenotypes......Page 413
16.2 Transcript Abundance as a Complex Phenotype......Page 414
16.3 Scaling up Genetic Analysis and Mapping Models for Microarrays......Page 418
16.4 Genetic Correlation Analysis......Page 421
16.5 Systems Genetic Analysis......Page 424
16.6 Using Expression QTLs to Identify Candidate Genes for the Regulation of Complex Phenotypes......Page 427
References......Page 432
17.1 Introduction......Page 437
17.2 Cancer Genomes......Page 438
17.3 Approaches to Studying Cancer Genetics......Page 439
17.4 General Resources for Cancer Genetics......Page 442
17.5 Cancer Genes and Mutations......Page 444
17.6 Copy Number Alterations in Cancer......Page 449
17.7 Loss of Heterozygosity in Cancer......Page 455
17.8 Gene-Expression Data in Cancer......Page 456
17.9 Multiplatform Gene Target Identification......Page 459
17.11 Tumour Modelling......Page 462
References......Page 463
18.1 Introduction......Page 471
18.2 Genome Scan Analysis Issues......Page 473
18.3 Ultra-High-Density Genome-Scanning Technologies......Page 483
18.4 Bioinformatics for Genome Scan Analysis......Page 493
18.5 Conclusions......Page 513
References......Page 514
19.1 Introduction......Page 519
19.2 Target Genetics......Page 522
19.3 Pharmacogenetics (PGx)......Page 532
References......Page 549
Appendix I......Page 553
Appendix II......Page 557
Index......Page 561