Foreword ....................................................... xi
Preface ........................................................ xv
Contributors ................................................. xvii
Glossary ...................................................... xix
SECTION I. AN INTRODUCTION TO BIOINFORMATICS FOR
THE GENETICIST ..................................... 1
1. Bioinformatics challenges for the geneticist ................. 3
Michael R. Barnes
1.1. Introduction ........................................... 3
1.2. The role of bioinformatics in genetics research ........ 4
1.3. Genetics in the post-genome era ........................ 5
1.4. Conclusions ........................................... 12
References .................................................. 15
2. Managing and manipulating genetic data ...................... 17
Karl W. Broman and Simon С. Heath
2.1. Introduction .......................................... 17
2.2. Basic principles ...................................... 18
2.3. Data entry and storage ................................ 20
2.4. Data manipulation ..................................... 21
2.5. Examples of code ...................................... 22
2.6. Resources ............................................. 30
2.7. Summary ............................................... 31
References .................................................. 31
SECTION II. MASTERING GENES, GENOMES AND GENETIC
VARIATION DATA .................................... 33
3. The HapMap - A haplotype map of the human genome ............ 35
Ellen M. Brown and Bryan J. Barratt
3.1. Introduction .......................................... 35
3.2. Accessing the data .................................... 38
3.3. Application of HapMap data in association studies ..... 42
3.4. Future perspectives ................................... 54
References .................................................. 54
4. Assembling a view of the human genome ....................... 59
Colin A. M. Semple
4.1. Introduction .......................................... 59
4.2. Genomic sequence assembly ............................. 60
4.3. Annotation from a distance: the generalities .......... 64
4.4. Annotation up close and personal: the specifics ....... 70
4.5. Annotation: the next generation ....................... 78
References .................................................. 80
5. Finding, delineating and analysing genes .................... 85
Christopher Southan and Michael R. Barnes
5.1. Introduction .......................................... 85
5.2. Why learn to predict and analyse genes in the
complete genome era? .................................. 86
5.3. The evidence cascade for gene products ................ 88
5.4. Dealing with the complexities of gene models .......... 95
5.5. Locating known genes in the human genome .............. 97
5.6. Genome portal inspection ............................. 100
5.7. Analysing novel genes ................................ 101
5.8. Conclusions and prospects ............................ 102
References ................................................. 103
6. Comparative genomics ....................................... 105
Martin S. Taylor and Richard R. Copley
6.1. Introduction ......................................... 105
6.2. The genomic landscape ................................ 106
6.3. Concepts ............................................. 109
6.4. Practicalities ....................................... 113
6.5. Technology ........................................... 118
6.6. Applications ......................................... 132
6.7. Challenges and future directions ..................... 137
Conclusion ................................................. 138
References ................................................. 139
SECTION III. BIOINFORMATICS FOR GENETIC STUDY DESIGN
AND ANALYSIS ..................................... 145
7. Identifying mutations in single gene disorders ............. 147
David P. Kelsell, Diana Blaydon and Charles A. Mein
7.1. Introduction ......................................... 147
7.2. Clinical ascertainment ............................... 147
7.3. Genome-wide mapping of monogenic diseases ............ 148
7.4. The nature of mutation in monogenic diseases ......... 152
7.5. Considering epigenetic effects in mendelian traits ... 160
7.6. Summary .............................................. 162
References ................................................. 162
8. From Genome Scan to Culprit Gene ........................... 165
Ian С. Gray
8.1. Introduction ......................................... 165
8.2. Theoretical and practical considerations ............. 166
8.3. A stepwise approach to locus refinement
candidate gene identification ........................ 176
8.4. Conclusion ........................................... 180
8.5. A list of the software tools and Web links
mentioned in this chapter ............................ 181
References ................................................. 182
9. Integrating Genetics, Genomics and Epigenomics to
Identify Disease Genes ..................................... 185
Michael R. Barnes
9.1. Introduction ......................................... 185
9.2. Dealing with the (draft) human genome sequence ....... 186
9.3. Progressing loci of interest with genomic
information .......................................... 187
9.4. In silico characterization of the IBD5 locus -
a case study ......................................... 191
9.5. Drawing together biological rationale - hypothesis
building ............................................. 209
9.6. Identification of potentially functional
polymorphisms ........................................ 211
9.7. Conclusions .......................................... 212
References ................................................. 213
10.Tools for statistical genetics ............................. 217
Aruna Bansal, Charlotte Vignal and Ralph McGinnis
10.1. Introduction ......................................... 217
10.2. Linkage analysis ..................................... 217
10.3. Association analysis ................................. 223
10.4. Linkage disequilibrium ............................... 229
10.5. Quantitative trait locus (QTL) mapping in
experimental crosses ................................. 235
10.6. Closing remarks ...................................... 239
References ................................................. 241
SECTION IV. MOVING FROM ASSOCIATED GENES TO
DISEASE ALLELES .................................. 247
11.Predictive functional analysis of polymorphisms:
An overview ................................................ 249
Mary Plumpton and Michael R. Barnes
11.1. Introduction ......................................... 249
11.2. Principles of predictive functional analysis of
polymorphisms ........................................ 252
11.3. The anatomy of promoter regions and regulatory
elements ............................................. 256
11.4. The anatomy of genes ................................. 258
11.5. Pseudogenes and regulatory mRNA ...................... 266
11.6. Analysis of novel regulatory elements and motifs in
nucleotide sequences ................................. 266
11.7. Functional analysis of non-synonymous coding
polymorphisms ........................................ 268
11.8. Integrated tools for functional analysis of genetic
variation ............................................ 273
11.9. A note of caution on the prioritization of in
silico predictions for further laboratory
investigation ........................................ 275
11.10.Conclusions .......................................... 275
References ................................................. 276
12.Functional in silico analysis of gene regulatory
polymorphism ............................................... 281
Chaolin Zhang, Xiaoyue Zhao, Michael Q. Zhang
12.1. Introduction ......................................... 281
12.2. Predicting regulatory regions ........................ 282
12.3. Modelling and predicting transcription factor-
binding sites ........................................ 288
12.4. Predicting regulatory elements for splicing
regulation ........................................... 295
12.5. Evaluating the functional importance of
regulatory polymorphisms ............................. 300
References ................................................. 302
13.Amino-acid properties and consequences of substitutions .... 311
Matthew J. Betts and Robert B. Russell
13.1. Introduction ......................................... 311
13.2. Protein features relevant to amino-acid behaviour .... 312
13.3. Amino-acid classifications ........................... 316
13.4. Properties of the amino acids ........................ 318
13.5. Amino-acid quick reference ........................... 321
13.6. Studies of how mutations affect function ............. 334
13.7. A summary of the thought process ..................... 339
References ................................................. 340
14.Non-coding RNA bioinformatics .............................. 343
James R. Brown, Steve Deharo, Barry Dancis, Michael
R. Barnes and Philippe Sanseau
14.1. Introduction ......................................... 343
14.2. The non-coding (nc) RNA universe ..................... 344
14.3. Computational analysis of ncRNA ...................... 349
14.4. ncRNA variation in disease ........................... 356
14.5. Assessing the impact of variation in ncRNA ........... 362
14.6. Data resources to support small ncRNA analysis ....... 363
14.7. Conclusions .......................................... 363
References ................................................. 364
SECTION V. ANALYSIS AT THE GENETIC AND GENOMIC DATA
INTERFACE ........................................ 369
15.What are microarrays? ...................................... 371
Catherine A. Ball and Gavin Sherlock
15.1. Introduction ......................................... 371
15.2. Principles of the application of microarray
technology ........................................... 373
15.3. Complementary approaches to microarray analysis ...... 377
15.4. Differences between data repository and research
database ............................................. 377
15.5. Descriptions of freely available research
database packages .................................... 377
References ................................................. 385
16.Combining quantitative trait and gene-expression data ...... 389
Elissa J. Chesler
16.1. Introduction: the genetic regulation of
endophenotypes ....................................... 389
16.2. Transcript abundance as a complex phenotype .......... 390
16.3. Scaling up genetic analysis and mapping models
for microarrays ...................................... 394
16.4. Genetic correlation analysis ......................... 397
16.5. Systems genetic analysis ............................. 400
16.6. Using expression QTLs to identify candidate genes
for the regulation of complex phenotypes ............. 403
16.7. Conclusions .......................................... 408
References ................................................. 408
17.Bioinformatics and cancer genetics ......................... 413
Joel Greshock
17.1. Introduction ......................................... 413
17.2. Cancer genomes ....................................... 414
17.3. Approaches to studying cancer genetics ............... 415
17.4. General resources for cancer genetics ................ 418
17.5. Cancer genes and mutations ........................... 420
17.6. Copy number alterations in cancer .................... 425
17.7. Loss of heterozygosity in cancer ..................... 431
17.8. Gene-expression data in cancer ....................... 432
17.9. Multiplatform gene target identification ............. 435
17.10.The epigenetics of cancer ............................ 438
17.11.Tumour modelling ..................................... 438
17.12.Conclusions .......................................... 439
References ................................................. 439
18.Needle in a haystack? Dealing with 500 000
SNP genome scans ........................................... 447
Michael R. Barnes and Paul S. Derwent
18.1. Introduction ......................................... 447
18.2. Genome scan analysis issues .......................... 449
18.3. Ultra-high-density genome-scanning technologies ...... 459
18.4. Bioinformatics for genome scan analysis .............. 469
18.5. Conclusions .......................................... 489
References ................................................. 490
19.A bioinformatics perspective on genetics in
drug discovery and development ............................. 495
Christopher Southan, Magnus Ulvsbäck and
Michael R. Barnes
19.1. Introduction ......................................... 495
19.2. Target genetics ...................................... 498
19.3. Pharmacogenetics (PGx) ............................... 508
19.4. Conclusions: toward 'personalized medicine' .......... 525
References ................................................ 525
Appendix I .................................................... 529
Appendix II ................................................... 531
Index ......................................................... 537
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