The Genom of Homo sapiens.pdf

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Genomic Disorders: Genome Architecture Resultsin Susceptibility to DNA Rearrangements CausingCommon Human TraitsP. STANKIEWICZ,* K. INOUE,* W. BI,* K. WALZ,* S.-S. PARK,* N. KUROTAKI,* C.J. SHAW,*P. FONSECA,* J. YAN,* J.A. LEE,* M. KHAJAVI,* AND J.R. LUPSKI* †‡Departments of *Molecular and Human Genetics and † Pediatrics, Baylor College of Medicine and‡ Texas Children’s Hospital, Houston, Texas 77030The beginnings of molecular medicine can perhaps betraced to Pauling’s work that recognized sickle cell anemiaas a molecular disease, or to Sanger’s demonstrationof a specific amino acid sequence for insulin. During thefour to five decades that followed these discoveries, andthat of the chemical basis of the gene, molecular medicineinvestigations have focused on genes (genocentric)—how mutations specifically alter DNA and how thesechanges affect the structure, function, and expression ofencoded proteins. Recently, however, advances in theHuman Genome Project and completion of the genomesfor several model organisms have enabled investigatorsto view genetic information in the context of the entiregenome. As a result, we recognize that the mechanismsfor some genetic diseases are best understood at the genomiclevel. Human diseases recognized to result fromDNA rearrangements involving unstable genomic regionshave been termed genomic disorders (Lupski1998). These rearrangements are not random events butrather reflect genome architecture consisting of regionspecificlow-copy repeats (LCRs), which contribute tothe susceptibility to DNA rearrangements. LCRs constituteat least 5–10% of the sequenced genome, perhaps>20% of some autosomal regions, and comprise 30–45%of the Y chromosome. These LCRs, also termed segmentalduplications or duplicons, usually span ~10–400 kb ofgenomic DNA and share >95–97% sequence identity(Bailey et al. 2001; Cheung et al. 2001; Eichler 2001;Lander et al. 2001; Hurles and Jobling 2003). By stimulatingand mediating nonallelic homologous recombination(NAHR), LCRs are responsible for genome instabilityand can lead to DNA rearrangements associated withseveral genomic disorders.In the last few years, the number of diseases recognizedas resulting from constitutional genomic rearrangementsdue to an LCR/NAHR-mediated (or unequal crossingover)mechanism has significantly increased (Table 1)(Emanuel and Shaikh 2001; Stankiewicz and Lupski2002a). This mechanism predicts a reciprocal duplicationcounterpart for each deletion syndrome described. However,probably because of ascertainment bias and milderphenotypes, reciprocal duplication events anticipated tooccur at the same frequency have been identified in onlya few cases to date.The vast majority of rearrangements responsible forgenomic disorders are 30 kb–4 Mb in size and can only beanalyzed by methods that enable the resolution ofchanges in the human genome of these magnitudes.Among the most powerful methods capable of resolvinggenomic changes of such sizes have been pulsed-field gelelectrophoresis (PFGE) and fluorescence in situ hybridization(FISH) techniques (Fig. 1). Breakpoint analysisof the rearrangements and the identification of junctionfragments that result from the products ofrecombination in patients with genomic disorders haveprovided insights into the functional consequences of humangenome architecture.Genomic disorders are frequent diseases (~1 per 1000births) and often sporadic resulting from de novo rearrangements(Shaffer and Lupski 2000). The clinical phenotypeis a consequence of abnormal dosage of a gene(s)located within the rearranged genomic fragment(s). Themutation event occurs via recombination because the architectureof the genome provides ample substrates forNAHR; it does not result from errors in DNA replication/repairthat may lead to population-specific alleles.Thus, no frequency differences among world populationswere initially anticipated (Shaffer and Lupski 2000). However,recently, there have been reports of significantly differentfrequencies of a common deletion (flanked byLCRs) in patients with Sotos syndrome among Japanese,British, and French populations (Kurotaki et al. 2002;Douglas et al. 2003; Rio et al. 2003), suggesting potentialongoing evolution of segmental duplications.CONSTITUTIONAL RECURRENT GENOMICDISORDERS IN PROXIMAL 17pThe unstable and LCR- and gene-rich human genomicregion 17p11.2-p12 is associated with a wide variety ofstructural chromosome aberrations. We have documentedLCRs and unique genome architecture at the breakpointsfor rearrangements in proximal 17p responsible for atleast four genomic disorders: Charcot-Marie-Tooth diseasetype 1A (CMT1A), hereditary neuropathy with liabilityto pressure palsies (HNPP), Smith-Magenis syndrome(SMS), and dup(17)(p11.2p11.2) syndrome, andhave obtained evidence for the involvement of genomeCold Spring Harbor Symposia on Quantitative Biology, Volume LXVIII. © 2003 Cold Spring Harbor Laboratory Press 0-87969-709-1/04. 445
446 STANKIEWICZ ET AL.Table 1. Selected Common Traits Resulting from Genomic RearrangementsChromosome Rearrangement LCR sizeTrait Gene location type size (kb) (kb)NeurobehavioralWBS ELN, GTF2I, ? 7q11.23 del 1600 320PWS ? 15q12pat del 3500 500AS UBE3A 15q12mat del 3500 500dup(15)(q11.2q13) GABRB3? 15q12mat dup 3500 500SMS RAI1 17p11.2 del 4000 200dup(17)(p11.2p11.2) RAI1? 17p11.2 dup 4000 200DGS/VCFS TBX1 22q11.2 del 3000/1500 225–400dup(22)(q11.2q11.2) TBX1? 22q11.2 dup 3000 225–400Peripheral neuropathyCMT1A PMP22 17p12 dup 1400 24HNPP PMP22 17p12 del 1400 24Hypertension CYP11B1/2 8q21 dup 45 10Color blindness RCP & GCP Xq28 del 0 39Male infertilityAZFa DBY, USP9Y Yq11.2 del 800 10AZFc RBMY, DAZ? Yq11.2 del 3500 229OvergrowthSotos syndrome NSD1 5q35.3 del 1300 a 560–600 a(del) Deletion; (dup) duplication; (inv) inversion; (WBS) Williams-Beuren syndrome; (PWS) Prader-Willisyndrome; (AS) Angelman syndrome; (DGS/VCFS) DiGeorge syndrome/Velocardiofacial syndrome.a N. Kurotaki and J.R. Lupski, unpubl.Figure 1. Genome architecture and methods to resolve structure of varying DNA sizes. Above are shown three levels of genome architecture,from viewing the entire human genome, resolved by conventional G-banding, PFGE, FISH, and direct DNA sequencing.Below is a scale of the human genome from 1 bp (10 0 bp) to ~3 x 10 9 bp and the size ranges (color coded) in which the different methodscan physically resolve differences. Note that the genome architecture and rearrangements responsible for genomic disorders occurin the size range of ~30 kb–4 Mb that cannot be resolved either by DNA sequencing and agarose gel electrophoresis or by conventionalG-banding, but has been successfully identified by PFGE and/or FISH.
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ForewordIn 2001, as we considered t
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The Finished Genome Sequence of Hom
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4 ROGERSFigure 2. Accumulation of h
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6 ROGERSFigure 4. Sequencing center
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8 ROGERSabcFigure 5. Ensembl view o
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10 ROGERS2000. Analysis of vertebra
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The Human Genome: Genes, Pseudogene
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VARIATION ON CHROMOSOME 7 15rived f
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VARIATION ON CHROMOSOME 7 17DNAs an
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VARIATION ON CHROMOSOME 7 19expecte
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VARIATION ON CHROMOSOME 7 21Drosoph
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Mutational Profiling in the Human G
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HUMAN MUTATIONAL PROFILING 25Anothe
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HUMAN MUTATIONAL PROFILING 27Figure
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HUMAN MUTATIONAL PROFILING 29Rieder
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32 SCHMUTZ ET AL.algorithm itself,
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34 SCHMUTZ ET AL.Figure 2. Genomic
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36 SCHMUTZ ET AL.compared. Some of
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Human Subtelomeric DNAH. RIETHMAN,
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HUMAN SUBTELOMERIC SEQUENCES 41The
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HUMAN SUBTELOMERIC SEQUENCES 43cate
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HUMAN SUBTELOMERIC SEQUENCES 45Figu
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HUMAN SUBTELOMERIC SEQUENCES 47pres
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50 COLLINSand expand the genomics r
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52 COLLINSFigure 2. A public-sector
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54 COLLINSdefine all the parts of t
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56 BENTLEYmon over many generations
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58 BENTLEYTable 1. Genetic Disease
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60 BENTLEY(Clark et al. 1998; Reich
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62 BENTLEYACKNOWLEDGMENTSThe author
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SNP Genotyping and Molecular Haplot
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GENETIC ANALYSIS OF DNA POOLS 67gen
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70 FAN ET AL.matrix is then mated t
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72 FAN ET AL.Figure 3. Views of gen
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74 FAN ET AL.including 32 duplicate
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76 FAN ET AL.Figure 7. Allele-speci
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78 FAN ET AL.microsphere-based assa
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80 BERTRANPETIT ET AL.function, may
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82 BERTRANPETIT ET AL.diversity in
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84 BERTRANPETIT ET AL.gree of block
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86 BERTRANPETIT ET AL.Figure 1. Dec
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88 BERTRANPETIT ET AL.1999. Populat
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90 WINDEMUTH ET AL.Expression data.
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92 WINDEMUTH ET AL.Table 1. A Summa
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94 WINDEMUTH ET AL.Table 2. Signifi
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96 WINDEMUTH ET AL.Table 3. Summary
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98 WINDEMUTH ET AL.Table 6. List of
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100 WINDEMUTH ET AL.Table 6. (Conti
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102 WINDEMUTH ET AL.Table 6. (Conti
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104 WINDEMUTH ET AL.much of a surpr
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106 WINDEMUTH ET AL.Given our resul
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Genetic Variation and the Control o
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GENETIC CONTROL OF TRANSCRIPTION 11
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GENETIC CONTROL OF TRANSCRIPTION 11
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Genome-wide Detection and Analysis
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RECENT SEGMENTAL DUPLICATIONS 117Fi
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RECENT SEGMENTAL DUPLICATIONS 119St
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RECENT SEGMENTAL DUPLICATIONS 121Co
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RECENT SEGMENTAL DUPLICATIONS 123Ho
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The Effects of Evolutionary Distanc
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EVOLUTIONARY DISTANCE AND GENE PRED
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EVOLUTIONARY DISTANCE AND GENE PRED
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Lineage-specific Expansion of KRAB
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EVOLUTION OF ZNF GENES 133Figure 2.
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EVOLUTION OF ZNF GENES 135Figure 4.
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EVOLUTION OF ZNF GENES 137get gene,
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EVOLUTION OF ZNF GENES 139Y., Goodw
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Sequence Organization and Functiona
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CENTROMERE ANNOTATION 143THE CENTRO
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CENTROMERE ANNOTATION 145Figure 4.
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CENTROMERE ANNOTATION 147CONCLUSION
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CENTROMERE ANNOTATION 149Schueler M
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152 PARKHILL AND THOMSONFigure 1. T
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154 PARKHILL AND THOMSONshow very h
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156 PARKHILL AND THOMSONGene Loss a
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158 PARKHILL AND THOMSONYersinia ad
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160 MCKAY ET AL.Choosing Candidate
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162 MCKAY ET AL.new comparative too
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164 MCKAY ET AL.rich. Based on a th
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166 MCKAY ET AL.Embryonic Muscle an
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168 MCKAY ET AL.native polyadenylat
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Building Comparative Maps Using 1.5
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HUMAN CHROMOSOME 1p IN THE DOG 1731
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HUMAN CHROMOSOME 1p IN THE DOG 175(
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HUMAN CHROMOSOME 1p IN THE DOG 177l
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180 GEORGES AND ANDERSSON5. There i
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182 GEORGES AND ANDERSSONplied to r
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184 GEORGES AND ANDERSSONbe common
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186 GEORGES AND ANDERSSONin humans
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Evolving Methods for the Assembly o
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ASSEMBLING LARGE GENOMES 191Figure
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ASSEMBLING LARGE GENOMES 193tant ad
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Mouse Genome Encyclopedia ProjectY.
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MOUSE GENOME ENCYCLOPEDIA PROJECT 1
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DNA Sequence Assembly and Multiple
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EULERIAN ASSEMBLY AND MULTIPLE ALIG
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Ensembl: A Genome InfrastructureE.
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ENSEMBL 215projects often submit th
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218 ZHANGthe majority of these are
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220 ZHANGFigure 2. Demonstration of
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222 ZHANG(G.X. Chen et al., in prep
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224 ZHANGWe are waiting for experim
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Ontologies for Biologists: A Commun
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ONTOLOGIES FOR BIOLOGISTS 229al. 20
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ONTOLOGIES FOR BIOLOGISTS 231TOPIC
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ONTOLOGIES FOR BIOLOGISTS 233a.b.Fi
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ONTOLOGIES FOR BIOLOGISTS 2352003.
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238 JOSHI-TOPE ET AL.Figure 1. The
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240 JOSHI-TOPE ET AL.state of knowl
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242 JOSHI-TOPE ET AL.and co-immunop
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The Share of Human Genomic DNA unde
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DNA UNDER SELECTION FROM HUMAN-MOUS
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Detecting Highly Conserved Regions
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DETECTING MULTISPECIES CONSERVED SE
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266 ROE ET AL.noncoding regions. On
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268 ROE ET AL.a48 hpf embryos in Mi
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270 ROE ET AL.aNovel gene KIAA0819[
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272 ROE ET AL.aMouseRatAP00354.2 Hu
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274 ROE ET AL.Tautz D. and Pfeifle
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276 JAILLON ET AL.Detection of Evol
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278 JAILLON ET AL.Table 1. Distribu
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280 JAILLON ET AL.Table 3. Distribu
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282 JAILLON ET AL.ecotig is a resul
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284 OVCHARENKO AND LOOTSdivergent r
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286 OVCHARENKO AND LOOTSmodulation
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288 OVCHARENKO AND LOOTSsequencing
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290 OVCHARENKO AND LOOTSments of cl
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Evolution of Eukaryotic Gene Repert
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EVOLUTION OF EUKARYOTIC GENES AND I
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304 PENNACCHIO, BAROUKH, AND RUBINA
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306 PENNACCHIO, BAROUKH, AND RUBINh
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308 PENNACCHIO, BAROUKH, AND RUBINA
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High-Throughput Mouse Knockouts Pro
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314 FRIDDLE ET AL.screen to lines o
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Identification of Novel Functional
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100 bp ladder68G1168G1168H1168H6100
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FUNCTIONAL ELEMENTS IN HUMAN DNA 32
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High-resolution Human Genome Scanni
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HUMAN GENOME SCANNING 325false-posi
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HUMAN GENOME SCANNING 327affecting
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HUMAN GENOME SCANNING 329methods fo
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332 MALEK ET AL.Figure 1. The bacte
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334 MALEK ET AL.J., Vincent S., and
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336 HARDISON ET AL.reflect blocks o
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338 HARDISON ET AL.plain the region
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340 HARDISON ET AL.CALIBRATION OF T
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342 HARDISON ET AL.PositionRP2.3noE
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344 HARDISON ET AL.cific chromosoma
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346 WESTON ET AL.these differences
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348 WESTON ET AL.els controlled by
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350 WESTON ET AL.ures prominently i
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352 WESTON ET AL.nal and Bop, which
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354 WESTON ET AL.ablp 1466 bopbcrtB
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356 WESTON ET AL.like fold (Fig. 6)
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Implications of Genomics for Public
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GENETIC EPIDEMIOLOGY 361lytic epide
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GENETIC EPIDEMIOLOGY 363curate risk
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A Model System for Identifying Gene
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PTC TASTE GENETICS 367Figure 2. Hap
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PTC TASTE GENETICS 369Table 2. Hapl
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PTC TASTE GENETICS 371the emergence
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374 MCCALLION ET AL.Figure 1. Schem
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376 MCCALLION ET AL.lier (Carrasqui
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378 MCCALLION ET AL.Table 3. HSCR A
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380 MCCALLION ET AL.Figure 3. Trans
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Genetics of Schizophrenia and Bipol
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SCHIZOPHRENIA AND BIPOLAR AFFECTIVE
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Page 400 and 401: SCHIZOPHRENIA AND BIPOLAR AFFECTIVE
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Page 416 and 417: Regulation of α-Synuclein Expressi
Page 418 and 419: α-SYNUCLEIN EXPRESSION AND PD 411T
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Page 433 and 434: 426 ANTONARAKIS ET AL.1316192225283
Page 435 and 436: 428 ANTONARAKIS ET AL.Figure 5. Sam
Page 437 and 438: 430 ANTONARAKIS ET AL.POPULATION VA
Page 439 and 440: 432 JORGENSEN ET AL.tive small mole
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Page 454 and 455: GENOME ARCHITECTURE AND GENOMIC DIS
Page 462 and 463: Human Versus Chimpanzee Chromosome-
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Page 468 and 469: Novel Transcriptional Units and Unc
Page 470 and 471: TRANSCRIPTIONAL UNITS AND GENE PAIR
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Page 484 and 485: mtDNA VARIATION 477Figure 8. Temper
Page 486 and 487: Positive Selection in the Human Gen
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Page 495 and 496: 488 UNDERHILLorigin episodes, each
Page 497 and 498: 490 UNDERHILLhaplogroups C through
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The New Quantitative BiologyM.V. OL
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NEW QUANTITATIVE BIOLOGY 497alone.
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NEW QUANTITATIVE BIOLOGY 499There w
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NEW QUANTITATIVE BIOLOGY 501ceded,
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