The Genom of Homo sapiens.pdf

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SNP GENOTYPING 71tem, consisting of artificial sequences that are not SNPspecific, allows any set of SNPs to be read out on a common,standard array (Gerry et al. 1999; Cai et al. 2000;Chen et al. 2000; Fan et al. 2000; Iannone et al. 2000).This provides flexibility and reduces array manufacturingcosts. Custom sets of assays can be made on demand, simplyby building the address sequences into the SNP-specificassay oligonucleotides. The use of universal PCRprimers to associate a fluorescent dye with each SNP allelealso saves on costs. Because only three primers, twolabeled and one unlabeled, are needed regardless of thenumber of SNPs to be assayed, the primer costs are negligible,as they are amortized over large numbers of assays.The GoldenGate assay uses ~40 bp surrounding theSNP. Either strand can be chosen for the assay, but we usedesign rules to designate a preferred strand. The ASOsare designed to have a T m of 60ºC (57–62ºC), whereas theLSO has a T m of 57ºC (54–60ºC). It is possible to designa similar assay that omits the allele-specific polymeraseextension step. However, we have found that allelic discriminationusing polymerase, followed by ligation, increasesthe signal-to-noise ratio (data not shown)(Abravaya et al. 1995). Another advantage is that a variablegap between the ASOs and LSO (typically 1–20bases) provides flexibility to position the LSO to avoidunfavorable sequences.Figure 2. The GoldenGate SNP genotyping assay scheme. SeeAppendix for detailed procedures.homozygote, or an equimolar mixture of P1-A-P3 andP2-G-P3 in the case of an AG heterozygote. Because P1is associated with the A allele and P2 with the G allele,the ratio of the two primer-specific fluorescent signalsidentifies the genotype as AA, AG, or GG.Each SNP is assigned a different address sequence,which is contained within the LSO. Each of these addressesis complementary to a unique capture sequencerepresented by one of the bead types in the array. Therefore,the products of the 1,152 assays hybridize to differentbead types in the array, allowing all 1,152 genotypesto be read out simultaneously. This universal address sys-GENOTYPING RESULTSTo date, we have developed well in excess of 100,000SNP assays. Representative data are shown in Figure 3.Figure 3A shows a fluorescence image from a single arrayin a 96-array matrix. The image is a false-color compositeof the Cy3 (green) and Cy5 (red) images collected in separatechannels. A portion of the image is expanded in Figure3B to show individual beads. Red and green beads areindicative of homozygous genotypes. Yellow indicates aheterozygous genotype, resulting from the presence ofboth Cy3 and Cy5 on the same bead (Fig. 2). In the nextstage of data processing, a trimmed mean intensity is calculatedfor each bead type, for both Cy3 and Cy5 (on average,there are ~30 beads of each of the 1,520 bead typesin an array). Figure 3C shows trimmed mean intensitiesfor 96 DNA samples genotyped on one SNP. The SNP isone of 1,152 assayed in a multiplex pool. As shown, the 96DNA samples cluster into three groups, showing that allthree genotypes are represented in the sample set.Actual genotype calls are made after transforming theintensity values into modified polar coordinates (Fig. 4).By taking into account the intensity distribution of beads,averaging, and rejecting outliers, measurement precisionis improved (Fig. 4A vs. 4B and 4C vs. 4D). It is alsoshown in Figure 4 that occasional beads are outliers, andwould, on their own, give inaccurate genotypes. Eventhough there are relatively few such beads, they couldhave a detrimental impact given the requirements for lowerror rates in large-scale genotyping studies. However,the redundancy in the system ensures a minimum of 5beads of each type, greatly reducing the chance of an incorrectcall.
72 FAN ET AL.Figure 3. Views of genotyping data. (A) Fluorescence hybridization image of an ~1.4-mm-diameter optical fiber bundle containing49,777 fibers in a monolithic, hexagonally packed array. (B) A portion of the hybridization image magnified to show individual beads.(C) Genotype calls for a single SNP on 96 DNA samples.Figure 4. Genotyping data for one SNP in a 1,152 multiplex pool. Genotyping plots were created by graphing normalized Intensity(R = normalized X + normalized Y) vs. Theta = 2 /π Tan –1 (Cy5/Cy3). (A) Bead type data for three DNAs representing three differentgenotypes. Each data point represents a trimmed mean intensity derived from a population of beads. (B) Data from individual beadscorresponding to the three data points shown in A. (C) Same as A, for 383 of 384 DNAs (one DNA sample failed to yield data for thisSNP). The number of DNAs in each genotype cluster is shown above the x axis. (D) Same as B, showing individual bead data for all383 DNAs.
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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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Page 30 and 31: Mutational Profiling in the Human G
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Page 36: HUMAN MUTATIONAL PROFILING 29Rieder
Page 39 and 40: 32 SCHMUTZ ET AL.algorithm itself,
Page 41 and 42: 34 SCHMUTZ ET AL.Figure 2. Genomic
Page 43 and 44: 36 SCHMUTZ ET AL.compared. Some of
Page 46 and 47: Human Subtelomeric DNAH. RIETHMAN,
Page 48 and 49: HUMAN SUBTELOMERIC SEQUENCES 41The
Page 50 and 51: HUMAN SUBTELOMERIC SEQUENCES 43cate
Page 52 and 53: HUMAN SUBTELOMERIC SEQUENCES 45Figu
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Page 57 and 58: 50 COLLINSand expand the genomics r
Page 59 and 60: 52 COLLINSFigure 2. A public-sector
Page 61 and 62: 54 COLLINSdefine all the parts of t
Page 63 and 64: 56 BENTLEYmon over many generations
Page 65 and 66: 58 BENTLEYTable 1. Genetic Disease
Page 67 and 68: 60 BENTLEY(Clark et al. 1998; Reich
Page 69 and 70: 62 BENTLEYACKNOWLEDGMENTSThe author
Page 72 and 73: SNP Genotyping and Molecular Haplot
Page 74: GENETIC ANALYSIS OF DNA POOLS 67gen
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Page 81 and 82: 74 FAN ET AL.including 32 duplicate
Page 83 and 84: 76 FAN ET AL.Figure 7. Allele-speci
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Page 87 and 88: 80 BERTRANPETIT ET AL.function, may
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Page 91 and 92: 84 BERTRANPETIT ET AL.gree of block
Page 93 and 94: 86 BERTRANPETIT ET AL.Figure 1. Dec
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Page 116 and 117: Genetic Variation and the Control o
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Page 122 and 123: Genome-wide Detection and Analysis
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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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The Genetics of Common Diseases: 10
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GENETICS OF COMMON DISEASES 397with
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GENETICS OF COMMON DISEASES 399SELE
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GENETICS OF COMMON DISEASES 401F.,
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404 CHEUNG ET AL.netic analysis. Ex
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406 CHEUNG ET AL.Figure 3. The expr
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Regulation of α-Synuclein Expressi
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α-SYNUCLEIN EXPRESSION AND PD 411T
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1. The levels of α-synuclein prote
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α-SYNUCLEIN EXPRESSION AND PD 415g
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418 BOTSTEINFigure 1. (A) Blectron
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420 BOTSTEINFigure 3. Cluster diagr
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422 BOTSTEINFigure 6. Kaplan-Meier
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424 BOTSTEINGarber M.E., Troyanskay
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426 ANTONARAKIS ET AL.1316192225283
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428 ANTONARAKIS ET AL.Figure 5. Sam
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430 ANTONARAKIS ET AL.POPULATION VA
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432 JORGENSEN ET AL.tive small mole
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434 JORGENSEN ET AL.FLAG-tagged pro
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436 JORGENSEN ET AL.visualization t
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438 JORGENSEN ET AL.AArp2/3 Complex
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Pathway40S440 JORGENSEN ET AL.ANutr
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442 JORGENSEN ET AL.Giaever G., Chu
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Genomic Disorders: Genome Architect
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GENOME ARCHITECTURE AND GENOMIC DIS
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Human Versus Chimpanzee Chromosome-
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HUMAN VS. CHIMP CHROMOSOME COMPARIS
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HUMAN VS. CHIMP CHROMOSOME COMPARIS
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Novel Transcriptional Units and Unc
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TRANSCRIPTIONAL UNITS AND GENE PAIR
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mtDNA Variation, Climatic Adaptatio
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mtDNA VARIATION 473Figure 3. Region
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ANALYSIS OF ADAPTIVE SELECTION FORR
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mtDNA VARIATION 477Figure 8. Temper
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Positive Selection in the Human Gen
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HUMAN-SPECIFIC EVOLUTIONARY CHANGES
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488 UNDERHILLorigin episodes, each
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490 UNDERHILLhaplogroups C through
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492 UNDERHILLO (Fig. 2e) that share
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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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