The Genom of Homo sapiens.pdf

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EVOLUTION OF EUKARYOTIC GENES AND INTRONS 297Table 1. Conservation of Intron Positions in Orthologous Gene Sets from Eight Eukaryotic SpeciesNumber of species 1 2 3 4 5 6 7 8Number of introns - total observed a 13,406 2,047 719 275 104 25 1 0expected 21,368 33 0 0 0 0 0 0expected - 10% 20,083 662 8 0 0 0 0 0Number of introns - conserved blocks observed a 5,446 1,122 411 163 74 19 1 0expected 9,982 42 0 0 0 0 0 0expected - 10% 8,613 689 25 0 0 0 0 0a The probability that intron sharing in different species was due to chance, p(Monte Carlo)
298 ROGOZIN ET AL.Dm Ag Hs Ce Sc Sp At Pf147156137194184477798735152471971200146307-87933379524471386279224835-Figure 4. Parsimonious evolutionary scenario of introngain/loss for the most likely topology of the eukaryotic phylogenetictree. Intron gains and losses are mapped to each speciesand each internal branch. The designations are as in Fig. 3. Thespecies abbreviations are as in Fig. 1, with the addition ofAnopheles gambiae (Ag) and Plasmodium falciparum (Pf).ancestral introns seem to have survived in plants and animals,but have been lost in yeasts, nematodes, andarthropods.We examined the evolutionary dynamics of introns ingreater detail by using phylogenetic analysis. To this end,intron positions were represented as a data matrix of intronpresence/absence (encoded as 1/0) and the matricesfor all analyzed KOGs were concatenated to produce onealignment, which consisted of 16,577 columns of “ones”and “zeroes” (7,236 columns in conserved portions ofalignments). In this form, the intron presence/absencedata are conducive to evolutionary parsimony analysisand, of the existing parsimony approaches, Dollo parsimonyseems to be most appropriate in this case (Nei andKumar 2000). The Dollo parsimony tree that we reconstructedfrom the matrix of intron presence/absence obviouslydid not mimic the species tree, with humans andArabidopsis forming a strongly supported cluster embeddedwithin the metazoan clade, and another anomalouscluster formed by yeast S. pombe and Plasmodium (notshown). Other phylogenetic approaches, including unweightedmaximum parsimony and several distancemethods, which were applied to the data of Table 2, reproducedthe same, incorrect topology (not shown). Thetopology of these trees supported the notion, already suggestedby the pair-wise comparisons summarized inTable 2, that ancestral introns have been, to a large extent,conserved in plants and vertebrates, but have been extensivelyeliminated in fungi, nematodes, and arthropods.Clustering of Plasmodium with S. pombe, to the exclusionof the other yeast species, S. cerevisiae, seems to bedue to the fact that Plasmodium shared approximately asmany introns with S. pombe as with worm and insects, butthe total number of introns in S. pombe was substantiallyless than in animals (Table 2). Thus, conservaton of intronpositions does not seem to be a good source of informationfor inferring phylogenetic relationships at longevolutionary distances.Having shown that evolution of introns in eukaryoticgenes did not follow the species tree, we applied Dolloparsimony in the opposite direction: Given a species treetopology, construct the most parsimonious scenario forthe evolution of gene structure, i.e., the distribution of introngain and loss events over the tree branches. This approachis completely analogous to the construction of thescenario for gene gain and loss described above.The resulting scenario suggests an intron-rich ancestorfor the crown group, with limited intron loss in the animalancestor, but massive losses in yeasts (particularly, S.cerevisiae), worm, and insects (Fig. 4). The differences inthe relative rates of intron gain and loss in the terminalbranches are remarkable: There is a huge excess of gainsover losses in humans and S. pombe, and equally obviousexcess of losses in insects and S. cerevisiae, whereas C.elegans shows nearly identical numbers of gains andlosses. All introns shared by Plasmodium and any of thecrown-group species (at least 210 as shown by analysis ofcomplete alignments) are assigned to the last common ancestorof alveolates and the crown group, which livedsome 1.5–2.0 billion years ago (Hedges 2002). At present,loss of ancestral introns in Plasmodium cannot bedocumented because Plasmodium is the outgroup to thecrown-group species; neither can losses be assigned tothe internal branch that leads to the ancestor of the crowngroup. Hence, we produced a conservative estimate of thenumber of the most ancient introns in the analyzed geneset, which is likely to be a substantial underestimate,given that Plasmodium is a parasite with a highly degradedgenome and low intron density. Sequencing andanalysis of genomes of other early branching eukaryotesis expected to substantially increase the number of intronsthat have survived since the dawn of eukaryotic evolution.The present analysis pushes the origin of numerousspliceosomal introns back to the stage of eukaryotic evolution,1.5–2.0 billion years ago, which precedes the originof multicellularity, perhaps to the very point of originof eukaryotes. Furthermore, as many as 25–30% of the intronsin vertebrates and plants are apparently inheritedfrom the common ancestor of the crown group. Othercrown-group lineages experienced massive loss of introns.Intron elimination had been extensive already inthe common ancestor of yeasts but was particularly catastrophicin S. cerevisiae, which apparently lost all ancestralintrons. Those few introns that this organism doeshave are not shared with other species and probably havebeen regained secondarily (Table 2 and Fig. 4). More unexpectedly,insects and, particularly, the nematode havealso lost the great majority of the ancestral introns, withthe latter having secondarily acquired numerous new introns(Fig. 4).Why have so many ancestral introns survived nearly 2billion years of evolution? One explanation would involvefunctional roles of introns in specific positions, butthere seems to be no evidence in support of such a possibility.The second and more likely explanation is thatelimination of introns, particularly in highly conservedgenes, which are often essential (such as those included inthe present study), would often lead to gene inactivationand lethality. We found that ancient introns tend to be locatedin more highly conserved portions of genes than recentlyinserted ones (data not shown), which is compati-143
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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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Page 273 and 274: 266 ROE ET AL.noncoding regions. On
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Page 277 and 278: 270 ROE ET AL.aNovel gene KIAA0819[
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Page 283 and 284: 276 JAILLON ET AL.Detection of Evol
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Page 291 and 292: 284 OVCHARENKO AND LOOTSdivergent r
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Page 295 and 296: 288 OVCHARENKO AND LOOTSsequencing
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Page 300 and 301: Evolution of Eukaryotic Gene Repert
Page 302 and 303: EVOLUTION OF EUKARYOTIC GENES AND I
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Page 351 and 352: 344 HARDISON ET AL.cific chromosoma
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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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