PreprintFor final versionc2003 Cold Spring Harbor Laboratory Press, seeGenome Research 13 (2003), 37–45.Genome Rearrangements in Mammalian Evolution: Lessons fromHuman and Mouse GenomesPavel Pevzner and Glenn TeslerDepartment of Computer Science and Engineering,University of California, San Diego, CAAbstractAlthough analysis of genome rearrangements was pioneered by Dobzhansky and Sturtevant 65 yearsago, we still know very little about the rearrangement events that produced the existing varieties of ge-nomic architectures. The genomic sequences of human and mouse provide evidence for a larger numberof rearrangements than previously thought and shed some light on previously unknown features of mam-malian evolution. In particular, they reveal that a large number of micro-rearrangements is requiredto explain the differences in draft human and mouse sequences. Below we describe a new algorithmfor constructing synteny blocks, study arrangements of synteny blocks in human and mouse, derive amost parsimonious human-mouse rearrangement scenario, and provide evidence that intrachromosomalrearrangements are more frequent than interchromosomal. Our analysis is based on the human-mousebreakpoint graph, which reveals related breakpoints and allows one to find a most parsimonious sce-nario. Since these graphs provide important insights into rearrangement scenarios, we introduce a newvisualization tool that allows one to view breakpoint graphs superimposed with genomic dot-plots.1 IntroductionAnalysis of genome rearrangements in molecular evolution was pioneered by Dobzhansky and Sturtevant,1938 [7], who published a milestone paper with an evolutionary tree presenting a rearrangement scenariowith 17 inversions for the species D. pseudoobscura and D. miranda. Every genome rearrangement studyinvolves solving a combinatorial puzzle to find a series of genome rearrangements to transform one genomeinto another. Palmer and co-authors (Palmer and Herbon, 1988 [26]) pioneered studies of the shortest (mostparsimonious) rearrangement scenarios and applied this approach to plant mtDNA and cpDNA. Since then,the analysis of the most parsimonious scenarios has become the dominant approach in genome rearrange-ment studies. For unichromosomal genomes, it usually amounts to analysis of inversions (also known asreversals), which are the most common rearrangement events. The problem of finding the minimum num-ber of reversals to transform one unichromosomal genome into another is known as the reversal distanceproblem. For multichromosomal genomes, the most common rearrangements are reversals, translocations,fusions, and fissions, and the number of such rearrangements in a most parsimonious scenario is known asthe genomic distance between multichromosomal genomes.Finding the reversal distance is a difficult combinatorial problem. In the very first computational studiesof genome rearrangements, Watterson et al., 1982 [38] and Nadeau and Taylor, 1984 [24] introduced thenotion of a breakpoint (disruption of gene order) and noticed some correlations between the reversal distance1and the number of breakpoints (in fact, Sturtevant and Dobzhansky, 1936 [33] implicitly discussed thesecorrelations 65 years ago!). The shortcoming of early genome rearrangement studies is that they consideredbreakpoints independently without revealing combinatorial dependencies between related breakpoints. Thesimplest example of related breakpoints are two breakpoints formed by a single reversal. Kececioglu andSankoff, 1993 [13] were the first to recognize the importance of dependencies between breakpoints and tocome up with an approximation algorithm for the reversal distance problem. The important result of Bafnaand Pevzner, 1993 [1] is the construction of the breakpoint graph, which reveals related breakpoints andallows one to find the most parsimonious scenarios.Based on the notion of the breakpoint graph, Hannenhalli and Pevzner, 1995 [10] developed a poly-nomial algorithm for the reversal distance problem, i.e., for computing a most parsimonious scenario totransform one unichromosomal genome into another. This approach was further extended to the genomicdistance problem, i.e., finding a most parsimonious scenario for multichromosomal genomes under inver-sions, translocations, fusions, and fissions of chromosomes (Hannenhalli and Pevzner, 1995 [9], Tesler,2002 [35]). However, these results, while useful, do not yet yield a meaningful estimate of the number ofthe rearrangement events on the evolutionary path from mouse to human. The problem is that the genomicsequences provide evidence for both micro-rearrangements (e.g., intrachromosomal rearrangements with aspan below 1 Mb) and macro-rearrangements (e.g., intrachromosomal rearrangements of larger span as wellas interchromosomal rearrangements). The existing rearrangement algorithms do not distinguish betweenthese two types of rearrangements. Since some micro-rearrangements may be caused by fragment assemblyerrors, mixing micro- and macro-rearrangements within one rearrangement scenario may produce a dis-torted picture greatly influenced by the sequencing errors in draft genomic sequences. Another difficulty isan unreliable assignment of orthologs (false orthologs) that may create an impression of a rearrangement thatnever happened (Tatusov et al., [34]). The conserved gene order can also be disrupted by recent duplicationsand insertions (Hardison et al., 1997 [11]).To address these complications we first describe a new approach to synteny block generation that sep-arates micro- from macro-rearrangements. It allows one to study micro- and macro-rearrangements sepa-rately and to arrive at a new estimate of the number of macro-rearrangements that cover about 170 Myr ofevolutionary distance between human and mouse. We also estimate the number of micro-rearrangements(but it remains to be seen to what extent this estimate is influenced by the fragment assembly errors) on theevolutionary path between mouse and human.2 Synteny blocksIn a pioneering paper, Nadeau and Taylor, 1984 [24] introduced the notion of conserved segments (i.e.,segments with preserved gene orders without disruption by rearrangements) and estimated that there areroughly 180 conserved segments in human and mouse. Later, Copeland et al., 1993 [22], DeBry and Seldin,1996 [6], Waterston et al., 2002 [28] and Gregory et al. [32] confirmed these estimates. In the past decade,the progress in understanding the evolutionary
View Full Document
Unlocking...