Reconstructing contiguous regions of an ancestral genome

Abstract

This article analyzes mammalian genome rearrangements at higher resolution than has been published to date. We identify 3171 intervals, covering ∼92% of the human genome, within which we find no rearrangements larger than 50 kilobases (kb) in the lineages leading to human, mouse, rat, and dog from their most recent common ancestor. Combining intervals that are adjacent in all contemporary species produces 1338 segments that may contain large insertions or deletions but that are free of chromosome fissions or fusions as well as inversions or translocations >50 kb in length. We describe a new method for predicting the ancestral order and orientation of those intervals from their observed adjacencies in modern species. We combine the results from this method with data from chromosome painting experiments to produce a map of an early mammalian genome that accounts for 96.8% of the available human genome sequence data. The precision is further increased by mapping inversions as small as 31 bp. Analysis of the predicted evolutionary breakpoints in the human lineage confirms certain published observations but disagrees with others. Although only a few mammalian genomes are currently sequenced to high precision, our theoretical analyses and computer simulations indicate that our results are reasonably accurate and that they will become highly accurate in the foreseeable future. Our methods were developed as part of a project to reconstruct the genome sequence of the last ancestor of human, dogs, and most other placental mammals.[Supplemental material is available online at www.genome.org and http://www.bx.psu.edu/miller_lab/.]Using computer simulations, we have shown (Blanchette et al. 2004) that the genome sequence of the so-called Boreoeutherian ancestor ( Fig. 1) can be computationally predicted at high accuracy within most euchromatic intervals that are free of large-scale rearrangements, given adequate data from living mammals. For instance, when sequences from 20 appropriately chosen mammalian species are available, we expect that >98% of the reconstructed nucleotides will be identical to the corresponding ancestral base. Because all mammals have experienced large-scale genomic rearrangements since their last common ancestor, in order to determine regional correspondence we analyze these rearrangements to infer a partition of each genome into intervals where nucleotide-level reconstruction methods can be applied.The regional correspondence between modern and ancestral chromosomes has been predicted with increasing accuracy by a number of groups using a variety of methods. Currently, the main experimental technique is chromosomal painting (for surveys, see Wienberg 2004 andFroenicke et al. 2006), in which fluorescently labeled chromosomes from one species are hybridized to chromosomes from another species. Although the requirement of optical visibility means that the cytogenetic approach can recognize only rearrangements with conserved segments longer than 4 Mb (Froenicke et al. 2006) and cannot identify intrachrom...

Whole-genome sequencing of the snub-nosed monkey provides insights into folivory and evolutionary history

“…To investigate the properties of these breakpoints, we explored 50-kb intervals centered on the ends of each conserved segment where the adjacent segments in the ancestor and target species differed. As in the mouse and human genomes 6 , the breakpoint regions in GSM were enriched for protein-coding genes (13.80 genes/Mb in breakpoint regions versus 7.64 genes/Mb in the whole genome), segmental duplication regions (12.78 in breakpoint regions versus 1.43 in the whole genome) and especially for repeat elements (Supplementary Table 15), suggesting that the occurrence of chromosome breakage in mammalian genomes is not random.…”

Analysis of Gene Order Evolution Beyond Single-Copy Genes

“…Chaining ancestral syntenies in an "optimal" and non-ambiguous way, to form a set of Contiguous Ancestral Regions (CARs) [78].…”

“…The first formal method based on this approach was developed by Ma et al [78]. In this algorithm: (i) Syntenies are adjacencies; (ii) Sets of PASs at a given internal node are computed by the Fitch parsimony algorithm (see Figure 6.…”

“…Using a more relaxed definition of synteny, Chauve and Tannier [31] developed an alternative "model-free" methodology with the following properties: (i) Syntenies are defined as a combination of maximum common intervals, unsigned adjacencies and approximate common intervals; (ii) a group of genomic markers is potentially contiguous in an ancestral genome (form a PAS) if it is contiguous in at least two extant species whose evolutionary path on the phylogenetic tree goes through the ancestral node being considered; (iii) a weight is attributed to each PAS following the weighting scheme used in [78]; (iv) at a given ancestral node, all PASs are encoded by a 0/1 matrix M, where each row i represents a given synteny S i , each column a given marker j, and M(i, j) = 1 if marker j belongs to S i , and 0 otherwise. Then, an approach known in graph theory as the Consecutive Ones problem (C1P) [47] is used: if the matrix can be reordered to satisfy C1P, then the set of syntenies has no conflicts, and the C1P ordering of M can be translated directly into a set of ancestral CARs.…”

Reconstructing Ancestral Genomic Orders Using Binary Encoding and Probabilistic Models

“…The problem of searching the longest path in such a graph by visiting each gene's head and tail exactly once is indeed NP-hard as shown in Tang and Wang's study [16]. As a trade-off for time efficiency in dealing with large-scale datasets, we adopted the same greedy algorithm used in Ma's work [18] to connect adjacencies into contiguous ancestral regions.…”