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Comparative Study
, 16 (12), 1557-65

Reconstructing Contiguous Regions of an Ancestral Genome

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Comparative Study

Reconstructing Contiguous Regions of an Ancestral Genome

Jian Ma et al. Genome Res.

Abstract

This article analyzes mammalian genome rearrangements at higher resolution than has been published to date. We identify 3171 intervals, covering approximately 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.

Figures

Figure 1.
Figure 1.
Position of the Boreoeutherian ancestor. Branch labels give the estimated number of chromosomal breaks from our study, also categorized as (interchromosomal, intrachromosomal). If conserved segments i and j are adjacent in the ancestral genome but not in the descendant genome, then we call the break interchromosomal if i and j are on different chromosomes in the descendant, and intrachromosomal otherwise. We suspect that many of the predicted intrachromosomal breaks in rat are assembly artifacts.
Figure 2.
Figure 2.
(A) Nets. Human is the reference species. The line between intervals indicates that a genomic interval of zero or more unaligned bases exists in the nonreference species between the adjacent intervals (see text). (B) Orthology blocks. (C) Conserved segments, including outgroup nets. The order and orientation of OB2 and OB3 are conserved in all four species, so we merge them into a conserved segment.
Figure 3.
Figure 3.
Length distribution of orthology blocks and conserved segments. Both orthology blocks and conserved segments are grouped into bins of 500 kb. Counts scaled by natural logarithm are plotted against lengths (in Mb).
Figure 4.
Figure 4.
Map of the Boreoeutherian ancestral genome. For lengths of each CAR and corresponding parts in mouse, rat, and dog, see Table 2. Numbers above bars indicate the corresponding human chromosomes. Black tick marks below the bars indicate ambiguous joins (Fig. 7 in Methods; for details, see Supplemental material). Our predicted CARs are colored and ordered to facilitate comparison with Froenicke et al. (2006). Gaps between CARs are joins suggested by Froenicke et al. (2006). Diagonal lines within each block show the orientation and position in the human chromosome (Bourque et al. 2006).
Figure 5.
Figure 5.
Length distribution of predicted inversions in human (A), mouse (B), rat (C), and dog (D). Inversions of lengths >10 kb are not represented in the plots. Inversions lengths are grouped into bins of 250 bp.
Figure 6.
Figure 6.
Detailed map of human chromosome 13q onto CAR 16. There are16 large-scale rearrangement-free pieces. Vertical lines above each piece indicate positions of small in-place inversions. The star indicates an inversion (around hg18.chr13:57,380,591–57,383,765) that happened on the branch from the Boreoeutherian ancestor to the human–rodent ancestor.
Figure 7.
Figure 7.
Three potential ambiguous cases. (A) i has several possible predecessors; (B) i has several possible successors; (C) i forms a cycle with j.

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