DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage

Abstract

Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.

Figure 1. Landscapes of human chromosome 17 and mouse chromosome 11

Approximate alignments of ideograms of the two chromosomes are shown in the centre of the figure, with red lines showing the relationships between orthologous genes. From top to bottom for each organism, tracks show gene density (in genes per Mb), G+C content on a scale from 35–65%, and densities of LINEs (red) and SINEs (blue) (fraction of bases). The vertical dashed line represents the approximate boundary between the distal region of mouse chromosome 11, which has shared synteny with human chromosome 17, and the proximal region, which does not. Chr, chromosome.

Figure 2. Syntenic relationship between mouse, human and the ancestral chromosome

a, Conserved syntenic blocks of 100 kb or more between human chromosome 17 (Hs17), mouse chromosome 11 (Mm11), and a most parsimonious primate–rodent ancestor (Anc) reconstructed using dog and opossum as outgroups. b, An enlargement of the CMT1A/SMS region and the mouse orthologous sequence (human 14–22 Mb, mouse 59–64 Mb), including conserved syntenic blocks of 10 kb or more between human and mouse, and human segmental duplications of 20 kb or more. Segmental duplications are shown above the human CMT1A/SMS line. Duplications with copies outside the enlarged region connect to 17q in a. Coloured blocks marked ‘C’ represent CMT1A duplicons, and those marked ‘S’ represent SMS duplicons. In both sections, direct (reference strand to reference strand) blocks of conserved synteny or segmental duplication are shown in blue; inverted blocks are shown in green. Chromosome blocks are labelled in megabases. The black circle indicates the location of the human chromosome 17 centromere.

Figure 3. Duplication landscape of chromosome 17 and its association with breaks in conserved synteny

The top line shows genes/breakpoints of interest for rearrangements mentioned in the text. Black triangles show the locations of the nine remaining gaps in the build. Below that, coloured triangles show breaks in synteny (blue for human, green for mouse, pink for dog). Intrachromosomal duplications are shown as an all-versus-all dot plot, coloured by class (class 1 in red, class 2 in green, class 3 in blue, all other classes in black; see Methods). Breaks in conserved synteny are represented as vertical bands coloured as above. The centromere is shown as a vertical dark grey band. Triangles at the bottom show core element locations (class 1 core elements in red, class 2 core elements in green), with direction showing orientation (up, forward strand; down, reverse strand). The panel at the bottom shows a density plot of intrachromosomal (blue) and interchromosomal (red) duplication, using 50-kb non-overlapping sliding windows.