Hotspots of mutation and breakage in dog and human chromosomes

Abstract

Sequencing of the dog genome allows an investigation of the location-dependent evolutionary processes that occurred since the common ancestor of primates and carnivores, ∼95 million years ago. We investigated variations in G+C nucleotide fraction and synonymous nucleotide substitution rates (K s ) across dog and human genomes. Our results show that dog genes located either in subtelomeric and pericentromeric regions, or in short synteny blocks, possess significantly elevated G+C fraction and K s values. Human subtelomeric, but not pericentromeric, genes also exhibit these elevations. We then examined 1.048 Gb of human sequence that is likely not to have been located near a primate telomere at any time since the common ancestor of dog and human. We observed that regions of highest G+C or K s ("hotspots"; median sizes of 0.5 or 1.3 Mb, respectively) within this sequence were preferentially segregated to dog subtelomeres and pericentromeres during the rearrangements that eventually gave rise to the extant canine karyotype. Our data cannot be accounted for solely on the basis of gradually elevating G+C fractions in subtelomeric regions as a consequence of biased gene conversion. Rather, we propose that high G+C sequences are found preferentially within dog subtelomeres as a direct consequence of chromosomal fission occurring more frequently within regions elevated in G+C.

Genome sequence, comparative analysis and haplotype structure of the domestic dog

“…We also observed a significant increase in divergence and GþC content in interstitial regions that are sites of syntenic breakpoints 54,56 ( Supplementary Fig. S7).…”

“…This regional variation shows significant correlation in orthologous windows across the dog, human and mouse genomes, but the strength of the correlation seems to decrease with total branch length (pair-wise correlation for orthologous 1-Mb windows: Spearman's rho ¼ 0.49 for dog-human and 0.24 for dog-mouse comparisons). Lineage-specific variation in the regional divergence rates may be coupled with changes in factors such as sequence composition or chromosomal position 23,54 . Consistent with this, the ratios of lineage-specific divergence rates in orthologous windows are positively correlated with the ratios of current GþC content in the same windows (Spearman's rho ¼ 0.16 for dog-human, 0.24 for dog-mouse).…”

Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

“…Segmental duplication. In human and other eutherians, segmental duplications (defined as pairs of regions with $90% sequence similarity over $1 kb) are associated with chromosomal fragility and syntenic breakpoints 55,56 . The relative karyotypic stability of metatherians therefore indicated that they might have a low proportion of segmental duplications.…”

Supernumerary chromosomes on Southern European populations of the cockle Cerastoderma edule: Consequence of environmental pollution?

“…Hence, in a recent study, Webber and Ponting (2005) proposed the occurrence of ''hotspots'' of mutation and breakage in dog and human chromosomes.…”