Abstract
BackgroundLarge-scale genome rearrangements brought about by chromosome breaks underlie numerous inherited diseases, initiate or promote many cancers and are also associated with karyotype diversification during species evolution. Recent research has shown that these breakpoints are nonrandomly distributed throughout the mammalian genome and many, termed "evolutionary breakpoints" (EB), are specific genomic locations that are "reused" during karyotypic evolution. When the phylogenetic trajectory of orthologous chromosome segments is considered, many of these EB are coincident with ancient centromere activity as well as new centromere formation. While EB have been characterized as repeat-rich regions, it has not been determined whether specific sequences have been retained during evolution that would indicate previous centromere activity or a propensity for new centromere formation. Likewise, the conservation of specific sequence motifs or classes at EBs among divergent mammalian taxa has not been determined.ResultsTo define conserved sequence features of EBs associated with centromere evolution, we performed comparative sequence analysis of more than 4.8 Mb within the tammar wallaby, Macropus eugenii, derived from centromeric regions (CEN), euchromatic regions (EU), and an evolutionary breakpoint (EB) that has undergone convergent breakpoint reuse and past centromere activity in marsupials. We found a dramatic enrichment for long interspersed nucleotide elements (LINE1s) and endogenous retroviruses (ERVs) and a depletion of short interspersed nucleotide elements (SINEs) shared between CEN and EBs. We analyzed the orthologous human EB (14q32.33), known to be associated with translocations in many cancers including multiple myelomas and plasma cell leukemias, and found a conserved distribution of similar repetitive elements.ConclusionOur data indicate that EBs tracked within the class Mammalia harbor sequence features retained since the divergence of marsupials and eutherians that may have predisposed these genomic regions to large-scale chromosomal instability.
Highlights
Large-scale genome rearrangements brought about by chromosome breaks underlie numerous inherited diseases, initiate or promote many cancers and are associated with karyotype diversification during species evolution
Defined regions of the tammar wallaby genome Previous studies have shown that junctions between conserved chromosome segments in the tammar wallaby (Macropus eugenii) karyotype, as defined by reciprocal chromosome painting [17], carry the kangaroo endogenous retrovirus, KERV [18]
In an effort to expand on the previous breakpoint map, a tammar wallaby bacterial artificial chromosome (BAC) library was screened with the gag open reading frame of KERV [18]
Summary
Large-scale genome rearrangements brought about by chromosome breaks underlie numerous inherited diseases, initiate or promote many cancers and are associated with karyotype diversification during species evolution. While genome instability and chromosome heterozygosity are often the immediate results of such genomic change [4,5,6], propagation in the germ line and subsequent fixation leading to species-specific karyotypes are potential outcomes [7,8] Each of these specific rearrangements, interchromosomal translocations, deletions or intrachromosomal inversions, requires double stranded breaks. The genetic sequences associated with, and mechanisms responsible for, these breaks and rearrangements are not well understood Tracking these chromosomal rearrangements in both species evolution and disease progression has led to a better understanding of the trajectory and character of chromosome segments during periods of instability
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