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Recurring genomic breaks in independent lineages support genomic fragility.

Hinsch H, Hannenhalli S - BMC Evol. Biol. (2006)

Bottom Line: We do this by quantifying the extent to which certain genomic regions are disrupted repeatedly in independent lineages.Furthermore, the fragile regions are enriched for segmental duplications.Based on a novel methodology, our work provides additional support for the existence of fragile regions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Penn Center for Bioinformatics, University of Pennsylvania, Philadelphia, PA, USA. hhinsch@yahoo.com <hhinsch@yahoo.com>

ABSTRACT

Background: Recent findings indicate that evolutionary breaks in the genome are not randomly distributed, and that certain regions, so-called fragile regions, are predisposed to breakages. Previous approaches to the study of genomic fragility have examined the distribution of breaks, as well as the coincidence of breaks with segmental duplications and repeats, within a single species. In contrast, we investigate whether this regional fragility is an inherent genomic characteristic and is thus conserved over multiple independent lineages.

Results: We do this by quantifying the extent to which certain genomic regions are disrupted repeatedly in independent lineages. Our investigation, based on Human, Chimp, Mouse, Rat, Dog and Chicken, suggests that the propensity of a chromosomal region to break is significantly correlated among independent lineages, even when covariates are considered. Furthermore, the fragile regions are enriched for segmental duplications.

Conclusion: Based on a novel methodology, our work provides additional support for the existence of fragile regions.

Show MeSH
The scheme to detect independent breakage of a region. (a) The region between human markers X and Y is conserved in chimpanzee, dog and chicken but is disrupted in mouse and rat. (b) Under the assumption of parsimony, all species breaks between X and Y can be explained by a single break in the rodent lineage (denoted by the dashed line). The region between human markers A and B in (a) is conserved in mouse, dog and chicken but disrupted in chimpanzee and rat. This can only be explained by two 'independent' breaks in chimpanzee and rat lineages (denoted by dotted lines).
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Figure 1: The scheme to detect independent breakage of a region. (a) The region between human markers X and Y is conserved in chimpanzee, dog and chicken but is disrupted in mouse and rat. (b) Under the assumption of parsimony, all species breaks between X and Y can be explained by a single break in the rodent lineage (denoted by the dashed line). The region between human markers A and B in (a) is conserved in mouse, dog and chicken but disrupted in chimpanzee and rat. This can only be explained by two 'independent' breaks in chimpanzee and rat lineages (denoted by dotted lines).

Mentions: Our main methodological contribution is the way in which we assess the fragility. Consider a set of markers common to the 6 species in Figure 1. Given two species, successive markers are either consecutive in the same orientation in both the species (adjacent), or not (a break). If the markers in the two species are adjacent, and yet if in a third species the markers are not adjacent, then we assert, using a parsimony argument, that the break occurred in the lineage between that third species and its ancestor on the unique evolutionary path between the two species. If we now examine a fourth species and find that it too shows a break, yet does not share a common branch with the other broken genome then we assert that we have identified two independent breaks of the same ancestral sequence (see Figure 1). (A similar idea was used to localize a break within the mouse-specific lineage or a rodent lineage (common to mouse and rat) in three species [8].) Given a genome wide set of markers homologous in multiple species (but in different order and orientation), we study the overall prevalence of fragile regions by measuring the frequency of breaks of the same region in multiple independent lineages and by comparing this frequency against a model which accounts for possible covariates such as region length and functional class (by removing exons from our analysis). Our results, based on an analysis using two different models and a large parameter space, suggest that the propensity of a chromosomal region to break is significantly correlated among independent lineages. Besides making a methodological contribution, our result provides further evidence for fragile regions, indicates that fragility is at least in part an inherent attribute of a chromosomal region, and further indicates this attribute is conserved across long evolutionary periods spanning multiple lineages. Consistent with previous studies, the fragile regions, detected using our alternative approach, are enriched for segmental duplications, although based on a small sample.


Recurring genomic breaks in independent lineages support genomic fragility.

Hinsch H, Hannenhalli S - BMC Evol. Biol. (2006)

The scheme to detect independent breakage of a region. (a) The region between human markers X and Y is conserved in chimpanzee, dog and chicken but is disrupted in mouse and rat. (b) Under the assumption of parsimony, all species breaks between X and Y can be explained by a single break in the rodent lineage (denoted by the dashed line). The region between human markers A and B in (a) is conserved in mouse, dog and chicken but disrupted in chimpanzee and rat. This can only be explained by two 'independent' breaks in chimpanzee and rat lineages (denoted by dotted lines).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1636669&req=5

Figure 1: The scheme to detect independent breakage of a region. (a) The region between human markers X and Y is conserved in chimpanzee, dog and chicken but is disrupted in mouse and rat. (b) Under the assumption of parsimony, all species breaks between X and Y can be explained by a single break in the rodent lineage (denoted by the dashed line). The region between human markers A and B in (a) is conserved in mouse, dog and chicken but disrupted in chimpanzee and rat. This can only be explained by two 'independent' breaks in chimpanzee and rat lineages (denoted by dotted lines).
Mentions: Our main methodological contribution is the way in which we assess the fragility. Consider a set of markers common to the 6 species in Figure 1. Given two species, successive markers are either consecutive in the same orientation in both the species (adjacent), or not (a break). If the markers in the two species are adjacent, and yet if in a third species the markers are not adjacent, then we assert, using a parsimony argument, that the break occurred in the lineage between that third species and its ancestor on the unique evolutionary path between the two species. If we now examine a fourth species and find that it too shows a break, yet does not share a common branch with the other broken genome then we assert that we have identified two independent breaks of the same ancestral sequence (see Figure 1). (A similar idea was used to localize a break within the mouse-specific lineage or a rodent lineage (common to mouse and rat) in three species [8].) Given a genome wide set of markers homologous in multiple species (but in different order and orientation), we study the overall prevalence of fragile regions by measuring the frequency of breaks of the same region in multiple independent lineages and by comparing this frequency against a model which accounts for possible covariates such as region length and functional class (by removing exons from our analysis). Our results, based on an analysis using two different models and a large parameter space, suggest that the propensity of a chromosomal region to break is significantly correlated among independent lineages. Besides making a methodological contribution, our result provides further evidence for fragile regions, indicates that fragility is at least in part an inherent attribute of a chromosomal region, and further indicates this attribute is conserved across long evolutionary periods spanning multiple lineages. Consistent with previous studies, the fragile regions, detected using our alternative approach, are enriched for segmental duplications, although based on a small sample.

Bottom Line: We do this by quantifying the extent to which certain genomic regions are disrupted repeatedly in independent lineages.Furthermore, the fragile regions are enriched for segmental duplications.Based on a novel methodology, our work provides additional support for the existence of fragile regions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Penn Center for Bioinformatics, University of Pennsylvania, Philadelphia, PA, USA. hhinsch@yahoo.com <hhinsch@yahoo.com>

ABSTRACT

Background: Recent findings indicate that evolutionary breaks in the genome are not randomly distributed, and that certain regions, so-called fragile regions, are predisposed to breakages. Previous approaches to the study of genomic fragility have examined the distribution of breaks, as well as the coincidence of breaks with segmental duplications and repeats, within a single species. In contrast, we investigate whether this regional fragility is an inherent genomic characteristic and is thus conserved over multiple independent lineages.

Results: We do this by quantifying the extent to which certain genomic regions are disrupted repeatedly in independent lineages. Our investigation, based on Human, Chimp, Mouse, Rat, Dog and Chicken, suggests that the propensity of a chromosomal region to break is significantly correlated among independent lineages, even when covariates are considered. Furthermore, the fragile regions are enriched for segmental duplications.

Conclusion: Based on a novel methodology, our work provides additional support for the existence of fragile regions.

Show MeSH