Limits...
Expansion of stochastic expression repertoire by tandem duplication in mouse Protocadherin-α cluster.

Kaneko R, Abe M, Hirabayashi T, Uchimura A, Sakimura K, Yanagawa Y, Yagi T - Sci Rep (2014)

Bottom Line: Tandem duplications are concentrated within the Pcdh cluster throughout vertebrate evolution and as copy number variations (CNVs) in human populations, but the effects of tandem duplication in the Pcdh cluster remain elusive.Interestingly, the 5'-located duplicated Pcdh-αc2, which is constitutively expressed in the wild-type brain, shifted to stochastic expression accompanied by increased DNA methylation.These results demonstrate that tandem duplication in the Pcdh cluster expands the stochastic expression repertoire irrespective of sequence divergence.

View Article: PubMed Central - PubMed

Affiliation: Bioresource center, Gunma University Graduate School of Medicine.

ABSTRACT
Tandem duplications are concentrated within the Pcdh cluster throughout vertebrate evolution and as copy number variations (CNVs) in human populations, but the effects of tandem duplication in the Pcdh cluster remain elusive. To investigate the effects of tandem duplication in the Pcdh cluster, here we generated and analyzed a new line of the Pcdh cluster mutant mice. In the mutant allele, a 218-kb region containing the Pcdh-α2 to Pcdh-αc2 variable exons with their promoters was duplicated and the individual duplicated Pcdh isoforms can be disctinguished. The individual duplicated Pcdh-α isoforms showed diverse expression level with stochastic expression manner, even though those have an identical promoter sequence. Interestingly, the 5'-located duplicated Pcdh-αc2, which is constitutively expressed in the wild-type brain, shifted to stochastic expression accompanied by increased DNA methylation. These results demonstrate that tandem duplication in the Pcdh cluster expands the stochastic expression repertoire irrespective of sequence divergence.

Show MeSH
Model for the expansion of stochastic Pcdh-α expression via tandem duplication.(a) Hypothetical evolutionary history from an ancestral single Pcdh gene. (b) Hypothetical evolutionary history from clustered Pcdh-α genes. Tandem duplication (orange shading) creates duplicated exons in the Pcdh-α cluster. Both of the duplicate stochastically expressed Pcdh-α isoforms (those with black-grey arrows) retain their stochastic expression. In contrast, from constitutively expressed isoforms (thick red arrow), the 3′-located duplicated Pcdh-α maintains its constitutive expression, but the 5′-located one shifts to stochastic expression accompanied by higher DNA methylation. Mutations in exons and/or regulatory sequences generate diverse coding exons, pseudogenes, and altered gene regulatory systems. Boxes, Pcdh-α exons. Dotted box, pseudogene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4151104&req=5

f7: Model for the expansion of stochastic Pcdh-α expression via tandem duplication.(a) Hypothetical evolutionary history from an ancestral single Pcdh gene. (b) Hypothetical evolutionary history from clustered Pcdh-α genes. Tandem duplication (orange shading) creates duplicated exons in the Pcdh-α cluster. Both of the duplicate stochastically expressed Pcdh-α isoforms (those with black-grey arrows) retain their stochastic expression. In contrast, from constitutively expressed isoforms (thick red arrow), the 3′-located duplicated Pcdh-α maintains its constitutive expression, but the 5′-located one shifts to stochastic expression accompanied by higher DNA methylation. Mutations in exons and/or regulatory sequences generate diverse coding exons, pseudogenes, and altered gene regulatory systems. Boxes, Pcdh-α exons. Dotted box, pseudogene.

Mentions: Tandem duplications are concentrated within the Pcdh cluster throughout vertebrate evolution and as CNVs in human populations31920, but the effects of tandem duplication in the Pcdh cluster remain elusive. Here we revealed a critical role for tandem duplication in the Pcdh cluster gene regulation. The individual duplicated Pcdh-α isoforms showed diverse expression level with stochastic expression manner, even though those have an identical promoter sequence. Interestingly, the 5′-located duplicated Pcdh-αc2, which is constitutively expressed in the wild-type brain, shifted to stochastic expression upon tandem duplication, accompanied by increased DNA methylation. These observations suggest that tandem duplication has been beneficial for the acquisition of the stochastic expression and the expansion of its repertoire through vertebrate evolution and in human populations (Fig. 7).


Expansion of stochastic expression repertoire by tandem duplication in mouse Protocadherin-α cluster.

Kaneko R, Abe M, Hirabayashi T, Uchimura A, Sakimura K, Yanagawa Y, Yagi T - Sci Rep (2014)

Model for the expansion of stochastic Pcdh-α expression via tandem duplication.(a) Hypothetical evolutionary history from an ancestral single Pcdh gene. (b) Hypothetical evolutionary history from clustered Pcdh-α genes. Tandem duplication (orange shading) creates duplicated exons in the Pcdh-α cluster. Both of the duplicate stochastically expressed Pcdh-α isoforms (those with black-grey arrows) retain their stochastic expression. In contrast, from constitutively expressed isoforms (thick red arrow), the 3′-located duplicated Pcdh-α maintains its constitutive expression, but the 5′-located one shifts to stochastic expression accompanied by higher DNA methylation. Mutations in exons and/or regulatory sequences generate diverse coding exons, pseudogenes, and altered gene regulatory systems. Boxes, Pcdh-α exons. Dotted box, pseudogene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151104&req=5

f7: Model for the expansion of stochastic Pcdh-α expression via tandem duplication.(a) Hypothetical evolutionary history from an ancestral single Pcdh gene. (b) Hypothetical evolutionary history from clustered Pcdh-α genes. Tandem duplication (orange shading) creates duplicated exons in the Pcdh-α cluster. Both of the duplicate stochastically expressed Pcdh-α isoforms (those with black-grey arrows) retain their stochastic expression. In contrast, from constitutively expressed isoforms (thick red arrow), the 3′-located duplicated Pcdh-α maintains its constitutive expression, but the 5′-located one shifts to stochastic expression accompanied by higher DNA methylation. Mutations in exons and/or regulatory sequences generate diverse coding exons, pseudogenes, and altered gene regulatory systems. Boxes, Pcdh-α exons. Dotted box, pseudogene.
Mentions: Tandem duplications are concentrated within the Pcdh cluster throughout vertebrate evolution and as CNVs in human populations31920, but the effects of tandem duplication in the Pcdh cluster remain elusive. Here we revealed a critical role for tandem duplication in the Pcdh cluster gene regulation. The individual duplicated Pcdh-α isoforms showed diverse expression level with stochastic expression manner, even though those have an identical promoter sequence. Interestingly, the 5′-located duplicated Pcdh-αc2, which is constitutively expressed in the wild-type brain, shifted to stochastic expression upon tandem duplication, accompanied by increased DNA methylation. These observations suggest that tandem duplication has been beneficial for the acquisition of the stochastic expression and the expansion of its repertoire through vertebrate evolution and in human populations (Fig. 7).

Bottom Line: Tandem duplications are concentrated within the Pcdh cluster throughout vertebrate evolution and as copy number variations (CNVs) in human populations, but the effects of tandem duplication in the Pcdh cluster remain elusive.Interestingly, the 5'-located duplicated Pcdh-αc2, which is constitutively expressed in the wild-type brain, shifted to stochastic expression accompanied by increased DNA methylation.These results demonstrate that tandem duplication in the Pcdh cluster expands the stochastic expression repertoire irrespective of sequence divergence.

View Article: PubMed Central - PubMed

Affiliation: Bioresource center, Gunma University Graduate School of Medicine.

ABSTRACT
Tandem duplications are concentrated within the Pcdh cluster throughout vertebrate evolution and as copy number variations (CNVs) in human populations, but the effects of tandem duplication in the Pcdh cluster remain elusive. To investigate the effects of tandem duplication in the Pcdh cluster, here we generated and analyzed a new line of the Pcdh cluster mutant mice. In the mutant allele, a 218-kb region containing the Pcdh-α2 to Pcdh-αc2 variable exons with their promoters was duplicated and the individual duplicated Pcdh isoforms can be disctinguished. The individual duplicated Pcdh-α isoforms showed diverse expression level with stochastic expression manner, even though those have an identical promoter sequence. Interestingly, the 5'-located duplicated Pcdh-αc2, which is constitutively expressed in the wild-type brain, shifted to stochastic expression accompanied by increased DNA methylation. These results demonstrate that tandem duplication in the Pcdh cluster expands the stochastic expression repertoire irrespective of sequence divergence.

Show MeSH