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Overlapping ATP2C1 and ASTE1 genes in human genome: implications for SPCA1 expression?

ABSTRACT: The ATP2C1 gene encodes for the secretory pathway calcium (Ca2+)-ATPase pump (SPCA1), which localizes along the secretory pathway, mainly in the trans-Golgi. The loss of one ATP2C1 allele causes Hailey-Hailey disease in humans but not mice. Examining differences in genomic organization between mouse and human we speculate that the overlap between ATP2C1 and ASTE1 genes only in humans could explain this different response to ATP2C1 dysregulation. We propose that ASTE1, overlapping with ATP2C1 in humans, affects alternative splicing, and potentially protein expression of the latter. If dysregulated, the composition of the SPCA1 isoform pool could diverge from the physiological status, affecting cytosolic Ca2+-signaling, and in turn perturbing cell division, leading to cell death or to neoplastic transformation.

SUBMITTER: Micaroni M

PROVIDER: S-EPMC3565288 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Overlapping ATP2C1 and ASTE1 genes in human genome: implications for SPCA1 expression?

Micaroni Massimo M Malquori Lorenzo L

International journal of molecular sciences 20130104 1

The ATP2C1 gene encodes for the secretory pathway calcium (Ca2+)-ATPase pump (SPCA1), which localizes along the secretory pathway, mainly in the trans-Golgi. The loss of one ATP2C1 allele causes Hailey-Hailey disease in humans but not mice. Examining differences in genomic organization between mouse and human we speculate that the overlap between ATP2C1 and ASTE1 genes only in humans could explain this different response to ATP2C1 dysregulation. We propose that ASTE1, overlapping with ATP2C1 in ...[more]

PMID: 23344038

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Project description:BACKGROUND: Overlapping genes (OGs) are defined as adjacent genes whose coding sequences overlap partially or entirely. In fact, they are ubiquitous in microbial genomes and more conserved between species than non-overlapping genes. Based on this property, we have previously implemented a web server, named OGtree, that allows the user to reconstruct genome trees of some prokaryotes according to their pairwise OG distances. By analogy to the analyses of gene content and gene order, the OG distance between two genomes we defined was based on a measure of combining OG content (i.e., the normalized number of shared orthologous OG pairs) and OG order (i.e., the normalized OG breakpoint distance) in their whole genomes. A shortcoming of using the concept of breakpoints to define the OG distance is its inability to analyze the OG distance of multi-chromosomal genomes. In addition, the amount of overlapping coding sequences between some distantly related prokaryotic genomes may be limited so that it is hard to find enough OGs to properly evaluate their pairwise OG distances. RESULTS: In this study, we therefore define a new OG order distance that is based on more biologically accurate rearrangements (e.g., reversals, transpositions and translocations) rather than breakpoints and that is applicable to both uni-chromosomal and multi-chromosomal genomes. In addition, we expand the term "gene" to include both its coding sequence and regulatory regions so that two adjacent genes whose coding sequences or regulatory regions overlap with each other are considered as a pair of overlapping genes. This is because overlapping of regulatory regions of distinct genes suggests that the regulation of expression for these genes should be more or less interrelated. Based on these modifications, we have reimplemented our OGtree as a new web server, named OGtree2, and have also evaluated its accuracy of genome tree reconstruction on a testing dataset consisting of 21 Proteobacteria genomes. Our experimental results have finally shown that our current OGtree2 indeed outperforms its previous version OGtree, as well as another similar server, called BPhyOG, significantly in the quality of genome tree reconstruction, because the phylogenetic tree obtained by OGtree2 is greatly congruent with the reference tree that coincides with the taxonomy accepted by biologists for these Proteobacteria. CONCLUSIONS: In this study, we have introduced a new web server OGtree2 at http://bioalgorithm.life.nctu.edu.tw/OGtree2.0/ that can serve as a useful tool for reconstructing more precise and robust genome trees of prokaryotes according to their overlapping genes.

Project description:BackgroundHsp70 chaperones are required for key cellular processes and response to environmental changes and survival but they have not been fully characterized yet. The human hsp70-gene family has an unknown number of members (eleven counted over ten years ago); some have been described but the information is incomplete and inconsistent. A coherent body of knowledge encompassing all family components that would facilitate their study individually and as a group is lacking. Nowadays, the study of chaperone genes benefits from the availability of genome sequences and a new protocol, chaperonomics, which we applied to elucidate the human hsp70 family.ResultsWe identified 47 hsp70 sequences, 17 genes and 30 pseudogenes. The genes distributed into seven evolutionarily distinct groups with distinguishable subgroups according to phylogenetic and other data, such as exon-intron and protein features. The N-terminal ATP-binding domain (ABD) was conserved at least partially in the majority of the proteins but the C-terminal substrate-binding domain (SBD) was not. Nine proteins were typical Hsp70s (65-80 kDa) with ABD and SBD, two were lighter lacking partly or totally the SBD, and six were heavier (>80 kDa) with divergent C-terminal domains. We also analyzed exon-intron features, transcriptional variants and protein structure and isoforms, and modality and patterns of expression in various tissues and developmental stages. Evolutionary analyses, including human hsp70 genes and pseudogenes, and other eukaryotic hsp70 genes, showed that six human genes encoding cytosolic Hsp70s and 27 pseudogenes originated from retro-transposition of HSPA8, a gene highly expressed in most tissues and developmental stages.ConclusionThe human hsp70-gene family is characterized by a remarkable evolutionary diversity that mainly resulted from multiple duplications and retrotranspositions of a highly expressed gene, HSPA8. Human Hsp70 proteins are clustered into seven evolutionary Groups, with divergent C-terminal domains likely defining their distinctive functions. These functions may also be further defined by the observed differences in the N-terminal domain.

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Overlapping ATP2C1 and ASTE1 genes in human genome: implications for SPCA1 expression?

Publications

Overlapping ATP2C1 and ASTE1 genes in human genome: implications for SPCA1 expression?

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