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Functionally enigmatic genes: a case study of the brain ignorome.

Pandey AK, Lu L, Wang X, Homayouni R, Williams RW - PLoS ONE (2014)

Bottom Line: Surprisingly, ignorome genes do not differ from well-studied genes in terms of connectivity in coexpression networks.The major distinguishing characteristic between these sets of genes is date of discovery, early discovery being associated with greater research momentum--a genomic bandwagon effect.In a majority of cases we have been able to extract and add significant information for these neglected genes.

View Article: PubMed Central - PubMed

Affiliation: UT Center for Integrative and Translational Genomics and Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

ABSTRACT
What proportion of genes with intense and selective expression in specific tissues, cells, or systems are still almost completely uncharacterized with respect to biological function? In what ways do these functionally enigmatic genes differ from well-studied genes? To address these two questions, we devised a computational approach that defines so-called ignoromes. As proof of principle, we extracted and analyzed a large subset of genes with intense and selective expression in brain. We find that publications associated with this set are highly skewed--the top 5% of genes absorb 70% of the relevant literature. In contrast, approximately 20% of genes have essentially no neuroscience literature. Analysis of the ignorome over the past decade demonstrates that it is stubbornly persistent, and the rapid expansion of the neuroscience literature has not had the expected effect on numbers of these genes. Surprisingly, ignorome genes do not differ from well-studied genes in terms of connectivity in coexpression networks. Nor do they differ with respect to numbers of orthologs, paralogs, or protein domains. The major distinguishing characteristic between these sets of genes is date of discovery, early discovery being associated with greater research momentum--a genomic bandwagon effect. Finally we ask to what extent massive genomic, imaging, and phenotype data sets can be used to provide high-throughput functional annotation for an entire ignorome. In a majority of cases we have been able to extract and add significant information for these neglected genes. In several cases--ELMOD1, TMEM88B, and DZANK1--we have exploited sequence polymorphisms, large phenome data sets, and reverse genetic methods to evaluate the function of ignorome genes.

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Expression of ignorome transcripts in the C57BL/6J brain.Pairs of low (scale on the lower left represents 1500 microns) and high (scale on the lower right represents 750 microns) resolution images of C57BL/6J brain sagittal sections (labeled using in situ probes) for six ignorome gene members taken from the Allen Brain Atlas (http://www.brain-map.org/). A) and B) are low and high resolution images showing in situ expression of ZCCHC18 in sagittal sections. C) and D) show expression of FRRS1L. E) and F) show expression of C8orf46 and G) and H) show expression of FAM123C, I) and J) show expression of KIAA2139, and K) and L) show expression of CMTM5.
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pone-0088889-g003: Expression of ignorome transcripts in the C57BL/6J brain.Pairs of low (scale on the lower left represents 1500 microns) and high (scale on the lower right represents 750 microns) resolution images of C57BL/6J brain sagittal sections (labeled using in situ probes) for six ignorome gene members taken from the Allen Brain Atlas (http://www.brain-map.org/). A) and B) are low and high resolution images showing in situ expression of ZCCHC18 in sagittal sections. C) and D) show expression of FRRS1L. E) and F) show expression of C8orf46 and G) and H) show expression of FAM123C, I) and J) show expression of KIAA2139, and K) and L) show expression of CMTM5.

Mentions: Calculation of the ignorome score relied on whole brain gene expression, and as expected 95% of the core has both intense and relatively uniform expression across many brain regions. However, there are interesting exceptions (Figure 3): (1) KIAA1239 has extraordinarily high and selective expression in Purkinje cells, habenula, pyriform cortex, superficial layer 2 of neocortex, and CA3 of hippocampus; (2) C8orf46 has extremely high expression only in cortex (archi-, paleo- and neocortex) but low expression in layer 4 of neocortex and part of CA3; (3) FAM123C has highest expression in granule cells of cerebellum, dentate gyrus, and olfactory bulbs, and finally, (4) FRRS1L has highest expression in Purkinje cells, neocortex, and CA1–3. We also used in situ hybridization images downloaded from the Allen Brain Atlas [14] to evaluate patterns of expression in subsets of easily resolvable cell types (e.g., Purkinje cells, Bergmann glia, astrocytes, dentate gyrus granule cells, pyramidal neurons, and white matter oligodendrocytes). Again, more than 95% of ignorome genes have high expression in neurons (e.g., ZCCHC18 has pan-neuronal expression in Figure 3) and comparatively modest, if any, expression in oligodendrocyte or astrocyte. Only two ignorome genes (SLC39A12, CMTM5) are expressed preferentially in astrocytes, Bergmann glia, and oligodendrocytes (Figure 3).


Functionally enigmatic genes: a case study of the brain ignorome.

Pandey AK, Lu L, Wang X, Homayouni R, Williams RW - PLoS ONE (2014)

Expression of ignorome transcripts in the C57BL/6J brain.Pairs of low (scale on the lower left represents 1500 microns) and high (scale on the lower right represents 750 microns) resolution images of C57BL/6J brain sagittal sections (labeled using in situ probes) for six ignorome gene members taken from the Allen Brain Atlas (http://www.brain-map.org/). A) and B) are low and high resolution images showing in situ expression of ZCCHC18 in sagittal sections. C) and D) show expression of FRRS1L. E) and F) show expression of C8orf46 and G) and H) show expression of FAM123C, I) and J) show expression of KIAA2139, and K) and L) show expression of CMTM5.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921226&req=5

pone-0088889-g003: Expression of ignorome transcripts in the C57BL/6J brain.Pairs of low (scale on the lower left represents 1500 microns) and high (scale on the lower right represents 750 microns) resolution images of C57BL/6J brain sagittal sections (labeled using in situ probes) for six ignorome gene members taken from the Allen Brain Atlas (http://www.brain-map.org/). A) and B) are low and high resolution images showing in situ expression of ZCCHC18 in sagittal sections. C) and D) show expression of FRRS1L. E) and F) show expression of C8orf46 and G) and H) show expression of FAM123C, I) and J) show expression of KIAA2139, and K) and L) show expression of CMTM5.
Mentions: Calculation of the ignorome score relied on whole brain gene expression, and as expected 95% of the core has both intense and relatively uniform expression across many brain regions. However, there are interesting exceptions (Figure 3): (1) KIAA1239 has extraordinarily high and selective expression in Purkinje cells, habenula, pyriform cortex, superficial layer 2 of neocortex, and CA3 of hippocampus; (2) C8orf46 has extremely high expression only in cortex (archi-, paleo- and neocortex) but low expression in layer 4 of neocortex and part of CA3; (3) FAM123C has highest expression in granule cells of cerebellum, dentate gyrus, and olfactory bulbs, and finally, (4) FRRS1L has highest expression in Purkinje cells, neocortex, and CA1–3. We also used in situ hybridization images downloaded from the Allen Brain Atlas [14] to evaluate patterns of expression in subsets of easily resolvable cell types (e.g., Purkinje cells, Bergmann glia, astrocytes, dentate gyrus granule cells, pyramidal neurons, and white matter oligodendrocytes). Again, more than 95% of ignorome genes have high expression in neurons (e.g., ZCCHC18 has pan-neuronal expression in Figure 3) and comparatively modest, if any, expression in oligodendrocyte or astrocyte. Only two ignorome genes (SLC39A12, CMTM5) are expressed preferentially in astrocytes, Bergmann glia, and oligodendrocytes (Figure 3).

Bottom Line: Surprisingly, ignorome genes do not differ from well-studied genes in terms of connectivity in coexpression networks.The major distinguishing characteristic between these sets of genes is date of discovery, early discovery being associated with greater research momentum--a genomic bandwagon effect.In a majority of cases we have been able to extract and add significant information for these neglected genes.

View Article: PubMed Central - PubMed

Affiliation: UT Center for Integrative and Translational Genomics and Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

ABSTRACT
What proportion of genes with intense and selective expression in specific tissues, cells, or systems are still almost completely uncharacterized with respect to biological function? In what ways do these functionally enigmatic genes differ from well-studied genes? To address these two questions, we devised a computational approach that defines so-called ignoromes. As proof of principle, we extracted and analyzed a large subset of genes with intense and selective expression in brain. We find that publications associated with this set are highly skewed--the top 5% of genes absorb 70% of the relevant literature. In contrast, approximately 20% of genes have essentially no neuroscience literature. Analysis of the ignorome over the past decade demonstrates that it is stubbornly persistent, and the rapid expansion of the neuroscience literature has not had the expected effect on numbers of these genes. Surprisingly, ignorome genes do not differ from well-studied genes in terms of connectivity in coexpression networks. Nor do they differ with respect to numbers of orthologs, paralogs, or protein domains. The major distinguishing characteristic between these sets of genes is date of discovery, early discovery being associated with greater research momentum--a genomic bandwagon effect. Finally we ask to what extent massive genomic, imaging, and phenotype data sets can be used to provide high-throughput functional annotation for an entire ignorome. In a majority of cases we have been able to extract and add significant information for these neglected genes. In several cases--ELMOD1, TMEM88B, and DZANK1--we have exploited sequence polymorphisms, large phenome data sets, and reverse genetic methods to evaluate the function of ignorome genes.

Show MeSH
Related in: MedlinePlus