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Characterization and prediction of haploinsufficiency using systems-level gene properties in yeast.

Norris M, Lovell S, Delneri D - G3 (Bethesda) (2013)

Bottom Line: Variation in gene copy number can significantly affect organism fitness.In this work, we identified associations between Saccharomyces cerevisiae gene properties and genome-scale haploinsufficiency phenotypes from previous work.Additionally, haploinsufficiency showed negative relationships with cell cycle regulation and promoter sequence conservation.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, Lancashire, M13 9PT, United Kingdom.

ABSTRACT
Variation in gene copy number can significantly affect organism fitness. When one allele is missing in a diploid, the phenotype can be compromised because of haploinsufficiency. In this work, we identified associations between Saccharomyces cerevisiae gene properties and genome-scale haploinsufficiency phenotypes from previous work. We compared the haploinsufficiency profiles against 23 gene properties and found that genes with higher level of connectivity (degree) in a protein-protein interaction network, higher genetic interaction degree, greater gene sequence conservation, and higher protein expression were significantly more likely to be haploinsufficient. Additionally, haploinsufficiency showed negative relationships with cell cycle regulation and promoter sequence conservation.

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Relationships between HI and non-HI gene properties for Sz. pombe in rich medium. (A) The p-values testing the difference between HI and non-HI gene property value distributions. These are on a log10 scale and are as estimated by the Mann-Whitney U-test. The vertical line shows a p-value of 0.05. (B) Mean z-scores of HI (red) and non-HI (blue) gene properties. Error bars represent the SEM. (C) The receiver-operating characteristic (ROC) area under curve (AUC) distributions. These were generated using cross-validation (see Materials and Methods). Whiskers represent the lowest point within 1.5 interquartile range (IQR) of the lower quartile and the highest point within 1.5 IQR of the upper quartile. Dots represent outliers of the aforementioned ranges. The vertical line in the center of the chart represents the random expectation for the ROC plot.
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fig6: Relationships between HI and non-HI gene properties for Sz. pombe in rich medium. (A) The p-values testing the difference between HI and non-HI gene property value distributions. These are on a log10 scale and are as estimated by the Mann-Whitney U-test. The vertical line shows a p-value of 0.05. (B) Mean z-scores of HI (red) and non-HI (blue) gene properties. Error bars represent the SEM. (C) The receiver-operating characteristic (ROC) area under curve (AUC) distributions. These were generated using cross-validation (see Materials and Methods). Whiskers represent the lowest point within 1.5 interquartile range (IQR) of the lower quartile and the highest point within 1.5 IQR of the upper quartile. Dots represent outliers of the aforementioned ranges. The vertical line in the center of the chart represents the random expectation for the ROC plot.

Mentions: In addition to our work performed on S. cerevisiae, we examined the available HI data for Sz. pombe (Kim et al. 2010). In particular, we looked at relationships between HI and DNA sequence conservation, PPI degree from BioGRID (Stark 2006), and predicted GI degree from a recent study (Koch et al. 2012). Other biological properties were not examined because of unavailability of comprehensive data in Sz. pombe. To determine gene sequence conservation, we compared the ORF sequence data between Sz. pombe and two closely related species, Sz. octosporus and Sz. cryophilus. Using genome annotations, we performed ORF alignments and calculated sequence conservation statistics before comparing these statistics against Sz. pombe HI data. Interestingly, we found significant positive associations with HI for DNA and protein sequence identity between Sz. pombe and both Sz. octosporus and Sz. cryophilus, although correlation between HI and dN/dS was insignificant (Figure 6). We also found a significant moderate positive relationship between HI and PPI degree. The association between HI and predicted GI degree was not significant. In general, these preliminary results suggest that our HI prediction method based on the biological properties of the cell could be applied to other microorganisms.


Characterization and prediction of haploinsufficiency using systems-level gene properties in yeast.

Norris M, Lovell S, Delneri D - G3 (Bethesda) (2013)

Relationships between HI and non-HI gene properties for Sz. pombe in rich medium. (A) The p-values testing the difference between HI and non-HI gene property value distributions. These are on a log10 scale and are as estimated by the Mann-Whitney U-test. The vertical line shows a p-value of 0.05. (B) Mean z-scores of HI (red) and non-HI (blue) gene properties. Error bars represent the SEM. (C) The receiver-operating characteristic (ROC) area under curve (AUC) distributions. These were generated using cross-validation (see Materials and Methods). Whiskers represent the lowest point within 1.5 interquartile range (IQR) of the lower quartile and the highest point within 1.5 IQR of the upper quartile. Dots represent outliers of the aforementioned ranges. The vertical line in the center of the chart represents the random expectation for the ROC plot.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815059&req=5

fig6: Relationships between HI and non-HI gene properties for Sz. pombe in rich medium. (A) The p-values testing the difference between HI and non-HI gene property value distributions. These are on a log10 scale and are as estimated by the Mann-Whitney U-test. The vertical line shows a p-value of 0.05. (B) Mean z-scores of HI (red) and non-HI (blue) gene properties. Error bars represent the SEM. (C) The receiver-operating characteristic (ROC) area under curve (AUC) distributions. These were generated using cross-validation (see Materials and Methods). Whiskers represent the lowest point within 1.5 interquartile range (IQR) of the lower quartile and the highest point within 1.5 IQR of the upper quartile. Dots represent outliers of the aforementioned ranges. The vertical line in the center of the chart represents the random expectation for the ROC plot.
Mentions: In addition to our work performed on S. cerevisiae, we examined the available HI data for Sz. pombe (Kim et al. 2010). In particular, we looked at relationships between HI and DNA sequence conservation, PPI degree from BioGRID (Stark 2006), and predicted GI degree from a recent study (Koch et al. 2012). Other biological properties were not examined because of unavailability of comprehensive data in Sz. pombe. To determine gene sequence conservation, we compared the ORF sequence data between Sz. pombe and two closely related species, Sz. octosporus and Sz. cryophilus. Using genome annotations, we performed ORF alignments and calculated sequence conservation statistics before comparing these statistics against Sz. pombe HI data. Interestingly, we found significant positive associations with HI for DNA and protein sequence identity between Sz. pombe and both Sz. octosporus and Sz. cryophilus, although correlation between HI and dN/dS was insignificant (Figure 6). We also found a significant moderate positive relationship between HI and PPI degree. The association between HI and predicted GI degree was not significant. In general, these preliminary results suggest that our HI prediction method based on the biological properties of the cell could be applied to other microorganisms.

Bottom Line: Variation in gene copy number can significantly affect organism fitness.In this work, we identified associations between Saccharomyces cerevisiae gene properties and genome-scale haploinsufficiency phenotypes from previous work.Additionally, haploinsufficiency showed negative relationships with cell cycle regulation and promoter sequence conservation.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, Lancashire, M13 9PT, United Kingdom.

ABSTRACT
Variation in gene copy number can significantly affect organism fitness. When one allele is missing in a diploid, the phenotype can be compromised because of haploinsufficiency. In this work, we identified associations between Saccharomyces cerevisiae gene properties and genome-scale haploinsufficiency phenotypes from previous work. We compared the haploinsufficiency profiles against 23 gene properties and found that genes with higher level of connectivity (degree) in a protein-protein interaction network, higher genetic interaction degree, greater gene sequence conservation, and higher protein expression were significantly more likely to be haploinsufficient. Additionally, haploinsufficiency showed negative relationships with cell cycle regulation and promoter sequence conservation.

Show MeSH