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Mayhew M.B.,Program in Computational Biology and Bioinformatics | Hartemink A.J.,Program in Computational Biology and Bioinformatics | Hartemink A.J.,Duke University
Proceedings - International Symposium on Biomedical Imaging | Year: 2013

High-resolution, multimodal microscopy grants an intimate view of the inner workings of cells. Complex processes like cell division can be monitored with microscope images, assuming identification of cells and their cell-cycle markers: cellular structures indicative of cell-cycle progress. Here, we explore how spatial relationships between these markers can facilitate their identification. We grew and synchronized Saccharomyces cerevisiae cell cultures and then acquired multimodal image data as the cells proceeded through the cell cycle. We trained a conditional random field model to capture pixel-level spatial relationships among three different cell-cycle markers observable in our images. We observed good predictive performance of this pixel-level model on three held-out test images, and performance improved when we used marker-level information from our training data to prune model predictions. Our results support the use of conditional random fields in bioimage labeling and encourage the use of as much multiscale information as available in training data when identifying cell-cycle markers. © 2013 IEEE. Source

Abyzov A.,Program in Computational Biology and Bioinformatics | Abyzov A.,Yale University | Iskow R.,Brigham and Womens Hospital | Iskow R.,Harvard University | And 16 more authors.
Genome Research | Year: 2013

In primates and other animals, reverse transcription of mRNA followed by genomic integration creates retroduplications. Expressed retroduplications are either "retrogenes" coding for functioning proteins, or expressed "processed pseudogenes," which can function as noncoding RNAs. To date, little is known about the variation in retroduplications in terms of their presence or absence across individuals in the human population. We have developed new methodologies that allow us to identify "novel" retroduplications (i.e., those not present in the reference genome), to find their insertion points, and to genotype them. Using these methods, we catalogued and analyzed 174 retroduplication variants in almost one thousand humans, which were sequenced as part of Phase 1 of The 1000 Genomes Project Consortium. The accuracy of our data set was corroborated by (1) multiple lines of sequencing evidence for retroduplication (e.g., depth of coverage in exons vs. introns), (2) experimental validation, and (3) the fact that we can reconstruct a correct phylogenetic tree of human subpopulations based solely on retroduplications. We also show that parent genes of retroduplication variants tend to be expressed at the M-to-G1 transition in the cell cycle and that M-to-G1 expressed genes have more copies of fixed retroduplications than genes expressed at other times. These findings suggest that cell division is coupled to retrotransposition and, perhaps, is even a requirement for it. © 2013 Abyzov et al. Source

Sisu C.,Program in Computational Biology and Bioinformatics | Sisu C.,Yale University | Pei B.,Program in Computational Biology and Bioinformatics | Leng J.,Program in Computational Biology and Bioinformatics | And 13 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Pseudogenes are degraded fossil copies of genes. Here, we report a comparison of pseudogenes spanning three phyla, leveraging the completed annotations of the human, worm, and fly genomes, which we make available as an online resource. We find that pseudogenes are lineage specific, much more so than proteincoding genes, reflecting the different remodeling processes marking each organism's genome evolution. The majority of human pseudogenes are processed, resulting from a retrotranspositional burst at the dawn of the primate lineage. This burst can be seen in the largely uniform distribution of pseudogenes across the genome, their preservation in areas with low recombination rates, and their preponderance in highly expressed gene families. In contrast, worm and fly pseudogenes tell a story of numerous duplication events. In worm, these duplications have been preserved through selective sweeps, so we see a large number of pseudogenes associated with highly duplicated families such as chemoreceptors. However, in fly, the large effective population size and high deletion rate resulted in a depletion of the pseudogene complement. Despite large variations between these species, we also find notable similarities. Overall, we identify a broad spectrum of biochemical activity for pseudogenes, with the majority in each organism exhibiting varying degrees of partial activity. In particular, we identify a consistent amount of transcription (~15%) across all species, suggesting a uniform degradation process. Also, we see a uniform decay of pseudogene promoter activity relative to their coding counterparts and identify a number of pseudogenes with conserved upstream sequences and activity, hinting at potential regulatory roles. © 2014 PNAS. Source

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