Current Protocols in Human Genetics

Department of Molecular Physiology & Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 01/2012; Chapter 1:Unit1.10. DOI: 10.1002/0471142905.hg0110s72
Source: PubMed


The recent success of genome-wide association studies has generated a trove of biologically significant variants implicated in human disease. However, many, if not most, of these variants fall in noncoding regions that have traditionally lacked much functional annotation. New data sets and tools allow for a more detailed assessment of potential importance of noncoding genetic variants. An overview of types of regulatory annotation that are currently available, and approaches to analyzing this data are provided with emphasis on usage of the UCSC genome browser.

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    • "With the knowledge of incomplete genomic annotations and several genes of unknown functions in cattle, the functional importance of noncoding regions under evolutionary selective pressure cannot be underestimated. Functional annotation approaches and resources [95] such as, across species comparison for conserved DNA sequences may help further elucidate the uncharacterized selective sweeps of our results. "
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    ABSTRACT: Discerning the traits evolving under neutral conditions from those traits evolving rapidly because of various selection pressures is a great challenge. We propose a new method, composite selection signals (CSS), which unifies the multiple pieces of selection evidence from the rank distribution of its diverse constituent tests. The extreme CSS scores capture highly differentiated loci and underlying common variants hauling excess haplotype homozygosity in the samples of a target population. The data on high-density genotypes were analyzed for evidence of an association with either polledness or double muscling in various cohorts of cattle and sheep. In cattle, extreme CSS scores were found in the candidate regions on autosome BTA-1 and BTA-2, flanking the POLL locus and MSTN gene, for polledness and double muscling, respectively. In sheep, the regions with extreme scores were localized on autosome OAR-2 harbouring the MSTN gene for double muscling and on OAR-10 harbouring the RXFP2 gene for polledness. In comparison to the constituent tests, there was a partial agreement between the signals at the four candidate loci; however, they consistently identified additional genomic regions harbouring no known genes. Persuasively, our list of all the additional significant CSS regions contains genes that have been successfully implicated to secondary phenotypic diversity among several subpopulations in our data. For example, the method identified a strong selection signature for stature in cattle capturing selective sweeps harbouring UQCC-GDF5 and PLAG1-CHCHD7 gene regions on BTA-13 and BTA-14, respectively. Both gene pairs have been previously associated with height in humans, while PLAG1-CHCHD7 has also been reported for stature in cattle. In the additional analysis, CSS identified significant regions harbouring multiple genes for various traits under selection in European cattle including polledness, adaptation, metabolism, growth rate, stature, immunity, reproduction traits and some other candidate genes for dairy and beef production. CSS successfully localized the candidate regions in validation datasets as well as identified previously known and novel regions for various traits experiencing selection pressure. Together, the results demonstrate the utility of CSS by its improved power, reduced false positives and high-resolution of selection signals as compared to individual constituent tests.
    Full-text · Article · Mar 2014 · BMC Genetics
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    • "Currently, there are no features of either the genome or epigenome that can be used to unequivocally identify regulatory elements. Nevertheless, some features, such as DNase hypersensitivity, transcription factor occupancy, and histone modifications, seem to be more reliable indicators of regulatory function than others[26]. Based on our analysis, for ENST0000051354 or RP11-473L15.2, "
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    ABSTRACT: Ventricular septal defects (VSD) are the most common form of congenital heart disease, which is the leading non-infectious cause of death in children; nevertheless, the exact cause of VSD is not yet fully understood. Long non-coding RNAs (lncRNAs) have been shown to play key roles in various biological processes, such as imprinting control, circuitry controlling pluripotency and differentiation, immune responses and chromosome dynamics. Notably, a growing number of lncRNAs have been implicated in disease etiology, although an association with VSD has not been reported. In the present study, we conducted an integrated analysis of dysregulated lncRNAs, focusing specifically on the identification and characterization of lncRNAs potentially involving in initiation of VSD. Comparison of the transcriptome profiles of cardiac tissues from VSD-affected and normal hearts was performed using a second-generation lncRNA microarray, which covers the vast majority of expressed RefSeq transcripts (29,241 lncRNAs and 30,215 coding transcripts). In total, 880 lncRNAs were upregulated and 628 were downregulated in VSD. Furthermore, our established filtering pipeline indicated an association of two lncRNAs, ENST00000513542 and RP11-473L15.2, with VSD. This dysregulation of the lncRNA profile provides a novel insight into the etiology of VSD and furthermore, illustrates the intricate relationship between coding and ncRNA transcripts in cardiac development. These data may offer a background/reference resource for future functional studies of lncRNAs related to VSD.
    Full-text · Article · Oct 2013 · PLoS ONE
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    ABSTRACT: Long noncoding RNAs (lncRNAs) represent a sub-group of noncoding RNAs that are longer than 200 nucleotides. The characterization of lncRNAs and their acceptance as crucial regulators of numerous developmental and biological pathways have suggested that the lncRNA study has gradually become one of the hot topics in the field of RNA biology. Many lncRNAs show spatially and temporally restricted expression patterns during embryogenesis and organogenesis. This study aimed to characterize the lncRNA profile of the fetal mouse heart at 3 key time-points [embryonic day E11.5, E14.5 and E18.5] in its development, by performing a microarray lncRNAs screen. Gene Ontology analysis and Ingenuity Pathway Analysis showed some significant gene functions and pathways were altered in heart development process. We compared lncRNAs profile between the three points [E14.5 vs E11.5(early development); E18.5 vs E14.5(later development)]. A total of 1237 lncRNAs were found to have consistent fold-changes (>2.0) between the 3 time-points. Among them, 20 dysregulated lncRNAs were randomly selected and confirmed by real-time qRT-PCR. Additionally, bioinformatics analysis of AK011347 suggested it may be involved in heart development through the target gene Map3k7. In summary, this study identified differentially expressed lncRNAs in the 3 time-points studied, and these lncRNAs may provide a new clue of mechanism of normal heart development. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    No preview · Article · May 2014 · Journal of Cellular Biochemistry
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