A Comparison of 100 Human Genes Using an Alu Element-Based Instability Model

Autor: John T. Fussell, Heath D. Herbold, Jerilyn A. Walker, Cook George W, Matthew G. Bourgeois, Mitchell L. Fullerton, Miriam K. Konkel, Mark A. Batzer
Rok vydání: 2013
Předmět:
Genome instability
lcsh:Medicine
Retrotransposon
Biochemistry
Genome
DNA transposons
Exon
Molecular cell biology
0302 clinical medicine
DNA Breaks
Double-Stranded
Precision Medicine
lcsh:Science
Genome Evolution
Genetics
0303 health sciences
Multidisciplinary
Exons
Genomics
Genome Scans
Retrotransposons
Oncology
Medicine
Transposons
Algorithms
Research Article
Biotechnology
Clinical Research Design
Alu element
Biology
Genomic Instability
Molecular Genetics
03 medical and health sciences
Alu Elements
Genome Analysis Tools
Diagnostic Medicine
Cancer Genetics
Humans
Gene
030304 developmental biology
Clinical Genetics
Evolutionary Biology
Models
Statistical
Models
Genetic
Genome
Human
lcsh:R
Computational Biology
Human Genetics
FANCA
lcsh:Q
Human genome
030217 neurology & neurosurgery
Genes
Neoplasm
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 6, p e65188 (2013)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0065188
Popis: The human retrotransposon with the highest copy number is the Alu element. The human genome contains over one million Alu elements that collectively account for over ten percent of our DNA. Full-length Alu elements are randomly distributed throughout the genome in both forward and reverse orientations. However, full-length widely spaced Alu pairs having two Alus in the same (direct) orientation are statistically more prevalent than Alu pairs having two Alus in the opposite (inverted) orientation. The cause of this phenomenon is unknown. It has been hypothesized that this imbalance is the consequence of anomalous inverted Alu pair interactions. One proposed mechanism suggests that inverted Alu pairs can ectopically interact, exposing both ends of each Alu element making up the pair to a potential double-strand break, or "hit". This hypothesized "two-hit" (two double-strand breaks) potential per Alu element was used to develop a model for comparing the relative instabilities of human genes. The model incorporates both 1) the two-hit double-strand break potential of Alu elements and 2) the probability of exon-damaging deletions extending from these double-strand breaks. This model was used to compare the relative instabilities of 50 deletion-prone cancer genes and 50 randomly selected genes from the human genome. The output of the Alu element-based genomic instability model developed here is shown to coincide with the observed instability of deletion-prone cancer genes. The 50 cancer genes are collectively estimated to be 58% more unstable than the randomly chosen genes using this model. Seven of the deletion-prone cancer genes, ATM, BRCA1, FANCA, FANCD2, MSH2, NCOR1 and PBRM1, were among the most unstable 10% of the 100 genes analyzed. This algorithm may lay the foundation for comparing genetic risks posed by structural variations that are unique to specific individuals, families and people groups.
Databáze: OpenAIRE
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