Punctuating the genome.
Recently Natalia Broude, an ENG research assistant professor at the Center for Advanced Biotechnology, was searching through DNA for specific sequences related to her research when she perceived an unexpected pattern. She enlisted the help of Lingang Zhang, an ENG postdoctoral research assistant. Using a rigorous computational analysis, Zhang supported Broude’s hypothesis: that she had spotted genomic punctuation marks, common characteristics that define transcriptional boundaries, or the beginnings and ends of sequences that control a particular cell process. Further analysis by a research team that also includes ENG Biomedical Engineering Professors Simon Kasif and Charles Cantor confirmed the hypothesis.
Double-stranded DNA is composed of two types of linked molecular pairs — either guanine and cytosine (GC) or adenine and thymine (AT). GC pairs are one and a half times stronger than AT pairs, because three hydrogen bonds hold them together, as opposed to AT’s two. The researchers found that a sharp increase or decrease in the concentration of GC bonds in an area indicates a transcriptional boundary. Correlation between DNA AT/GC content and biological functions has been long suspected, but never subjected to a detailed analysis on a level of thousands of genes.
The researchers analyzed the genomes of six species: humans, mice, rats, chickens, fruit flies, and roundworms. They found that in the four vertebrate species a strong upward spike in the number of GC links indicated the beginning of a transcription sequence, and a strong downward spike in the number of such links marked the end. In the invertebrates (fruit flies and roundworms), the beginning was marked by an upward spike closely followed by a downward spike, and the end by a downward spike followed by an upward spike.
Now that the researchers have confirmed the pattern in silico — by computational methods — Broude and Zhang plan to design laboratory experiments to test if features defined by the patterns on DNA can be linked with specific biological functions. Being able to easily define and find functional genomic sequences will aid researchers to understand how changes in the genome composition affect gene expression and may ultimately lead to a new understanding of the root causes of diseases.
This research was reported in the November 17 issue of the Proceedings of the National Academy of Sciences.
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