Harvard Medicine

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Genome Expressionism

‘Oligopaints’ allow researchers to probe virtually any sequenced region

Photo: Brian Beliveau, Eric Joyce, and Nicholas ApostolopoulosSequencing genomes, from those of simple organisms to those of creatures as complex as humans, produces torrents of information that grow as technical advances push down the cost of generating genetic data. But researchers’ ability to study the chemical nature of DNA has outstripped their ability to actually “see” chromosomes and their position in the nucleus. Yet knowing how chromosomes fold or stretch is critical to understanding gene expression and also has implications for understanding congenital abnormalities as well as cancer.

A new tool, called oligopaints, may change the imbalance between what can be sequenced and what can be seen. By developing renewable, highly specific fluorescent probes that can “paint” the genome, a research team led by Ting Wu, an HMS professor of genetics, has produced a low-cost, high-resolution method for bringing chromosomes to light. The team reported its findings in the December 26, 2012, issue of Proceedings of the National Academy of Sciences.

“There have been some fantastic technologies that have given people a molecular handle on how chromosomes are folded—these involve looking at millions of cells at once,” Wu says. “What people are also hankering for is the ability to see every nucleus for itself.”

Scientists have long used chemical stains to view chromosomes in the nucleus, but such methods did not provide the precision needed to detect the nuclear arrangement and integrity of individual chromosomes. To light up chromosomes, a paint technique called fluorescent in situ hybridization was developed, but it has remained both laborious and expensive. Wu’s lab focused on lowering the cost of painting by employing easily made oligonucleotides, which are short, single-stranded DNA sequences. The probes they developed contain as few as 32 bases, compared to the 100 bases or more of other methods, and can target any sequenced region of the genome along a chromosome. Each oligopaint probe carries single-fluorophore primers, so it lights up at only one point, allowing for greater precision in super-resolution microscopy and image interpretation.

One of the goals of Wu’s lab is to make chromosomal analysis as inexpensive as a blood test. Such a test could potentially be used to screen newborns for congenital abnormalities or to guide treatment for cancer patients. The lab has thus far been working in fruit flies and human cell lines, but the principle could apply to any organism, including humans.