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Sudoku Puzzle Paradigm Used to Facilitate DNA Sequence Pooling

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Not just for your grandmother anymore, Sudoku, the widely popular numerical logic puzzle, may have a place in your genomics toolbox. A team of researchers at Cold Spring Harbor Laboratory cobbled together "DNA Sudoku" that allows them to combine tens of thousands of samples and their sequences to be determined simultaneously.

Normally, researchers would use multiplexing to shuffle together and sequence a large number of DNA samples simultaneously. This involves tagging each sample with a barcode and then mixing them all together. However, this is not a cheap approach and it takes a considerable amount of time as more and more samples are involved in the study.

"We all know that next-gen sequencers have deep sequencing capacity, but when we try to take just the genotype — the short region but in many segments — until now, it wasn't feasible," says Yaniv Erlich, a graduate student in Gregory Hannon's lab at Cold Spring Harbor and first author on the DNA Sudoku paper. "But people devised methods in which they put unique barcode to each one of the specimens [and] it works great when you have hundreds of specimens but it doesn't scale more than that."

To address this limitation, Erlich and his colleagues decided to mix the samples into specific patterns to create pools of samples. But rather than having to tag each and every sample in a pool, they tagged each pool in its entirety with a barcode. They named the approach DNA Sudoku because the logic used in their pooling approach is just like the rules of Sudoku.

And if this all seems a bit too theoretical, think again. The group has teamed up with Dor Yeshorim, a New York-based organization that collects DNA from orthodox Jewish teenagers, in an effort to prevent genetic diseases common to these communities, such as Tay-Sachs or cystic fibrosis. Each teenager is genotyped and receives a six-digit number but is not told his or her genetic results in order to avoid a stigma, says Erlich. When they are old enough for their marriages to be arranged, the families of the possible bride and groom combine both parties' numbers into a 12-digit number. They then call a hotline, give the 12-digit number and then they get a result — either compatible or incompatible.

"We started a collaboration with them and we would like to do the same thing but with next-gen sequencing; currently they do it with regular ABI and other genotyping methods," says Erlich. "We would like to take thousands of specimens from them and to use our pooling strategy plus next-gen sequence to genotype those specimens, and we think that we can do it with even one run of a Illumina Genome Analyzer."

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