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Constructing Highly Accurate Reference Genomes

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Accurate reference genomes are important for understanding an organism’s biology, learning about the genetic causes of health and disease and, in animals, making breeding decisions.

Making reference genomes for humans and other vertebrates has been costly and time-consuming. Their genomes are too big to be sequenced from end to end in a single step. Instead, DNA must first be broken into smaller pieces. Each piece is then subjected to chemical reactions that allow the identity and order of its base pairs to be deduced. Researchers then read many shorter fragments (of a few hundred or thousand letters each) and assemble the genome, like a puzzle, from these smaller pieces. Gaps and errors are corrected through a labor intensive and expensive finishing process.

A team of researchers developed a new technique for reconstructing highly accurate reference genomes. Dr. Adam M. Phillippy of NIH’s National Human Genome Research Institute (NHGRI) and Drs. Timothy P. Smith and Curtis Van Tassell at the United States Department of Agriculture (USDA) Agricultural Research Service in Clay Center, Nebraska, led the group. The team started with the goat because of the animal’s importance as a food source in developing countries. A goat reference genome had been attempted before, but like many genomes analyzed using past technologies, it was incomplete and highly fragmented. The study appeared online on March 6, 2017, in Nature Genetics.

The scientists analyzed DNA from a male goat named Papadum who descended from animals living on San Clemente Island off the coast of San Diego, California. To create the new reference genome, they combined complimentary methods. A technology called PacBio sequencing allowed for long DNA fragments to be sequenced. Shorter pieces were sequenced to boost accuracy. To link these smaller maps together, the researchers used optical mapping to observe the structure of long, single strands of DNA, and a technique called chromosome interaction mapping (Hi-C) to reconstruct the thread-like structure of folded DNA in the nucleus of each cell.

“PacBio sequencing, optical mapping, and Hi-C have all been used for genome assembly before, but we showed that by combining all of them together, we could get a very comprehensive and accurate map of the genome at an affordable price,” says Dr. Sergey Koren, a senior scientist at NHGRI. “Previous methods have left the chromosomes either incomplete or broken into many pieces, making it very expensive to finish.”

“A finished, accurate goat genome will eventually allow farmers to select and breed animals with essential traits such as high quality milk and meat and the ability to tolerate extreme environments,” USDA’s Smith notes.

“Now that we’ve proven these methods produce high-quality genome reconstructions,” Phillippy says, “they can be applied to the study of genetic diseases in individual human genomes and other animals.”

This article has been republished from materials provided by NIH. Note: material may have been edited for length and content. For further information, please contact the cited source.


Bickhart, D. M., Rosen, B. D., Koren, S., Sayre, B. L., Hastie, A. R., Chan, S., ... & Burton, J. N. (2017). Single-molecule sequencing and chromatin conformation capture enable de novo reference assembly of the domestic goat genome. Nature Research.