Cell division: A specialized microfluidics device first isolates a single cell (left). Chemicals digest the cell membrane, releasing the chromosomes (middle) and individual chromosomes are captured (right) in a chamber, where they are amplified and analyzed.
Haplotyping also makes it possible to determine a person’s human leukocyte antigen (HLA) type, from immune genes that must be closely matched between donor and recipient in cases of bone marrow or organ transplant. “It’s one of the most polymorphic [variable] parts of human genome,” says Quake. Current methods to determine HLA type generate a list of variations but give no information about which of them lie on which chromosome. “If you don’t keep track of this, you may not able to get a perfect match,” says Quake. “We showed you can measure [the haplotype] and get information that in principle can be used for better matching for bone marrow transplants.”
The technology might also be used to sequence fetal genomes from DNA collected from the mother’s blood, in order to detect genetic abnormalities. (The DNA in the fetal blood is a mix of the mother’s and the child’s, making it particularly difficult to generate a whole genome sequence.)
Beyond medicine, researchers say, haplotype information will aid research in population genetics, such as estimating the size and timing of human expansions and migrations. “You can capture diversity to higher resolution if you have individual chromosomes,” says Nicholas Schork, a geneticist at the Scripps Research Institute who was not involved in either project and wrote a commentary on the research for Nature Biotechnology. “You lose a lot of information if you look at things at a genotype level versus a haplotype level.”
Researchers have been able to statistically infer haplotype for European populations, thanks to the fact that Europeans went through a genetic bottleneck thousands of years ago. (Haplotypes very gradually grow shorter, as the chromosome pairs break and reassemble with each generation. Europeans have long haplotypes that haven’t yet broken down, making them easier to analyze.) But statistical techniques have not worked for African populations, meaning that genetic information for this group is much sparser. For this reason, most of the genome-wide association studies done to date have focused on European populations.
Both approaches add to the cost of genome sequencing, so it’s not clear how quickly they will catch on, Schork says. “Shendure’s approach is one people could likely implement in labs now,” he says. Quake’s approach generates much more complete data—a haplotype that is the length of an entire chromosome—but it is technically more challenging, requiring specialized chips to analyze the single cells. “Single cell sequencing and the ability to separate chromosomes in a dish is complicated,” says Schork. “Unless someone builds an affordable assay, it won’t be used routinely.” Quake says that the chips that his lab and close collaborators use are currently being built at an academic foundry at Stanford. He says, “Perhaps there will be a commercial solution at some point.”