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First Whole Genome Sequencing of Entire Family

Collaborating institutions, including the Institute for Systems Biology (ISB), Complete Genomics, the University of Washington, and the University of Utah, have sequenced and analyzed the first whole genomes of a human family of four. The authors said that the benefits of sequencing an entire family include lowering DNA sequencing error rates, identifying rare genetic variants, and identifying disease-linked genes. "We were very pleased and a little surprised at how much additional information can come from examining the full genomes of the same family," said Dr. David Galas, co-corresponding author on the article and senior vice president at ISB. "Comparing the sequences of unrelated individuals is useful, but for a family the results are more accurate. We can now see all the genetic variations, including rare ones, and can construct the inheritance of every piece of the chromosomes, which is critical to understanding the traits important to health and disease. The continuing decline in the difficulty and cost of sequencing now enables us to use these new strategies for deriving genetic information that was too difficult or expensive to access in the past.” A particular family of four with two children with extremely rare genetic diseases turned out to be ideal for the study. Although the parents had no genetic abnormalities, they each carried recessive genes that resulted in their son and daughter being born with two extremely rare conditions--Miller's syndrome and primary ciliary dyskinesia (PCD). Miller's syndrome, a disorder characterized by facial and limb malformations, is thought to occur in perhaps one in one million people and has been diagnosed in only two families in the world, along with a few sporadic other cases. PCD is a condition in which the tiny hair-like structures that are supposed to move mucus out of airways in the lungs do not function. The chances of having PCD are estimated at one in 10,000. The odds of someone having both PCD and Miller's syndrome are less than one in 10 billion, according to co-author Dr. Lynn Jorde professor and chair of the Department of Human Genetics at the University of Utah School of Medicine.

By comparing the variants in the children's DNA sequences with the Human Genome Project database and other public databases, the researchers identified four candidate genes consistent with recessive inheritance of rare variations.

One of the candidate genes (DHODH) had recently been identified by others as the causative gene for Miller’s syndrome in an exome sequencing study (Nature Genetics, January 2010). Variations in a second candidate gene (DNAH5) had previously been shown to cause PCD.

In addition to the candidate gene discoveries, "an important finding is that, by determining the genome sequences of an entire family, one can identify many DNA sequencing errors, and thus greatly increase the accuracy of the data," said Dr. Leroy Hood, the paper's other corresponding author, and co-founder and president of ISB. "This will ultimately help us understand the role of genetic variations in the diagnosis, treatment, and prevention of disease."

Another exciting finding from this study is how much the genome changes from one human generation to the next--the so-called “intergenerational mutation rate.” The researchers found that gene mutations from parent to child occurred at half the most widely estimated rate.

"Comparing the family's sequences to the Human Genome Project allowed us to screen out potential errors in the DNA sequencing process," Dr. Jorde said. "To estimate the mutation rate, we compared the parents' sequences with those of their children. Differences in the sequences that were not caused by sequencing errors were caused by mutations.” By comparing the parents' DNA sequences to those of their children, the researchers estimated with a high degree of certainty that each parent passes 30 mutations—for a total of 60—to their offspring.

Scientists had long estimated that each parent passes 75 gene mutations to their children."That's the kind of power you get from looking at the whole genome," said Dr. Jorde,. "The mutation rate was less than half of what we'd thought."

"This estimate could have implications for how we think about genetic diversity, but more importantly the approach has the potential to increase enormously the power and impact of genetic research," said Dr. Galas. "Our study illustrates the beginning of a new era in which the analysis of a family's genome can aid in the diagnosis and treatment of individual family members. We could soon find that our family's genome sequence will become a normal part of our medical records.”

The study opens the door for numerous other investigations in the future. Dr. Jorde expects researchers will use family sequence analysis to begin narrowing down the genetic causes of more common diseases. And, as the cost of genome sequencing continues to drop—the Human Genome Project cost approximately $3 billion, and now individuals can have their genome sequenced for $5,000 to $10,000—it will become an important part of individual medical records, the authors believe.

“Our results demonstrate the unique value of complete genome sequencing in families,” the researchers said. “We would predict that the information derived from family genomes, along with relevant environmental and medical information, will constitute the medical records of the future."

This whole genome family sequencing study was reported online on March 10, 2010 in Science Express. [Press release 1] [Press release 2] [Press release 3] [Press release 4] [Nature Genetics abstract] [Science Express abstract]