NEW YORK (GenomeWeb News) – Researchers from the Institute for Systems Biology and elsewhere reported in the early, online version of Science last night that they have used whole-genome sequencing to identify mutations behind a Mendelian condition called Miller syndrome and an inherited lung disorder called ciliary dyskinesia in a family of four.
The team used Complete Genomics' sequencing service to sequence the genomes of two affected siblings and their parents.
"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," co-senior author David Galas, senior vice president for strategic partnerships at ISB, said in a statement.
The study comes on the heels of a related paper by a University of Washington-led research team, appearing in Nature Genetics late last year. For that study, researchers used exome sequencing to find Miller syndrome- and ciliary dyskinesia-related mutations in the same family. That study suggested mutations in a gene called DHODH caused Miller syndrome, while ciliary dyskinesia was due to mutations in a gene called DNAH5.
For the current study, collaborators at Complete Genomics sequenced the genomes of each family member to an average of about 40 times coverage using nanoarray-based short read sequencing-by-ligation technology.
The family-based sequencing approach helped the researchers find an estimated 70 percent of sequencing errors, they reported, making it easier to pick out authentic genetic variants that might play a role in disease.
"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," co-senior author Leroy Hood, ISB's president and co-founder, said in a statement. "This will ultimately help us understand the role of genetic variations in the diagnosis, treatment, and prevention of disease."
Overall, the researchers found 4,471,510 SNPs in the family that are not in the human reference genome.
Their subsequent analyses, which included looking at the distribution of variants between the affected siblings and unaffected parents, helped the team narrow in on mutations in four genes. Three of these — DHODH and DNAH5, which showed up in the exome-sequencing study, and KIAA0556 — fit a compound heterozygote mode of inheritance. Meanwhile, mutations in a gene called CES1 fit a simple recessive model of inheritance.
Along with the disease-related mutations they detected, the team was also able to use the family's genome sequences to begin exploring the DNA mutation rate from one generation to the next.
"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," Galas said. "We could soon find that our family's genome sequence will become a normal part of our medical records."