When is less more? When a smaller part of the genome - the exome that contains the DNA record for the protein coding part of the genome - can be read at greater "coverage" than a whole genome, said researchers from Baylor College of Medicine.
In a report that appears online in the open access journal Genome Medicine, researchers compared sequencing technologies on the genetic code of a single person with the genetic disease Charcot-Marie-Tooth disease. They found that they could reliably identify that genetic variation behind this disease by sequencing the coding regions alone - the exome - as well as resolve previous ambiguities.
While whole genome sequencing has gained popularity because it captures the entirety of an individual’s genome sequence as opposed to exome sequencing, it is a larger proposition and is often done at less "coverage" than the exome. Coverage refers to how many times the sequencing is done over each genome letter. When coverage is 12X, it means that a particular letter in the DNA is read by 12 fragments of the total sequence.
"Exomes are a good approach until we can provide genomes in which the information is presented at much greater coverage," said Dr. Claudia Gonzaga-Jauregui, a postdoctoral fellow in the laboratory of Dr. James Lupski, vice chair of molecular and human genetics at BCM, who holds the Cullen Foundation Endowed Chair in Molecular Genetics. "The genome gives you more information, but we would still want to provide it at greater coverage. Therefore, exomes are a good alternative."
In sequencing the whole genome and exome of the person with Charcot-Marie-Tooth, Lupski, colleague Dr. Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center, who holds the Wofford Cain Chair in Molecular and Human Genetics, and others used a variety of technologies. Lupski said that both the genome and exome methods found 12 variants that affect the ways cells respond to specific drugs in this patient as well as identify the novel mutations in the gene SH3TC2 that encodes a protein with a role in the way nerves in the periphery of the body are covered with a myelin sheath.
Because the exome sequencing was at a higher coverage, there were fewer false positives than with whole genome sequencing. It enabled the correct identification of ambiguous nucleotides - the adenine (A), thymine (T), guanine (G) and cytosine (C) that make up the genetic code and determine whether they were associated with a disease or drug metabolism.
Gibbs said the exome sequencing was a superior approach and not a “shortcut” in determining who has a disease and which drugs might work.
Others who took part in this work include Yaping Yang; Matthew N. Bainbridge; Shalini Jhangiani; Christian J. Buhay; Christie L. Kovar; Min Wang; Alicia C. Hawes; Jeffrey G. Reid; Christine Eng and Donna M. Muzny, all of BCM.
Funding for this work came from the National Institute of Neurological Disorders and Stroke (NINDS) (grant R01NS058529), and the National Human Genome Research Institute (NHGRI) (grants U54HG006542 and U54HG003273).