Genomics, transcriptomics, proteomics, big words describing huge, growing sets of data. The challenge, however, lies not so much in adding more and more to these databases, but in extracting from them the information that can be used to explain our complex biology and what makes it sometimes go awry.
In today’s PNAS early online edition, researchers from the labs of John Rioux and Eric Lander at the Whitehead Institute/MIT, together with colleagues from Quebec, Canada, and Odense, Denmark, have done just that. They have combined analysis of several databases to reveal a single gene responsible for a debilitating illness, Leigh syndrome French Canadian type (LSFC). In this disease, a deficiency in cytochrome c oxidase (COX) leads to neurodegeneration in the brainstem and basal ganglia, and often to acute metabolic acidosis and coma. Being the final electron carrier in the respiratory chain, COX is absolutely required to keep oxidative phosphorylation-and us-alive and kicking.
Previous work from the principle author's labs had mapped the candidate gene for LSFC to an approximately two million base pair-region on the short arm of chromosome two. In the present work, the integrative approach of first author Vamsi Mootha et al. combined whole genome analysis of this region with analysis of mitochondrial protein and mRNA databases.
First, by analyzing genome databases, Mootha et al. found 15 distinct genes in the LSFC stretch of chromosome two, but none of them had any known connection to mitochondrial function. The authors then examined each of these genes using large-scale mRNA expression data sets. They found that the expression profile of one of them, LRPPRC, closely matched that of transcripts for mitochondrial proteins, suggesting it may be a likely candidate for the LSFC gene. The icing on the cake came when Mootha et al. generated a proteome database of mitochondrial peptides by mass spectrometry and cross-referenced it to the LSFC gene region. All the mitochondrial peptides that could be coded for in this region of the genome mapped to the same gene, LRPPRC.
To confirm that this gene is indeed responsible for Leigh syndrome, Mootha et al. performed sequencing analysis of patient, carrier, and control DNA samples and found two mutations in LRPPRC, a single base pair transition leading to an alanine to valine substitution in exon 9, and an eight nucleotide deletion in exon 35 leading to truncation of the protein.
While the power of this integrative approach is obvious in this case, there may be shortcomings in applying it to Alzheimer's and other diseases (see comments below by Vamsi Mootha, Gerard Drewes, and Stephen Ginsberg).—Tom Fagan
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- Mootha VK, Lepage P, Miller K, Bunkenborg J, Reich M, Hjerrild M, Delmonte T, Villeneuve A, Sladek R, Xu F, Mitchell GA, Morin C, Mann M, Hudson TJ, Robinson B, Rioux JD, Lander ES. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):605-10. PubMed.