Whole-exome sequencing (WES) is helping physicians diagnose a genetic condition that has defied diagnosis by traditional means. The implication here is that exons in the nuclear genome are sequenced in the hopes that, by comparison with the genomes of nonaffected individuals, a diagnosis might be revealed.
If you were ordering WES for a patient, would you also include an analysis of the patient's mitochondrial genome?

Whole-exome sequencing (WES) is helping physicians diagnose a genetic condition that has defied diagnosis by traditional means. The implication here is that exons in the nuclear genome are sequenced in the hopes that, by comparison with the genomes of nonaffected individuals, a diagnosis might be revealed.

What are the strengths and weaknesses of this approach?

Comparisons between human and chimpanzee genomes indicate that a gene that may function as a wild-type or normal gene in one primate may function as a disease-causing gene in another [The Chimpanzee Sequencing and Analysis Consortium (2005). Nature 437:69–87]. For instance, the PPARG locus (regulator of adipocyte differentiation) is a wild-type allele in chimps but is clearly associated with Type 2 diabetes in humans. What factors might cause this apparent contradiction? Would you consider such apparent contradictions to be rare or common? What impact might such findings have on the use of comparative genomics to identify and design therapies for disease-causing genes in humans?

Genomic sequencing has opened the door to numerous studies that help us understand the evolutionary forces shaping the genetic makeup of organisms. Using databases containing the sequences of 25 genomes, scientists examined the relationship between GC content and global amino acid composition [Kreil, D. P., and Ouzounis, C. A. (2001) Nucl. Acids Res. 29:1608–1615]. They found that it is possible to identify thermophilic species on the basis of their amino acid composition alone, which suggests that evolution in a hot environment selects for a certain whole organism amino acid composition. In what way might evolution in extreme environments influence genome and amino acid composition? How might evolution in extreme environments influence the interpretation of genome sequence data?

Recall that when the HGP was completed, more than 40 percent of the genes identified had unknown functions. The PANTHER database provides access to comprehensive and current functional assignments for human genes (and genes from other species).

Go to http://www.pantherdb.org/data/. In the frame on the left side of the screen locate the 'Quick links' and use the 'Whole genome function views' link to a view of a pie chart of current functional classes for human genes. Mouse over the pie chart to answer these questions. What percentage of human genes encode transcription factors? Cytoskeletal proteins? Transmembrane receptor regulatory/adaptor proteins?