Chapter 20, Problem 25
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?
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Dominguez et al. (2004) suggest that by studying genes that determine growth and tissue specification in the eye of Drosophila, much can be learned about human eye development.
What evidence indicates that the eyeless gene is part of a developmental network?
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?
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?
Although a single activator may bind many enhancers in the genome to control several target genes, in many cases, the enhancers have some sequence conservation but are not all identical. Keeping this in mind, consider the following hypothetical example:
- Undifferentiated cells adopt different fates depending on the concentration of activator protein, Act1.
- A high concentration of Act1 leads to cell fate 1, an intermediate level leads to cell fate 2, and low levels to cell fate 3.
- Research shows that Act1 regulates the expression of three different target genes (A, B, and C) with each having an enhancer recognized by Act1 but a slightly different sequence that alters the affinity of Act1 for the enhancer. Act1 has a high affinity for binding the enhancer for gene A, a low affinity for the gene B enhancer, and an intermediate affinity for the gene C enhancer.
From these data, speculate on how Act1 concentrations can specify different cell fates through these three target genes? Furthermore, which target genes specify which fates?
Hereditary spherocytosis (HS) is a disorder characterized by sphere-shaped red blood cells, anemia, and other abnormal traits. Ankyrin-1 (ANK1) is a protein that links membrane proteins to the cytoskeleton. Loss of this activity is associated biochemically to HS. However, Gallagher et al. (2010) (J. Clin. Invest. 120:4453–4465) show that HS can also be caused by mutations within a region from -282 to -101 relative to the transcriptional start site, which lead to constitutive transcriptional repression in erythroid cells due to local chromatin condensation. Propose a hypothesis for the function of the -282 to -101 region of the ANK1 gene.