hms_3422

hms_3422 - Harvard-MIT Division of Health Sciences and...

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Computing at the Center of Genomic Medicine Isaac S. Kohane Harvard-MIT Division of Health Sciences and Technology HST.512: Genomic Medicine Prof. Isaac Samuel Kohane
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The Challenge of a (Sometimes Forced) Interdisciplinary Pipeline
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Finding the Needle in the Haystack: A Case History Cerebellum has pivotal roles in the coordination of posture and locomotion Laminar organization of the cerebellar cortex has facilitated understanding its basic circuitry, functions and ontogeny
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Sonic Hedgehog (Shh), development and tumorigenesis
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The challenge Find novel members (the needles) of the Shh pathway in a large haystack. The haystack ± Large number of probes ± Whole cerebellum ² ( whole organ, multiple cell types) But the signal of interest is confined to thin superficial layer Can we find the signal in time and space?
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Overall schema Please see Figure 1 of Proc Natl Acad Sci U S A. 2002 Apr 16; 99(8): 5704-9. Identification of genes expressed with temporal-spatial restriction to developing cerebellar neuron precursors by a functional genomic approach. Zhao Q, Kho A, Kenney AM, Yuk Di DI, Kohane I, Rowitch DH. Harvest PN5 Mouse cerebellum Shh Rx 3 or 24 hrs Vehicle 3 or 24 hrs Growth Arrest Affymetrix 11KMu GeneChip analysis Noise Models Bioinformatic Analysis Clone/sequence 9 significantly upregulated genes and 10 genes not significantly upregulated Screen for expression in PN7 EGL by in situ hybridization
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A noise model with triplicate measurements 0.1 0 -8 -6 -4 -2 0 2 4 6 μ + σ 8 10 12 0.2 0.3 0.4 Fold noise and signal distributions a gene, G 1 μ - σ μ 1 1 μ 1 1 Noise Signal G 1 μ μ 1
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What average are we calculating? s 1 s 2 s 3 v 1 v 2 v 3 i = 1 3 3 3 3 1 1 s i v i i = 1
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4 How do you calculate average interest rate? If 4 different interest rates over four years (1+r1)(1+r2)(1+r3)(1+r4) P Q 4 P Q= + r + r + r + r (1 1)(1 2)(1 3)(1 4)
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Biological validation: In situ hybridization Please see Figure 3 of Proc Natl Acad Sci U S A. 2002 Apr 16; 99(8): 5704-9. ± Identification of genes expressed with temporal-spatial restriction to developing ± cerebellar neuron precursors by a functional genomic approach. ± Zhao Q, Kho A, Kenney AM, Yuk Di DI, Kohane I, Rowitch DH. ± 1/2 FP of ratio of means Same sensitivity
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Relevance to Human Disease How can we leverage this developmental view of the mouse?
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This note was uploaded on 03/27/2008 for the course HST 512 taught by Professor Ramoni during the Spring '06 term at MIT.

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hms_3422 - Harvard-MIT Division of Health Sciences and...

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