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Kaitlin E Samocha - One of the best experts on this subject based on the ideXlab platform.

  • quantifying prion disease penetrance using large Population Control cohorts
    Science Translational Medicine, 2016
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Karol Estrada, Kaitlin E Samocha, Fah J Sathirapongsasuti, Cory Y Mclean
    Abstract:

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance—the probability that a carrier of the purported disease-causing genotype will indeed develop the disease—is generally unknown. We assess the impact of variants in the prion protein gene ( PRNP ) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 Population Control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the Population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

  • quantifying prion disease penetrance using large Population Control cohorts
    Science Translational Medicine, 2016
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Karol Estrada, Kaitlin E Samocha, Monkol Lek
    Abstract:

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 Population Control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the Population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

Eric Vallabh Minikel - One of the best experts on this subject based on the ideXlab platform.

  • quantifying prion disease penetrance using large Population Control cohorts
    Science Translational Medicine, 2016
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Karol Estrada, Kaitlin E Samocha, Fah J Sathirapongsasuti, Cory Y Mclean
    Abstract:

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance—the probability that a carrier of the purported disease-causing genotype will indeed develop the disease—is generally unknown. We assess the impact of variants in the prion protein gene ( PRNP ) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 Population Control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the Population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

  • quantifying prion disease penetrance using large Population Control cohorts
    Science Translational Medicine, 2016
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Karol Estrada, Kaitlin E Samocha, Monkol Lek
    Abstract:

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 Population Control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the Population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

Sonia M Vallabh - One of the best experts on this subject based on the ideXlab platform.

  • quantifying prion disease penetrance using large Population Control cohorts
    Science Translational Medicine, 2016
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Karol Estrada, Kaitlin E Samocha, Fah J Sathirapongsasuti, Cory Y Mclean
    Abstract:

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance—the probability that a carrier of the purported disease-causing genotype will indeed develop the disease—is generally unknown. We assess the impact of variants in the prion protein gene ( PRNP ) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 Population Control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the Population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

  • quantifying prion disease penetrance using large Population Control cohorts
    Science Translational Medicine, 2016
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Karol Estrada, Kaitlin E Samocha, Monkol Lek
    Abstract:

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 Population Control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the Population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

Karol Estrada - One of the best experts on this subject based on the ideXlab platform.

  • quantifying prion disease penetrance using large Population Control cohorts
    Science Translational Medicine, 2016
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Karol Estrada, Kaitlin E Samocha, Fah J Sathirapongsasuti, Cory Y Mclean
    Abstract:

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance—the probability that a carrier of the purported disease-causing genotype will indeed develop the disease—is generally unknown. We assess the impact of variants in the prion protein gene ( PRNP ) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 Population Control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the Population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

  • quantifying prion disease penetrance using large Population Control cohorts
    Science Translational Medicine, 2016
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Karol Estrada, Kaitlin E Samocha, Monkol Lek
    Abstract:

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 Population Control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the Population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

Frances H Arnold - One of the best experts on this subject based on the ideXlab platform.

  • long term monitoring of bacteria undergoing programmed Population Control in a microchemostat
    Science, 2005
    Co-Authors: Frederick K Balagadde, Lingchong You, Frances H Arnold, Carl L Hansen, Stephen R Quake
    Abstract:

    Using an active approach to preventing biofilm formation, we implemented a microfluidic bioreactor that enables long-term culture and monitoring of extremely small Populations of bacteria with single-cell resolution. We used this device to observe the dynamics of Escherichia coli carrying a synthetic “Population Control” circuit that regulates cell density through a feedback mechanism based on quorum sensing. The microfluidic bioreactor enabled long-term monitoring of unnatural behavior programmed by the synthetic circuit, which included sustained oscillations in cell density and associated morphological changes, over hundreds of hours.

  • long term monitoring of bacteria undergoing programmed Population Control in a microchemostat
    Science, 2005
    Co-Authors: Frederick K Balagadde, Frances H Arnold, Carl L Hansen, Stephen R Quake
    Abstract:

    Using an active approach to preventing biofilm formation, we implemented a microfluidic bioreactor that enables long-term culture and monitoring of extremely small Populations of bacteria with single-cell resolution. We used this device to observe the dynamics of Escherichia coli carrying a synthetic “Population Control” circuit that regulates cell density through a feedback mechanism based on quorum sensing. The microfluidic bioreactor enabled long-term monitoring of unnatural behavior programmed by the synthetic circuit, which included sustained oscillations in cell density and associated morphological changes, over hundreds of hours.

  • Programmed Population Control by cell-cell communication and regulated killing
    Nature, 2004
    Co-Authors: Lingchong You, Robert Sidney Cox, Ron Weiss, Frances H Arnold
    Abstract:

    De novo engineering of gene circuits inside cells is extremely difficult, and efforts to realize predictable and robust performance must deal with noise in gene expression and variation in phenotypes between cells. Here we demonstrate that by coupling gene expression to cell survival and death using cell–cell communication, we can programme the dynamics of a Population despite variability in the behaviour of individual cells. Specifically, we have built and characterized a ‘Population Control’ circuit that autonomously regulates the density of an Escherichia coli Population. The cell density is broadcasted and detected by elements from a bacterial quorum-sensing system, which in turn regulate the death rate. As predicted by a simple mathematical model, the circuit can set a stable steady state in terms of cell density and gene expression that is easily tunable by varying the stability of the cell–cell communication signal. This circuit incorporates a mechanism for programmed death in response to changes in the environment, and allows us to probe the design principles of its more complex natural counterparts.