Mendel's principles of heredity, by W. Bateson

Bateson, William; Mendel, Gregor

doi:10.5962/bhl.title.1057

Cited by 231 publications

(219 citation statements)

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“…Our findings would also provide evidence that complex diseases such as PD can be due to the joint effects of many genes that, taken singly, would show only small effects (additive effects model and epistasis) [40–43]. While the available datasets were exploratory and may have been underpowered to detect the main effects of single SNPs or probe sets, our findings are consistent with recent studies that report greater statistical power to detect the joint effects of multiple loci than the main effects of single loci [44,45].…”

Section: Discussionmentioning

confidence: 88%

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

et al. 2007

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While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R 2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

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Section: Discussionmentioning

confidence: 88%

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

et al. 2007

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“…Colloquially, epistasis can be regarded as our surprise at the phenotype when mutations are combined, given the constituent mutations’ individual effects. The recognition of epistasis between pairs of mutations in both discrete, Mendelian [1] and continuous [2,3] traits goes back roughly 100 years, but recent experimental advances draw attention to interactions between more than two mutations. For example, how often does pairwise epistasis itself vary with genetic background [4•,5••]?…”

Section: Introductionmentioning

confidence: 99%

Should evolutionary geneticists worry about higher-order epistasis?

Weinreich

Lan

Wylie

et al. 2013

Current Opinion in Genetics & Development

279

396

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Natural selection drives evolving populations up the fitness landscape, the projection from nucleotide sequence space to organismal reproductive success. While it has long been appreciated that topographic complexities on fitness landscapes can arise only as a consequence of epistatic interactions between mutations, evolutionary genetics has mainly focused on epistasis between pairs of mutations. Here we propose a generalization to the classical population genetic treatment of pairwise epistasis that yields expressions for epistasis among arbitrary subsets of mutations of all orders (pairwise, three-way, etc.). Our approach reveals substantial higher-order epistasis in almost every published fitness landscape. Furthermore we demonstrate that higher-order epistasis is critically important in two systems we know best. We conclude that higher-order epistasis deserves empirical and theoretical attention from evolutionary geneticists.

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“…Bateson observed this phenomenon as a departure from Mendelian inheritance ratios in mouse coat color in 1909 [31] and it has now become known as compositional epistasis. While compositional epistasis can be clearly defined in model organisms with a common genetic background, in human populations with diverse genetic profiles it is difficult to discern an event of compositional epistasis.…”

Section: Genetic Association Studiesmentioning

confidence: 99%

Statistical Optimization of Pharmacogenomics Association Studies: Key Considerations from Study Design to Analysis

Grady¹,

Ritchie²

2011

CPPM

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Research in human genetics and genetic epidemiology has grown significantly over the previous decade, particularly in the field of pharmacogenomics. Pharmacogenomics presents an opportunity for rapid translation of associated genetic polymorphisms into diagnostic measures or tests to guide therapy as part of a move towards personalized medicine. Expansion in genotyping technology has cleared the way for widespread use of whole-genome genotyping in the effort to identify novel biology and new genetic markers associated with pharmacokinetic and pharmacodynamic endpoints. With new technology and methodology regularly becoming available for use in genetic studies, a discussion on the application of such tools becomes necessary. In particular, quality control criteria have evolved with the use of GWAS as we have come to understand potential systematic errors which can be introduced into the data during genotyping. There have been several replicated pharmacogenomic associations, some of which have moved to the clinic to enact change in treatment decisions. These examples of translation illustrate the strength of evidence necessary to successfully and effectively translate a genetic discovery. In this review, the design of pharmacogenomic association studies is examined with the goal of optimizing the impact and utility of this research. Issues of ascertainment, genotyping, quality control, analysis and interpretation are considered.

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Mendel's principles of heredity, by W. Bateson

Cited by 231 publications

References 0 publications

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

Should evolutionary geneticists worry about higher-order epistasis?

Statistical Optimization of Pharmacogenomics Association Studies: Key Considerations from Study Design to Analysis

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