Bird's Eye View of QTLs
Brian Yandell, UW-Madison (emeritus)
8-9 November 2023
https://docs.google.com/presentation/d/1UPueI38aK_yRJUWviHR-eNJRRFVR9f-EOWpLpUMQASU
Central Dogma
Complicated Biochemical Pathways
From Markers to Maps
Dozens of markers initially provided isolated tests of association
Lander and Botstein (1989) introduced concept of map of markers
Physical maps to DNA base pairs and SNPs
https://knowgenetics.org/snps/
From 1 QTL to Genetic Architecture
Classic QTL: is there evidence for a quantitative trait locus here?
Could there be 2 QTL?
From 1 QTL to Genetic Architecture
Markers and QTLs
Genetic Architecture
Model Selection
Bigger Picture of Genetic Architecture
Many genetic "things" affect organism over its lifetime
Measured trait is a snapshot
Liu et al Laurie (1997)
complicated shape trait
ordered shape trait
multiple QTL model fit
Zeng et al Laurie (2000) 19 QTL
From 1 Trait to Multiple Related Traits
Chaibub Neto et al.
Pearl 2000 Causality book
QTL2 Software Resources
There are many resources for R and Rstudio these days. Karl Broman maintains an excellent web site about QTLs, in particular is R/qtl and R/qtl2 packages. Brian Yandell has developed some useful extensions.
Many other people developed QTL software over the years, and some of those have been incorporated into comprehensive pipelines. Always insist on open source so that you can evaluate exactly what is done with any tools.
“The ideal … is the study of the direct influence of one condition on another …[when] all other possible causes of variation are eliminated.... The degree of correlation between two variables … [includes] all connecting paths of influence…. [Path coefficients combine] knowledge of … correlation among the variables in a system with … causal relations.
Sewall Wright (1921) Correlation and causation. J Agric Res
“The old view of cause and effect … could only fail; things are not in our experience either independent or causative. All classes of phenomena are linked together, and the problem in each case is how close is the degree of association.”
Karl Pearson (1911) The Grammar of Science
Systems Genetics
"phenotypic variation … often results from multiple interactions among numerous genetic and environmental factors. Systems genetics seeks to understand this complexity by integrating the questions and methods of systems biology with those of genetics to solve the fundamental problem of interrelating genotype and phenotype in complex traits and disease."
Joe Nadeau and Aimée Dudley (2011 Science)
Systems genetics is an approach to understand the flow of biological information that underlies complex traits. It … integrate[s] intermediate phenotypes, such as transcript, protein or metabolite levels … [to provide] the first global view of the molecular architecture of complex traits and are useful for the identification of genes, pathways and networks that underlie common human diseases.
Mete Civelek and Jake Lucis (2013 Nature Review Genetics)
Systems Genetics
Our lab is actively applying a systems approach to study the genetics of health and disease, incorporating new statistical methods for the investigation of complex disease-related traits in the mouse. We are developing new methods and software that will improve the power of quantitative trait loci mapping and microarray analysis, as well as graphical models that aim to characterize the genetic architecture of disease intuitively and precisely.
Gary Churchill Lab Site
www.jax.org/research-and-faculty/research-labs/the-churchill-lab
see extensive references