Evidence of a Large-Scale Functional Organization of Mammalian Chromosomes

Abstract

Evidence from inbred strains of mice indicates that a quarter or more of the mammalian genome consists of chromosome regions containing clusters of functionally related genes. The intense selection pressures during inbreeding favor the coinheritance of optimal sets of alleles among these genetically linked, functionally related genes, resulting in extensive domains of linkage disequilibrium (LD) among a set of 60 genetically diverse inbred strains. Recombination that disrupts the preferred combinations of alleles reduces the ability of offspring to survive further inbreeding. LD is also seen between markers on separate chromosomes, forming networks with scale-free architecture. Combining LD data with pathway and genome annotation databases, we have been able to identify the biological functions underlying several domains and networks. Given the strong conservation of gene order among mammals, the domains and networks we find in mice probably characterize all mammals, including humans. The arrangement of genes along chromosomes affects their function as well as the likelihood that particular combinations of genes will be inherited together, and evolution has had many millions of years to optimize these arrangements. Because the arrangements are nearly identical in all mammals, one can use the powerful techniques of mouse genetics to explore their roles in our own genomes. The authors find that genes that cooperate in bringing about various cellular and physiological functions, such as immune responses, are often clustered together on chromosomes, and that detailed maps of these relationships can be built. The new techniques have proven so powerful that they can identify functional interactions among genes that are not even on the same chromosome. Beyond illuminating the evolutionary pressures that brought them about, mapping these arrangements will be of great utility in the ongoing searches in many laboratories for the genes underlying our common diseases, such as cancer, heart disease, and diabetes.