Two opposite explanations that endeavored to explain the formations of isochores were vigorously debated as part of the neutralist-selectionist controversy. The first view was that isochores reflect variable mutation processes among genomic regions consistent with the neutral model.
 Alternatively, isochores were posited as a result of natural selection for certain compositional environment required by certain genes. Several hypotheses derive from the selectionist view, such as the thermodynamic stability hypothesis  and the biased gene conversion hypothesis. Thus far, none of the theories provides a comprehensive explanation to the genome structure, and the topic is still under debate.