Although the possibility of function in gene deserts was predicted as early as the 1960s, genetic identification tools were unable to uncover any specific characteristics of the long noncoding regions, other than that no coding occurred in those regions. Before the completion of the human genome in 2001 through the Human Genome Project, most of the early associative gene comparisons relied on the belief that essential housekeeping genes were clustered in the same areas of the genome for ease of access and tight regulation. This belief later constructed a hypothesis that gene deserts are therefore previous regulatory sequences that are highly linked (and hence do not undergo recombination), but have had substitutions between them over time. These substitutions could cause tightly conserved genes to separate over time, thus forming regions of nonsense codes with a few essential genes. However, uncertainty due to differential gene conservation rates in different portions of chromosomes prevented accurate identification. 
Later associations were remodeled when regulatory sequences were associated with transcription factors, leading to the birth of large-scale genome-wide mapping. Thus began the hunt for the contents and functions of gene deserts. Recent advancements in the screening of chromatin signatures on chromosomes (for instance, chromosome conformation capture, also known as 3C) have allowed the confirmation of the long-range gene activation model, which postulates that there are indeed physical links between regulatory enhancers and their target promoters. Research on gene deserts, although centralized on human genetics, has also been applied to mice, various birds, and Drosophila melanogaster. Although conservation is variable among selected species’ genomes, orthologous gene deserts function similarly. Thus, the prevailing the contention of gene deserts is that these noncoding sequences harbor active and important regulatory elements.