Bejerano Lab, Stanford University

The Gene Regulatory Landscape of the Human Genome

The human genome contains millions of putatively functional genomic regions that do not code for protein. COMPARATIVE GENOMICS of multiple primate, mammalian and vertebrate genomes allows us to pinpoint the exact locations of an ever growing number of human genomic loci that are clearly evolving under purifying selection, the hallmark of functional sequences.

The conserved non coding regions clearly cluster in the human genome near important developmental genes. The vast majority of human non-coding RNAs are transcribed autonomously. These RNAs have no need to be genomically encoded near the genes whose products they affect. DEVELOPMENTAL BIOLOGY teaches us that the key genes next to which the conserved non coding regions cluster are reused over and over again in different contexts at different timepoints to pattern the growing embryo.

Hundreds of conserved non coding regions tested drive gene expression in exquisite patterns during embryonic development. FUNCTIONAL GENOMICS allows us to test individual sequences by manipulating the mouse and zebrafish genomes. We can attach these sequences to reporter genes, delete them from the genome, mutate them, and more, in order to understand their function.

Many of the validated enhancers lie hundreds of kilobases away from the key developmental genes they regulate. In fact, most key developmental genes are surrounded by thousands of conserved non coding regions. This suggests a clear paradigm shift in basic MOLECULAR BIOLOGY in our understanding of how complex metazoan genes are regulated.

A handful of validated enhancer mutations, deletions, translocations and duplications have already been implicated in human disease. Other types of experiments, including a growing number of genome-wide association studies all point to much unexplored regulatory contribution to HUMAN DISEASE.

Because cis-regulatory sequences often appear to control only a narrow facet of the complex expression pattern of developmental genes, many scientists now suspect that cis-regulatory changes may underlie much of human evolution. EVOLUTIONARY DEVELOPMENTAL BIOLOGY (or "evo-devo") researchers studying the way human and other species adapt to their environment are now focusing their attention on regulatory modifications that may lead to more focused, less pleiotropic, and thus more favourable adaptive changes.

The sequencing of a growing number of related species is also allowing us to reconstruct the evolution of the human genome at the basepair level. PALEONTOLOGY has shown us how different species have evolved, independently modifying a common morphological blueprint. For the first time, we can now attempt to correlate the progression of phenotypic changes with the genomic changes that underlie them.

It is this cis-regulatory landscape of the human genome which forms the focus of the Bejerano Lab work.