Chromosome 18 : Barren but not a wasteland
There are not many genes on human chromosome 18, especially in comparison to its 23 siblings. Yet chromosome 18 is far from a genomic backwater. Indeed, as described by a research team led by Broad scientists in the September 22 issue of Nature, evolution has worked hard to conserve a surprisingly large number of non-gene regions of the chromosome. This discovery offers tantalizing evidence that "extra" sequence plays an important role in genome function.
It was known that chromosome 18 has a low density of protein-coding genes, which may explain why fetuses carrying three copies of chromosome 18 can survive to birth (although with devastating consequences). Most protein-coding gene sequences are highly conserved among mammals, but since they represent only about 1.5% of the genome, they are not sufficient for understanding how the genome works. The non-genic sequences are undoubtedly also important, but these are poorly understood. It is known that about 3% of the human genome that is not in genes is highly conserved among mammals, but to what end is still mysterious.
Taking advantage of the low gene number on chromosome 18 and comparing both gene-dense and gene-sparse regions of 18 and the other human chromosomes to the genomes of mouse and dog, the authors of the Nature paper sought to determine how much of the conserved non-coding sequence is actually associated with protein-coding genes (e.g., classic promoter-like elements) and how much is something else. They found that although chromosome 18 is very low on genes, it still has the average amount of non-genic sequence that is conserved among mammals.
Chad Nusbaum of the Broad Institute's Genome Biology Program and lead author on the Nature paper, says that "this surprising result suggests that the conservation of genes and non-genic sequence are at least somewhat independent of each other. If we assume that the major role of non-genic elements is in gene regulation, this implies that not all genes are created equal, as genes in sparser neighborhoods are associated with more non-genic elements than those in denser neighborhoods. Perhaps genes that require more regulatory elements to function properly fare better with more space to work with."
Scientists are only beginning to understand the nature of this evolutionarily valuable sequence. In addition to elements that directly regulate gene function, conserved non-genic elements may include RNA genes (which do not code for proteins), structural elements of the chromosome itself, or unique regulatory elements for protein-coding genes that perform their function at a distance or in concert with an elaborate mix of such elements that just happens to take up a lot of space. Research is underway to test these various explanations.
This work was made possible by the availability of the human and other genome sequences, which have given scientists incredible leverage in understanding fundamental features of human biology. Additional new surprises are undoubtedly forthcoming.