Contiguous Genes

The order of genes on a chromosome and the existence of directly contiguous genes can be useful in understanding their individual functions and in mapping the genome to understand the function of chromosomal domains. In prokaryotes there is often a close linkage of genes involved in a common metabolic pathway. This type of linkage is uncommon in eukaryotes, although examples exist, including five genes in Neurospora crassa involved in synthesis of chorismic acid (1) and genes in Drosophila melanogaster involved in purine metabolism (2.(

 There are several families of closely linked genes in humans. These include genes for alcohol dehydrogenase, a-amylase, the major histocompatibility complex, a-globins, b-globins, chorionic gonadotropin, luteinizing hormone, and growth hormone. Every chromosome has at least one family cluster of undispersed genes. These clusters vary in size from several thousand base pairs to millions of base pairs with a large cluster like the major histocompatibility complex. The members of a single gene family are derived from the gene duplication of single ancestral genes. Whereas gene families are rare in prokaryotes, the more complex differentiative states in eukaryotes require similar gene products with subtle differences in function. An example of a well-studied locus, where genes with closely related functions are linked together, occurs at the a- and b-globin loci. At these chromosomal sites, globin genes specific for embryos, neonatal and adult animals are linked together and expressed in a sequential fashion during development (Fig. 1). The globin loci also present interesting examples of where gene linkage helps understanding the chromosomal function. All of the globin genes depend on a super enhancer known as a locus control region (LCR), which functions over an entire chromosomal domain. 

Figure 1. The b-globin gene cluster, which is on the short arm of chromosome 11 in humans and includes five genes that are sequentially expressed during development. Its locus control region (LCR) consists of five short stretches of DNA extending over a span of 12 bp. Similarly, there are three a-globin genes on the short arm of chromosome 16, but that LC comprises only one DNA sequence far upstream.

The relative order of genes is often conserved within a chromosome.This is termed linkage conservation. Linkage conservation often occurs in chromosomes isolated from distinct species. For example, in the X-chromosome there are many genes that have the same order along the chromosome in both mouse and humans. This is a useful aid in mapping new genes. There are several potential evolutionary advantages to linking certain genes together, which include common regulatory mechanisms, at the level of establishing a functional chromosomal domain, as described for the globin genes (3), or in terms of coordinate expression, as described for two genes involved in a particular metabolic pathway. There may also be regulatory mechanisms where genes compete with each other for a common regulatory element, as occurs in the globin genes at certain times in development (4).

References

1. F. H. Gaertner and K. W. Cole (1977) Biochem. Biophys. Res. Comm. 75, 259–270. 

2. M. E. Johnstone (1985) Biochem. Genet. 23, 539–546. 

3. F. Grosveld, G. B. van Assendelft, D. R. Greaves, and G. Kollias (1987) Cell 51, 975–985.

4. M. Wijgerde, F. Grosveld, and P. Fraser (1995) Nature 377, 209–213.