CLUSTERS AND REPEATS

KEY TERMS:

• A gene family consists of a set of genes whose exons are related; the members were derived by duplication and variation from some ancestral gene.
• A translocation is a rearrangement in which part of a chromosome is detached by breakage or aberrant recombination and then becomes attached to some other chromosome.
• A gene cluster is a group of adjacent genes that are identical or related.
• Nonreciprocal recombination (unequal crossing-over) results from an error in pairing and crossing-over in which nonequivalent sites are involved in a recombination event. It produces one recombinant with a deletion of material and one with a duplication.
• Satellite DNA (Simple-sequence DNA) consists of many tandem repeats (identical or related) of a short basic repeating unit.
• Minisatellite DNAs consist of ~10 copies of a short repeating sequence. the length of the repeating unit is measured in 10s of base pairs. The number of repeats varies between individual genomes. 

A set of genes descended by duplication and variation from some ancestral gene is called a gene family. Its members may be clustered together or dispersed on different chromosomes (or a combination of both). Genome analysis shows that many genes belong to families; the 40,000 genes identified in the human genome fall into ~15,000 families, so the average gene has a couple of relatives in the genome (see Figure 3.15). Gene families vary enormously in the degree of relatedness between members, from those consisting of multiple identical members to those where the relationship is quite distant. Genes are usually related only by their exons, with introns having diverged (see 2.5 Exon sequences are conserved but introns vary). Genes may also be related by only some of their exons, while others are unique (see 2.10 Some exons can be equated with protein functions).

The initial event that allows related exons or genes to develop is a duplication, when a copy is generated of some sequence within the genome. Tandem duplication (when the duplicates remain together) may arise through errors in replication or recombination. Separation of the duplicates can occur by a translocation that transfers material from one chromosome to another. A duplicate at a new location may also be produced directly by a transposition event that is associated with copying a region of DNA from the vicinity of the transposon. Duplications may apply either to intact genes or to collections of exons or even individual exons. When an intact gene is involved, the act of duplication generates two copies of a gene whose activities are indistinguishable, but then usually the copies diverge as each accumulates different mutations.

The members of a well-related structural gene family usually have related or even identical functions, although they may be expressed at different times or in different cell types. So different globin proteins are expressed in embryonic and adult red blood cells, while different actins are utilized in muscle and nonmuscle cells. When genes have diverged significantly, or when only some exons are related, the proteins may have different functions.

Some gene families consist of identical members. Clustering is a prerequisite for maintaining identity between genes, although clustered genes are not necessarily identical. Gene clusters range from extremes where a duplication has generated two adjacent related genes to cases where hundreds of identical genes lie in a tandem array. Extensive tandem repetition of a gene may occur when the product is needed in unusually large amounts. Examples are the genes for rRNA or histone proteins. This creates a special situation with regards to the maintenance of identity and the effects of selective pressure.

Gene clusters offer us an opportunity to examine the forces involved in evolution of the genome over larger regions than single genes. Duplicated sequences, especially those that remain in the same vicinity, provide the substrate for further evolution by recombination. A population evolves by the classical recombination illustrated in Figure 1.31 - Figure 1.32, in which an exact crossing-over occurs. The recombinant chromosomes have the same organization as the parental chromosome. They contain precisely the same loci in the same order, but contain different combinations of alleles, providing the raw material for natural selection. However, the existence of duplicated sequences allows aberrant events to occur occasionally, changing the content of genes and not just the combination of alleles.

Unequal crossing-over describes a recombination event occurring between two sites that are not homologous. The feature that makes such events possible is the existence of repeated sequences. Figure 4.1 shows that this allows one copy of a repeat in one chromosome to misalign for recombination with a different copy of the repeat in the homologous chromosome, instead of with the corresponding copy. When recombination occurs, this increases the number of repeats in one chromosome and decreases it in the other. In effect, one recombinant chromosome has a deletion and the other has an insertion. This mechanism is responsible for the evolution of clusters of related sequences. We can trace its operation in expanding or contracting the size of an array in both gene clusters and regions of highly repeated DNA.

The highly repetitive fraction of the genome consists of multiple tandem copies of very short repeating units. These often have unusual properties. One is that they may be identified as a separate peak on a density gradient analysis of DNA, which gave rise to the name satellite DNA. They are often associated with inert regions of the chromosomes, and in particular with centromeres (which contain the points of attachment for segregation on a mitotic or meiotic spindle). Because of their repetitive organization, they show some of the same behavior with regard to evolution as the tandem gene clusters. In addition to the satellite sequences, there are shorter stretches of DNA that show similar behavior, called minisatellites. They are useful in showing a high degree of divergence between individual genomes that can be used for mapping purposes.

All of these events that change the constitution of the genome are rare, but they are significant over the course of evolution.