In general, the sequences of individual genes are much more tightly conserved than is overall genome structure. Features of genome organization such as genome size, number of chromosomes, order of genes along chromosomes, abundance and size of introns, and amount of repetitive DNA are found to differ greatly when comparing distant organisms, as does the number of genes that each organism contains.
A first obstacle in interpreting the sequence of the 3.2 billion nucleotide pairs in the human genome is the fact that much of it is probably functionally unimportant. The regions of the genome that code for the amino acid sequences of proteins (the exons) are typically found in short segments (average size about 145 nucleotide pairs), small islands in a sea of DNA whose exact nucleotide sequence is thought to be mostly of little consequence. This arrangement makes it difficult to identify all the exons in a stretch of DNA, and it is often hard too to determine exactly where a gene begins and ends.
One very important approach to deciphering our genome is to search for DNA sequences that are closely similar between different species, on the principle that DNA sequences that have a function are much more likely to be conserved than those without a function. For example, humans and mice are thought to have diverged from a common mammalian ancestor about 80 × 106 years ago, which is long enough for the majority of nucleotides in their genomes to have been changed by random mutational events. Consequently, the only regions that will have remained closely similar in the two genomes are those in which mutations would have impaired function and put the animals carrying them at a disadvantage, resulting in their elimination from the population by natural selection. Such closely similar pieces of DNA sequence are known as conserved regions. In addition to revealing those DNA sequences that encode functionally important exons and RNA molecules, these conserved regions will include regulatory DNA sequences as well as DNA sequences with functions that are not yet known. In contrast, most nonconserved regions will reflect DNA whose sequence is much less likely to be critical for function.
The power of this method can be increased by including in such comparisons the genomes of large numbers of species whose genomes have been sequenced, such as rat, chicken, fish, dog, and chimpanzee, as well as mouse and human. By revealing in this way the results of a very long natural “experiment,” lasting for hundreds of millions of years, such comparative DNA sequencing studies have highlighted the most interesting regions in our genome. The comparisons reveal that roughly 5% of the human genome consists of “multispecies conserved sequences.” To our great surprise, only about one-third of these sequences code for proteins (see Table 4–1, p. 184). Many of the remaining conserved sequences consist of DNA containing clusters of protein-binding sites that are involved in gene regulation, while others produce RNA molecules that are not translated into protein but are important for other known purposes. But, even in the most intensively studied species, the function of the majority of these highly conserved sequences remains unknown. This remarkable discovery has led scientists to conclude that we understand much less about the cell biology of vertebrates than we had thought. Certainly, there are enormous opportunities for new discoveries, and we should expect many more surprises ahead.
genome Alterations Are Caused by Failures of the Normal mechanisms for Copying and maintaining DNA, as well as by Transposable DNA Elements
Evolution depends on accidents and mistakes followed by nonrandom survival. Most of the genetic changes that occur result simply from failures in the normal mechanisms by which genomes are copied or repaired when damaged, although the movement of transposable DNA elements (discussed below) also plays an important part. As we will explain in Chapter 5, the mechanisms that maintain DNA sequences are remarkably precise—but they are not perfect. DNA sequences are inherited with such extraordinary fidelity that typically, along a given line of descent, only about one nucleotide pair in a thousand is randomly changed in the germ line every million years. Even so, in a population of 10,000 diploid individuals, every possible nucleotide substitution will have been “tried out” on about 20 occasions in the course of a million years—a short span of time in relation to the evolution of species.