The mass of DNA sequence now in databases (hundreds of billions of nucleotide pairs) provides a rich resource that scientists can mine for many purposes. This information can be used not only to unscramble the evolutionary pathways that have led to modern organisms, but also to provide insights into how cells and organisms function. Perhaps the most remarkable discovery in this realm comes from the observation that a striking amount of DNA sequence that does not code for protein has been conserved during mammalian evolution (see Table 4–1, p. 184). This is most clearly revealed when we align and compare DNA synteny
Figure 4–71 Comparison of the genomic sequences of the human and Fugu genes encoding the protein huntingtin. both genes (indicated in red) contain 67 short exons that align in 1:1 correspondence to one another; these exons are connected by curved lines. The human gene is 7.5 times larger than the Fugu gene (180,000 versus 24,000 nucleotide pairs). The size difference is entirely due to larger introns in the human gene. The larger size of the human introns is due in part to the presence of retrotransposons (discussed in Chapter 5), whose positions are represented by green vertical lines; the Fugu introns lack retrotransposons. In humans, mutation of the huntingtin gene causes Huntington’s disease, an inherited neurodegenerative disorder. (Adapted from S. baxendale et al., Nat. Genet. 10:67–76, 1995. with permission from macmillan Publishers ltd.)
Figure 4–72 The Neanderthals. (A) map of Europe showing the location of the cave in Croatia where most of the bones used to isolate the DNA used to derive the Neanderthal genome sequence were discovered. (b) Photograph of the vindija cave. (C) Photograph of the 38,000-yearold bones from vindija. more recent studies have succeeded in extracting DNA sequence information from hominid remains that are considerably older (see movie 8.3). (b, courtesy of Johannes krause; C, from R.E. green et al., Science 328: 710–722, 2010. Reprinted with permission from AAAS.) cave in Vindija, Croatia blocks from many different species, thereby identifying large numbers of so-called multispecies conserved sequences: some of these code for protein, but most of them do not (Figure 4–73).
Most of the noncoding conserved sequences discovered in this way turn out to be relatively short, containing between 50 and 200 nucleotide pairs. Among the most mysterious are the so-called “ultraconserved” noncoding sequences, exemplified by more than 5000 DNA segments over 100 nucleotides long that are exactly the same in human, mouse, and rat. Most have undergone little or no change since mammalian and bird ancestors diverged about 300 million years ago. The strict conservation implies that even though the sequences do not encode proteins, each nevertheless has an important function maintained by purifying selection. The puzzle is to unravel what those functions are.
Many of the conserved sequences that do not code for protein are now known to produce untranslated RNA molecules, such as the thousands of long noncoding RNAs (lncRNAs) that are thought to have important functions in regulating gene transcription. As we shall also see in Chapter 7, others are short regions of DNA scattered throughout the genome that directly bind proteins involved in gene regulation. But it is uncertain how much of the conserved noncoding DNA can be accounted for in these ways, and the function of most of it remains a mystery. This enigma highlights how much more we need to learn about the fundamental biological mechanisms that operate in animals and other complex organisms, and its solution is certain to have profound consequences for medicine.