Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

HOW GENOMES EVOlvE
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nucleotide sequences with the sequences of genes that have been characterized
in other more readily studied organisms.
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.
Genome Comparisons Reveal Functional DNA Sequences by their
Conservation Throughout Evolution
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 × 10 6 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