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

226 Chapter 4: DNA, Chromosomes, and Genomes
for it to succeed in nature. Moreover, calculations based on population genetics
reveal that just a tiny selective advantage—less than a 0.1% difference in survival—can
be enough to strongly favor retaining a particular DNA sequence over
evolutionary time spans. One should therefore not be surprised to find that many
DNA sequences that are ultraconserved can be deleted from the mouse genome
without any noticeable effect on that mouse in a laboratory.
A second important approach for discovering the function of a mysterious
noncoding DNA sequence uses biochemical techniques to identify proteins or
RNA molecules that bind to it—and/or to any RNA molecules that it produces.
Most of this task still lies before us, but a start has been made (see p. 435).
Changes in Previously Conserved Sequences Can Help Decipher
Critical Steps in Evolution
Given genome sequence information, we can tackle another intriguing question:
What alterations in our DNA have made humans so different from other animals—or
for that matter, what makes any individual species so different from its
relatives? For example, as soon as both the human and the chimpanzee genome
sequences became available, scientists began searching for DNA sequence
changes that might account for the striking differences between us and chimpanzees.
With 3.2 billion nucleotide pairs to compare in the two species, this
might seem an impossible task. But the job was made much easier by confining
the search to 35,000 clearly defined multispecies conserved sequences (a total
of about 5 million nucleotide pairs), representing parts of the genome that are
most likely to be functionally important. Though these sequences are conserved
strongly, they are not conserved perfectly, and when the version in one species is
compared with that in another they are generally found to have drifted apart by
a small amount corresponding simply to the time elapsed since the last common
ancestor. In a small proportion of cases, however, one sees signs of a sudden evolutionary
spurt. For example, some DNA sequences that have been highly conserved
in other mammalian species are found to have accumulated nucleotide
changes exceptionally rapidly during the 6 million years of human evolution since
we diverged from the chimpanzees. These human accelerated regions (HARs) are
thought to reflect functions that have been especially important in making us different
in some useful way.
About 50 such sites were identified in one study, one-fourth of which were
located near genes associated with neural development. The sequence exhibiting
the most rapid change (18 changes between human and chimpanzee, compared
to only two changes between chimpanzee and chicken) was examined further
and found to encode a 118-nucleotide noncoding RNA molecule, HAR1F (human
accelerated region 1F), that is produced in the human cerebral cortex at a critical
time during brain development. The function of this HAR1F RNA is not yet known,
but findings of this type are stimulating research studies that may shed light on
crucial features of the human brain.
A related approach in the search for the important mutations that contributed
to human evolution likewise begins with DNA sequences that have been conserved
during mammalian evolution, but rather than screening for accelerated
changes in individual nucleotides, it focuses instead on chromosome sites that
have experienced deletions in the 6 million years since our lineage diverged from
that of chimpanzees. More than 500 such sequences—conserved among other
species but deleted in humans—have been discovered. Each deletion removes an
average of 95 nucleotides of DNA sequence. Only one of these deletions affects a
protein-coding region: the rest are thought to alter regions that affect how nearby
genes are expressed, an expectation that has been experimentally confirmed
in a few cases. A large proportion of the presumed regulatory regions identified
in this way lie near genes that affect neural function and/or near genes involved in
steroid signaling, suggesting that changes in the nervous system and in immune
or reproductive functions have played an especially important role in human
evolution.