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

234 Chapter 4: DNA, Chromosomes, and Genomes
effects on human health, physiology, behavior, and physique. A major challenge
in human genetics is to recognize those relatively few variations that are functionally
important against a large background of variation that is neutral and of no
consequence.
Summary
Comparisons of the nucleotide sequences of present-day genomes have revolutionized
our understanding of gene and genome evolution. Because of the extremely
high fidelity of DNA replication and DNA repair processes, random errors in maintaining
the nucleotide sequences in genomes occur so rarely that only about one
nucleotide in a thousand is altered in every million years in any particular eukaryotic
line of descent. Not surprisingly, therefore, a comparison of human and chimpanzee
chromosomes—which are separated by about 6 million years of evolution—
reveals very few changes. Not only are our genes essentially the same, but their order
on each chromosome is almost identical. Although a substantial number of segmental
duplications and segmental deletions have occurred in the past 6 million
years, even the positions of the transposable elements that make up a major portion
of our noncoding DNA are mostly unchanged.
When one compares the genomes of two more distantly related organisms—such
as a human and a mouse, separated by about 80 million years—one finds many
more changes. Now the effects of natural selection can be clearly seen: through purifying
selection, essential nucleotide sequences—both in regulatory regions and in
coding sequences (exons)—have been highly conserved. In contrast, nonessential
sequences (for example, much of the DNA in introns) have been altered to such an
extent that one can no longer see any family resemblance.
Because of purifying selection, the comparison of the genome sequences of
multiple related species is an especially powerful way to find DNA sequences with
important functions. Although about 5% of the human genome has been conserved
as a result of purifying selection, the function of the majority of this DNA (tens of
thousands of multispecies conserved sequences) remains mysterious. Future experiments
characterizing its functions should teach us many new lessons about vertebrate
biology.
Other sequence comparisons show that a great deal of the genetic complexity of
present-day organisms is due to the expansion of ancient gene families. DNA duplication
followed by sequence divergence has clearly been a major source of genetic
novelty during evolution. On a more recent time scale, the genomes of any two
humans will differ from each other both because of nucleotide substitutions (single-nucleotide
polymorphisms, or SNPs) and because of inherited DNA gains and
DNA losses that cause copy number variations (CNVs). Understanding the effects
of these differences will improve both medicine and our understanding of human
biology.
What we don’t know
• How many different types of
chromatin structure are important for
cells? How is each of these structures
established and maintained, and
which ones tend to be inherited
following DNA replication?
• Why are there so many different
chromatin remodeling complexes in
cells? What are their essential roles,
and how do they get loaded onto
chromatin at specific places and at
specific times?
• How do chromosomal loops form
during interphase, and what happens
to these loops in condensed mitotic
chromosomes?
• What genetic changes made
us uniquely human? What further
aspects of our recent evolutionary
development can be reconstructed
by sequencing DNA from remains of
ancient hominids?
• How much of the enormous
complexity that we find in cell biology
is unnecessary, having evolved by
random drift?
Problems
Which statements are true? Explain why or why not.
4–1 Human females have 23 different chromosomes,
whereas human males have 24.
4–2 The four core histones are relatively small proteins
with a very high proportion of positively charged amino
acids; the positive charge helps the histones bind tightly to
DNA, regardless of its nucleotide sequence.
4–3 Nucleosomes bind DNA so tightly that they cannot
move from the positions where they are first assembled.
4–4 In a comparison between the DNAs of related
organisms such as humans and mice, identifying the conserved
DNA sequences facilitates the search for functionally
important regions.
4–5 Gene duplication and divergence is thought to
have played a critical role in the evolution of increased biological
complexity.
Discuss the following problems.
4–6 DNA isolated from the bacterial virus M13 contains
25% A, 33% T, 22% C, and 20% G. Do these results
strike you as peculiar? Why or why not? How might you
explain these values?