Evolution__3rd_Edition

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Box 7.4
Model Organisms for Biomedical Research
In late 1994, a hormone called leptin
was discovered in mice. Leptin had the
ability to make fat mice slim. Mice that
are deficient in leptin are grossly obese;
if those mice are fed leptin they become
slim in a few weeks (and without
noticeable side effects). A biotechnology
company immediately snapped up
the rights to leptin, for $20 million.
Since then, there has been intense
research on whether leptin influences
human obesity, but little or no evidence
of any effect has been found.
Leptin influences body weight in
mice, but what about other species?
Leptin genes have been found in several
mammal species. We can measure the
rates of non-synonymous to synonymous
evolution (dN/dS) in various
branches of the mammalian family tree
(Figure B7.3). The ratio is generally
low, at a typical level for genes in general;
but it spurted up to more than
two in the lineage between Old World
monkeys and great apes.
The elevated ratio may be a chance
dN __ ≈ 0.21
dS
dN __ ≈ 2.2
dS
CHAPTER 7 / Natural Selection and Random Drift 183
blip, or artifact of the preliminary data,
and meaningless. However, it may
indicate a phase of adaptive evolution,
when several new amino acids were
established in the leptin molecule of
apes. This could have caused a change
in the function of leptin, such that
leptin no longer regulates body weight
in apes. Alternatively, leptin may have
added or subtracted some functions, or
changed its metabolic interactions.
Many interpretations are compatible
with the simple elevated dN/dS ratio.
Further research would be needed to
test between them. The point here is
that the elevated dN/dS ratio alone is a
clue that something happened to leptin
in the evolution of the apes. If leptin
simply evolved by random drift in all
mammals, then leptin would probably
have the same function in humans and
mice. The elevated ratio is evidence of
positive natural selection. In expensive
and vital biomedical technologies, clues
are valuable even when they are not
decisive.
Great apes
Old World monkey
Rodents
Artiodactyls
The result has several implications.
One is that mice may not be a good
model organism for research on
human leptin. A second concerns the
way related genes are identified by
searching genomic databases. Leptin
genes, related to the mouse leptin gene,
were soon found in other mammalian
genome libraries a but before jumping
to conclusions about the function of
the genes it is useful to know the dN/dS
ratios in the phylogenetic branches
connecting the species. Thirdly, the
dN/dS ratios hint at an important
change in leptin between mice and
men. Such a change could explain why
research has been slow to find an
influence of leptin on human body
weight. If the dN/dS ratios had been
available in early 1995, that quick-draw
biotechnology company might been
slower with its wallet.
Further reading: Benner et al. (2002),
newspiece in Nature, April 6, 2000,
pp. 538–40.
Figure B7.3
A spurt of meaningful evolution in the leptin gene
during the origin of apes. The ratio of non-synonymous
to synonymous evolution in the leptin gene has generally
been low, such as the 0.2 figure for the rodent lineage.
The ratio increased during the origin of apes, perhaps
indicating a phase of adaptive modification. From
Benner et al. (2002).