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http://www.scienceblog.com/cms/most_human-chimp_differences_due_to_gene_regulation_10178.html

Most human-chimp differences due to gene regulation

The vast differences between humans and chimpanzees are due more to
changes in gene regulation than differences in individual genes
themselves, researchers from Yale, the University of Chicago, and the
Hall Institute in Parkville, Victoria, Australia argue in the March 9
issue of the journal Nature.

The scientists provide powerful new evidence for a 30-year-old theory,
proposed in a classic paper from Mary-Claire King and Allan Wilson of
Berkeley. That 1975 paper documented the 99-percent similarity of
genes from humans and chimps and suggested that altered gene
regulation, rather than changes in coding, might explain how so few
genetic changes could produce the wide anatomic and behavioral
differences between the two.

Using novel gene-array technology to measure the extent of gene
expression in thousands of genes simultaneously, this study shows that
as humans diverged from their ape ancestors in the last five million
years, genes for transcription factors -- which control the expression
of other genes -- were four times as likely to have changed their own
expression patterns as the genes they regulate.

Because they influence the activity of many "downstream" genetic
targets, small changes in the expression of these regulatory genes can
have an enormous impact.

"When we looked at gene expression, we found fairly small changes in
65 million years of the macaque, orangutan, and chimpanzee evolution,"
said study author Yoav Gilad, assistant professor of human genetics at
the University of Chicago, "followed by rapid change, along the five
million years of the human lineage, that was concentrated on these
specific groups of genes. This rapid evolution in transcription
factors occurred only in humans."

"For 30 years scientists suspected that gene regulation has played a
central role in human evolution," said Kevin White, associate
professor of genetics and ecology and evolution at Yale and senior
author of the study. "In addition to lending support to the idea that
changes in gene regulation are a key part of our evolutionary history,
these new results help to define exactly which regulatory factors may
be important, at least in certain tissues. This helps open the door to
a functional dissection of the role of gene regulation during the
evolution of modern humans."

To measure changes in gene expression from different species, White
and Gilad developed the first multi-species gene array. This allowed
them to compare the level of expression of more than 1,000 genes
between humans, chimps, orangutans and rhesus macaques – representing
about 70 million years of evolution. To make the samples comparable,
the researchers studied tissue from the liver -- one of the most
homogeneous sources -- from five adult males from each of the four
species.

They focused their search on expression levels of two sets of genes,
those that remained largely unchanged across all four species,
suggesting that there was little room -- or need -- for improvement,
and those that changed most dramatically, usually in the human lineage
-- an indication of powerful incentives to adapt to a changing
environment.

Of the 1,056 genes from all four species, 60 percent had fairly
consistent expression levels across all four species. "The expression
levels of these genes seem to have remained constant for about 70
million years," the authors wrote, "suggesting that their regulation
is under evolutionary constraint."

Many of these genes are involved in basic cellular processes. The
authors suggest that altering the regulation of these fundamental and
ancient genes may be harmful. In fact, five of the 100 most stable
genes have altered expression levels in liver cancer.

When they also looked for human genes with significantly higher or
lower expression levels, they found 14 genes with increased expression
and five with decreased expression. While only ten percent of the
genes in the total array were transcription factors, 42 percent of
those with increased expression in humans were among these. None of
those with lower expression were transcription factors. This pattern,
the authors note, is consistent with "directional selection."

Previous studies have found that many of these same genes have also
evolved rapidly in humans, accumulating changes in their coding
sequence as well as in expression rates. "Together," they add, "these
findings raise the possibility that the function and regulation of
transcription factors have been substantially modified in the human
lineage."

This is a very efficient way to make big changes with very little
effort, according to Gilad. By altering transcription factors, the
entire regulatory network can change with very few mutations,
increasing the impact and minimizing the risk.

"The big question," he said, "is why are humans so different? What
sort of changes in the environment or lifestyle would drive such a
rapid shift in the expression of genes -- in this case in the liver --
in humans and in no other primate?"

Part of the answer, he suspects, is rapid alterations in diet,
probably related to the acquisition of fire and the emerging
preference for cooked food. "No other animal relies on cooked food,"
he said. "Perhaps something in the cooking process altered the
biochemical requirements for maximal access to nutrients as well as
the need to process the natural toxins found in plant and animal
foods."

>From Yale University