Thumbs up -- a tiny ancestral remnant lends developmental edge to humans

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Thumbs up -- a tiny ancestral remnant lends developmental edge to

humans

http://www.eurekalert.org/pub_releases/2008-09/dgi-tut090408.php

Subtle genetic changes that confer an evolutionary advantage upon a

species, such as the dexterity characteristic of the human hand,

while difficult to detect and even harder to reproduce in a model

system, have nevertheless generated keen interest amongst

evolutionary biologists. In findings published online in the

September 5 edition of the journal Science, researchers from the U.S.

Department of Energy's Lawrence Berkeley National Laboratory

(Berkeley Lab) and their collaborators, have uncovered a specifically

human 13-nucelotide change concealed in the vast three-billion-letter

landscape of the human genome. Their experiments reveal this stretch

of DNA to be a recently evolved regulator of gee expression that,

when introduced into a mouse embryo system, influence the molecular

machinery to yield human limb and thumb development patterns.

The study reinforces the conclusion that certain regions of genomes—

those which are conserved across many species over evolutionary time

and do not encode genes—can have a powerful regulatory influence on

gene expression or the production of proteins.

" The study points to how human nucleotide substitutions can alter the

regulation of genes in humans distinct from that of non-human

primates, such as chimps, " said one of the study's

corresponding/senior authors Eddy Rubin, Director of Berkeley Lab's

Genomics Division and the U.S. Department of Energy Joint Genome

Institute. " This highlights a strategy that could be applied across

the genome to understand at a molecular level what leads to

differences between humans and non-human primates. "

The goal of the experiment was not to produce mice with human

fingers. Rather, an indirect assay was employed to test the

expression readout of a single human genetic fragment and compare it

with the chimp version. The strategy, which links a color-inducing

reporter gene when expression is activated, turns the targeted tissue

blue, as it did in the published case. This led to the conclusion

that the human-versus-chimp pattern of activation was different,

consistent with the fast evolution of the human sequence, which may

also give rise to a new function.

Previously published work from the Rubin lab by co-authors Shyam

Prabhakar (now at the Genome Institute of Singapore), Noonan

(now at the Yale University School of Medicine), and postdoctoral

fellows describes a global survey they conducted of genomes—human,

chimpanzee, rhesus macaque, mouse, rat, and dog. They screened across

these species to find the most conserved regions, but where humans

had many more changes relative to the others. By comparing the

occurrence of these features, they were seeking to home in on

evidence of positive selection—sequence changes that evolve more

rapidly since the human and chimp paths split six million years ago.

When queried about the extent of variation between humans and

chimpanzees on a DNA level, the prevailing consensus amongst

researchers is that humans are only about one percent different from

our furrier friends—meaning one changed letter of code in one hundred

nucleotides. It has long been postulated that the differences are not

a consequence of protein-encoding changes, but must be attributed to

a more cryptic mechanism because there are not enough sequence

changes to account for the obvious differences.

Building on pioneering work in the Rubin lab on the identification

and characterization of these conserved noncoding sequences and the

changes they induce in the genome the researchers generated a long

list of such conserved elements. Using what is known as

the " surprisal " test, a statistical tool for determining whether a

particular event occurs at a rate greater than chance, they uncovered

such a feature, dubbed human-accelerated conserved noncoding sequence

1 (HACNS1). Following the hypothesis that this was a gene regulatory

sequence, they took this 546-base pair element, one that they

determined has changed the most in humans relative to the other

species over time, and plugged it into their mouse transgenic assay.

They discovered that the human sequence enhances gene expression in

limb and brain—a gain of function.

The next question that they asked was if the human and chimp elements

have sequence differences, why do they still function similarly. They

took the chimp version, placed it in an identical construct in mice

and found that the human and chimp sequences have very different

expression properties.

" Our results led us to believe that HACNS1 has contributed to

uniquely human aspects of digit and limb patterning, " Rubin said. " We

suspect the gain of function in HACNS1 may have influenced the

evolution of these or other human limb features by altering the

expression of nearby genes during limb development. "

The researchers have yet to define the precise molecular mechanism by

which the substitutions in HACNS1 confer the human expression

patterns. " To get a more complete picture of our HACNS1 factors into

human morphological evolution will require additional studies, " Rubin

said.

" If this really is deterministic, you should see some type of change.

But it will be a long, hard path forward, " according to Rubin.

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The other authors of the Science study include Berkeley Lab's Axel

Visel, Akiyama, Malak Shoukry, , Amy Holt, Ingrid

Plajzer-Frick, Veena Afzal, and Len Pennacchio; and on

and Fitz from the MRC Human Genetics Unit, Western

General Hospital, Edinburgh.

The study was supported by a National Heart, Lung and Blood Institute

grant and a National Human Genome Research Institute grant, among

other sources.

Berkeley Lab is a U.S. Department of Energy national laboratory

located in Berkeley, California. It conducts unclassified scientific

research and is managed by the University of California. Visit our

website at http://www.lbl.gov.