[ RadSafe ] Article: MicroRNA mutations abundant (something besides radiation at work)

[John Jacobus]

>From The Scientist at
http://www.the-scientist.com/news/daily/23533/

Another example of why biology is not like physics.  

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MicroRNA mutations abundant

Mice and humans have sequences that create or destroy
microRNA binding sites

[Published 5th June 2006 07:19 PM GMT]

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 Mutations that create or destroy microRNA binding
sites in genes appear abundant in humans and mice and
could affect genetic function, scientists report in
the June 4 online edition of Nature Genetics. 

The study "is going to suggest to people that a lot of
variation in phenotypes in mammals may be due to these
target sites," James Womack at Texas A&M University in
College Station, who did not participate in the study,
told The Scientist. 

Study author Michel Georges, of the University of
Liège in Belgium, and colleagues began the work to
investigate why Texel sheep are exceptionally meaty.
They crossed Texel sheep with another breed to
generate offspring representing a range of 37
phenotypes with respect to muscularity, fat deposition
and body composition. They mapped the locus to an
interval encompassing the myostatin gene GDF8, loss of
function of which causes double-muscling in mice,
cattle and humans. 

The investigators found no polymorphism differences
between the coding regions of GDF8 from Texel and
control sheep. Of 20 single nucleotide polymorphisms
(SNPs) the researchers did find, one, dubbed g+6723G-A
was found in 99% of Texels versus 1% of controls. This
SNP creates an eight-nucleotide-long octamer motif in
the 3' untranslated region (UTR) that three miRNAs are
known to target. PCR analysis found that sheep highly
expressed two of these miRNAs, miR-1 and miR-206, in
their skeletal muscle. 

In monkey kidney cells transfected with GDF8 linked to
bioluminescent luciferase reporters, miR-1 and miR-206
expression cut luminescence of cells with g+6723G-A in
their GDF8 down to 70% of cells with wild-type GDF8.
This suggests the SNP boosts meatiness by inhibiting
translation of the myostatin gene, according to the
authors. Georges and his colleagues found Texel sheep
apparently had one third the amount of circulating
myostatin that other sheep did. 

To see how often point mutations may affect the genes
of other species in a similar manner, the researchers
searched among 73,497 SNPs in the 3' UTR of 13,621
human genes that might create or destroy known miRNA
target octamers. To determine which alleles might be
ancestral, the researchers looked at chimpanzee
sequences. Georges and his colleagues identified 2,490
SNPs that created and 2,597 that destroyed putative
miRNA target sites. Of the latter, 483 affect octamers
conserved between primates and rodents. Analyses
performed for the mouse using rat sequences to infer
the ancestral states for 77,283 SNPs in the 3' UTR of
10,200 genes identified 1,182 SNPs creating and 1,321
destroying putative miRNA target sites, 234 of the
latter are evolutionary conserved. 

"If the sites are conserved, they are probably
functional, so destroying them would have a higher
likelihood of destroying a phenotype," said Georges,
who along with colleagues has developed Patrocles, a
database to help scientists identify such interactions
between microRNAs (miRNAs) and gene polymorphisms. 

Future research should understand the function of
these motifs systematically, "either through SNPs,
animal models, or in vitro assays," Manolis Kellis at
the Massachusetts Institute of Technology in
Cambridge, who was not a study author, told The
Scientist. 

Experiments could immunoprecipitate RNA-induced
silencing complex proteins (RISCs), the enzymes
mediating microRNA inhibition of messenger RNAs, from
sheep expressing both the mutant and wild-type alleles
of a gene and see if their RISC complexes pull down
more of the mutant allele. "If we are able to see
that, that would be a method that could probably also
open the way for systematic tests of these mutations,"
Georges said. 

Charles Q. Choi 
cchoi at the-scientist.com 

Links within this article 

D. Steinberg. "MicroRNA target practice." The
Scientist, June 20, 2005 
http://www.the-scientist.com/article/display/15538/ 

A. Clop et al. "A mutation creating a potential
illegitimate microRNA target site in the myostatin
gene affects muscularity in sheep." Nature Genetics,
published online June 4, 2006. 
http://www.nature.com/ng/ 

James Womack 
http://vtpb-www.cvm.tamu.edu/people/womack2.html 

Michel Georges 
http://www.the-scientist.com/article/display/13337/ 

J. Weitzman. "Blocking myostatin." The Scientist,
November 28, 2002. 
http://www.the-scientist.com/article/display/20897/ 

Patrocles 
http://www.patrocles.org 

Manolis Kellis 
http://web.mit.edu/manoli/www/ 

+++++++++++++++++++
"You get a lot more authority when the workforce doesn't think it's amateur hour on the top floor."
GEN. MICHAEL V. HAYDEN, President Bush's nominee for C.I.A. director.

-- John
John Jacobus, MS
Certified Health Physicist
e-mail:  crispy_bird at yahoo.com

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