New Approach Allows for Insights into Evolution of Human Gene Regulation
With their new approach, the bioformatics expert and systems biologist Professor Nikolaus Rajewsky from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Dr. Kevin Chen from the Center for Comparative Functional Genomics, New York University, New York (USA) are now able to look more systematically for structures in the human genome which are likely to be deleterious and are the causes of human disease.
Looking at single
inherited variations in the human genome, the researchers try to gain new
insights into gene regulation and their impact on health and disease. They are
especially interested in the development of gene regulation throughout millions
of years of human evolution.
To do this, they
combined two methods in genome research – the search for single nucleotide
polymorphisms (SNPs), which can influence the correct expression of genes, with
population genetics. This strategy enables the researchers not only to look at
gene regulation, but also to detect those variations in the genome which can
cause human disease. Their findings have now been published as a research
highlight in Nature Genetics* (Vol.
38, No. 11, October 29, 2006).
Gene regulation is
a basic process which regulates human development and is important for health
and disease. Genes are sections of the hereditary molecule DNA which contains
the blue print for proteins, the building blocks and molecular machineries of
life.
The DNA molecule
is made up of 3,2 billion nucleotides. However, each human individual has a
different sequence of nucleotides. One individual, for example, can have an
Adenin (A) nucleotide whereas, at the same position, another individual has a
cytosin (C) nucleotide.
Eleven Million
Variations
Researchers
estimate that, all in all, the human genome has eleven million of such single
nucleotide variants or polymorphisms (SNPs). Their aim is, to detect these SNPs
and find out their function in health and disease.
Various consortia
have measured how often these millions of SNPs occur in different human
populations. Based on this data, Professor Rajewsky and Dr. Chen were able to
develop their new approach.
Professor
Rajewsky, who until recently has been working at New York University, and Dr.
Chen looked at microRNAs to research gene regulation. MicroRNAs are thought to
regulate thousands of human genes, as Professor Rajewsky and other labs have
previously shown. New studies suggest that they also play a key role in
development, cancer, and metabolism.
MicroRNAs bind to
specific short regions of DNA, called cis
regulatory sites or microRNA targets. They are widely scattered over the genome
and, at these binding sites, block the messenger RNA (mRNA) molecule. Thus,
microRNAs repress the production of proteins and, therefore, also influence
which genes and proteins are expressed, since mRNA is the transcribed DNA.
Professor Rajewsky
and Dr. Chen combined information from SNP databases about bioinformatically
predicted microRNA targets with population genetics. This way they were able to
demonstrate that 80 per cent of the predicted microRNA targets are likely to be
functional and good candidates to better understand human disease. At the same
time, they could estimate how many functional microRNA targets exist
specifically in humans, which may cause disease specific for humans. Finally,
the researchers believe that their approach can be applied to other genetic
regulatory mechanisms in the future.
*Natural
Selection on Human MicroRNA Binding Sites Inferred from Single Nucleotide
Polymorphism Data
Kevin
Chen1 and Nikolaus Rajewsky1,2
1Center for Comparative
Functional Genomics, Department of Biology, New York
University, New YorkNY10003, USA.
2 Max
Delbrück Centrum für Molekulare Medizin, RobertRössleStrasse 10, BerlinBuch, Germany
Correspondence should be addressed to Nikolaus Rajewsky rajewsky@mdcberlin.de
Barbara
Bachtler
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