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New Approach Allows for Insights into Evolution of Human Gene Regulation

Finding Genomic Elements involved in Human Disease

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


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



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.


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.


Selection on Human MicroRNA Binding Sites Inferred from Single Nucleotide

Polymorphism Data


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

and Public Affairs
Center for Molecular Medicine (MDC)
13125 Berlin
Phone.: +49 (0) 30 94 06 - 38 96
Fax:  +49 (0) 30
94 06 - 38 33