Ill? You could be plain unlucky

Studying normal mouse and human tissue,Anindya Dutta,Yoshiyuki Shibata,Pankaj Kumar and their colleagues found tens of thousands of tiny,previously unknown DNA entities existing outside of chromosomes. They call these micro-DNA 200 to 400 base pair-long circles that are minuscule compared to the millions of base pairs found in chromosomal DNA,and the 16,000 found in mitochondrial DNA. The researchers,writing in a paper to be published in the journal Science this week,say these extra-chromosomal entities could be a result of micro-deletions from specific sites in the genome.

Their theory introduces an element of luck bad luck in case of deletions in key areas affecting cell function in the dissemination of genetic information from the fertilized egg to all the cells in the body,and points a finger at the DNA replication and repair machinery at work in cell division,a process thus far thought to be nearly flawless.

We are seeing tens of thousands of sites that are popping out as circles in different tissues. Based on this,I would say that there could be several hundred thousand micro-DNA in the human body,perhaps even a million, Dutta said in a telephonic interview.

According to Dutta,there seem to be certain properties that predispose a sequence to excise out as micro-DNA: for instance,they are rich in guanine-cytosine base pairs as opposed to adenine-thymine pairs. The resulting variation in tissue could be important for diseases like schizophrenia or autism that have genetic predisposition but for which a single gene with a causative mutation has not yet been found, he added.

Imagine that the copy of a potassium channel gene I got from my father has a mutation. So my hippocampal cells are dependent on proper functioning of the other gene I got from my mother. Now imagine that micro-deletions inactivate or partially inactivate this good copy in enough cells in the hippocampus,so that the potassium channel activity is low in these cells. Could this lead to diseases like autism or schizophrenia? Wed never find out by looking at the DNA from our blood cells, Dutta said.

Similarly,many cancers are caused by loss of activity of both copies of protective genes called tumour suppressors. If both copies of a specific tumour suppressor gene are inactivated,one by a pre-existing mutation and the other by a micro-deletion,the cell will then tend to grow into a cancer,he said.

The researchers do not know if micro-DNA circles serve a purpose,or if they can pop back into chromosomal DNA as micro-insertions. There have been studies,especially focused on the immune system,where DNA rearrangements have been reported in tissue. The team of scientists who stumbled upon the micro-DNA was in fact looking for circular by-products of such shuffling.

In the Science paper,the authors describe how modern technology helped them identify these new entities and recognise how widespread they were: they used polymerases,ultra-high-throughput sequencing,and a bioinformatics programme that looked specifically for linear sequences whose ends had joined to form a circle.

We are very excited. We are hoping to look through cancer genomes next, Dutta said.

Dr Sorab N Dalal,principal investigator,The Advanced Centre for Treatment,Research and Education in Cancer ACTREC at the Tata Memorial Centre,said: The work described in this paper provides a potential mechanism by which genetic heterogeneity can be generated in somatic cells in mammalian cells. These differences could lead to differences in gene expression in different cells within the same tissue/organism that could have consequences for development and disease progression. However,the contribution of the generation of micro-DNAs to differences in phenotype or clonal variation in tissues remains to be determined.