WE are all Mosaics !!

Every cell in our body was initially thought to have the same genetic content. Recent findings suggest that this is no longer the case. It appears that there are intercellular differences in chromosomal content even within the same individual (Ref.1). Right from the fertilized egg to death a person may accumulate these genetic changes such that different tissues or even cells within the same tissue of an individual can differ genetically. A significant number of human pathogenic conditions may be associated with chromosomal mosaicism (Ref. 2). We would all look something like these maize here with regard to the DNA content in our cells.

Chromosomal mosaicism is not a new concept and was known for decades as somatic variations or mosaic aneuploidy but was thought to be confined to specific tissues like palcenta, embryonic brains and ovarian tissues. They have been implicated in major psychiatric disorders, autoimmune diseases, aging and early prenatal brain development. Meiotic aneuploidy and ovarian germ line mosaicism is suggested to be the leading cause of prenatal mortality among human fetuses resulting in the 25% rate of spontaneous abortions or miscarriages and postnatal morbidity (Ref. 3).

Many endogenous factors such as interchromosomal recombinations, mobile transposable elements, inefficient DNA repair, replicon misfiring, unbalanced chromosomal segregation, reverse transcription, fragmentation of chromosomal DNA by endogenous nucleases and some exogenous factors like UV exposure, nicotine or pollutants were thought to contribute to the generation of somatic mutations, thereby leading to somatic mosaicism (Ref.2).

Extrachromosomal circular DNAs (eccDNA’s) can be divided into two major classes based on their size (Ref 4):

1. Small polydisperse circular DNA’s of 150-20,000bps found in both nucleus and cytoplasm.
2. Large circular DNAs 150,000 – 900,00bps found in nucleus only.

In addition to these two, recently a team of scientists from the University of Virginia and University of North Carolina in the US have discovered a previously unidentified 3rd type of extrachromosomal small circular DNA molecule in mouse and human cells (Ref.1). This new type of DNA was termed as MicroDNA but unlike their larger counterparts; they contain non-repetitive sequence and are smaller (200-400bps) in size and usually found associated with particular genes. It appears that they are produced by excision or micro deletions of small sections of chromosomal DNA(Ref.1). They are enriched in 5’ untranslated regions of genes, exons and CpG islands (Ref 1). These DNA circles were identified by ultra-high throughput sequencing and by a new bioinformatics program(Ref.1).

These findings suggest that the DNA in different tissues may exhibit more variation (mosaicism) than previously thought as a result of these microdeletions. PBMCs (Peripheral Blood Mononuclear Cells), or blood cells that are normally used for DNA sequencing may give misleading results if microdeletions have occurred in the DNA of other tissue cells but not in the blood cells. This may have immediate consequences on genetic screening of diseases like Autism and Schizophrenia which could be a result of somatic microdeletions of related genes in brain tissue. Similarly, for tumors resulting from various types of cancer, using blood cells DNA may give misleading results (Ref1).

References:

1. Extrachromosomal MicroDNAs and Chromosomal Microdeletions in Normal Tissues ; Science DOI: 10.1126 /  science.1213307 Yoshiyuki Shibata 1,*, Pankaj Kumar1,*, Ryan Layer1, Smaranda Willcox2, Jeffrey R. Gagan1, Jack D. Griffith2, Anindya Dutta1,†
2. Somatic mosaicism in healthy human tissues; Trends in Genetics Volume 27, Issue 6, June 2011, Pages 217–223; Subhajyoti De
3. Chromosomal mosaicism goes global. Molecular Cytogenetics 2008, 1:26 Ivan Y Iourov, Svetlana G Vorsanova and Yuri B Yurov
4. Extrachromosomal DNA in mammalian cells. Tsitologiia. 1990; 32(11):1061-71. [Article in Russian] Sal’nokov.KV. PubMed ID: 2093240