Structural Genomic Changes During Mammalian Ontogeny: A New Dimension

Abstract

mutations, happening spontaneously or from environmental insult. Mammalian brains are somatic mosaics, due to aneuploidy and genomic copy number variations. Recently, it also has been found that active transposable elements, long interspersed nuclear elements 1 (LINE-1) in neuronal tissue, contribute to the mosaicism, with tissue specificity [4,5]. LINE-1 elements influence chromosome integrity and gene expression. Retrotransposition activity for the LINE-1 elements was strong during neuronal different iation and occurred with high frequency. Activity was also found in the adult brain. Regulatory events leading to LINE-1 activation were elucidated [6]. These observations led to the proposition that LINE-1 element transposition has a purpose: adaptive increase in neuronal variation and plasticity and in brain-controlled phenotypes [7]. However, specific sites of insertion will need to be located to confirm this idea. Another line of evidence, implicating the occurrence of developmentally-programmed genomic structural changes, comes from a recent study of the gene for ribosomal DNA (rDNA) during ontogeny in the mouse [8]. There are hundreds of copies of rDNA in each cell on several chromosomes. The rDNA of the mice was found to present several SNPs in promoter regions of the gene. The relative percentages of these variant SNPs, indicative of rDNA structural status, were determined in sperm, embryos and two differentiated tissues, lung and liver, using a highthroughput quantitative pyrosequencing technique. The percentage of the variants changed in the differentiated tissues: in the males they differed significantly in lung and liver compared with sperm, and in the females they differed in lung compared with liver. Second, within-litter Differentiated tissues are elaborated during mammalian ontogeny by the coordinated sequential execution of cell type-specific gene expression programs. A common supposition is that basic inherited genomic structure remains constant during this process. This supposition is critically important for the recently developed procedures for obtaining induced pluripotent stem cells from somatic tissues, with great potential for clinical applications. Is this supposition comprehensively true? Would it not make sense, in terms of energy conservation, to program the necessary changes permanently through alterations in genome structure? Several special-case examples of such purposeful, site-specific manipulation of primary genome structure have long been known to exist [1,2] and have obvious functional consequences during a specific life-cycle stage. These are most common in unicellular organisms but also occur in higher organisms, for example, amplification of specific genes for rapid production of proteins, such as those of the chorion of insect eggs, and rearrangements to produce diversification of variant surface glycoprotein in trypanosomes. Vertebrates also utilize genomic re arrangement to enhance diversity of antigen receptors, through the action of the DNA sequence-specific V(D)J recombinases. Evidence is emerging that programmatic modification of the primary structure of the inherited genome may in fact be common, during development and in adult tissues. Structural genetic differences are known to occur between cell populations within an individual, including individual humans, constituting somatic mosaicism [3]. These differences, though frequent, have been interpreted as abnormalities, resulting from uncorrected somatic