Ontogenetic and Pathogenetic Views on Somatic Chromosomal Mosaicism

Abstract

Intercellular karyotypic variability has been a focus of genetic research for more than 50 years. It has been repeatedly shown that chromosome heterogeneity manifesting as chromosomal mosaicism is associated with a variety of human diseases. Due to the ability of changing dynamically throughout the ontogeny, chromosomal mosaicism may mediate genome/chromosome instability and intercellular diversity in health and disease in a bottleneck fashion. However, the ubiquity of negligibly small populations of cells with abnormal karyotypes results in difficulties of the interpretation and detection, which may be nonetheless solved by post-genomic cytogenomic technologies. In the post-genomic era, it has become possible to uncover molecular and cellular pathways to genome/chromosome instability (chromosomal mosaicism or heterogeneity) using advanced whole-genome scanning technologies and bioinformatic tools. Furthermore, the opportunities to determine the effect of chromosomal abnormalities on the cellular phenotype seem to be useful for uncovering the intrinsic consequences of chromosomal mosaicism. Accordingly, a post-genomic review of chromosomal mosaicism in the ontogenetic and pathogenetic contexts appears to be required. Here, we review chromosomal mosaicism in its widest sense and discuss further directions of cyto(post)genomic research dedicated to chromosomal heterogeneity.

Keywords: aneuploidy; chromosomal instability; chromosome; chromosome heterogeneity; genome instability; genomic variations; somatic mosaicism.

Figure 1

Profiling of decrease trend in somatic chromosomal mosaicism (SCM) rates throughout the prenatal development (according to [3,13,16,18,19,22,23,24,25,28,31,35]). Up to 70% of preimplantation embryos exhibit SCM/chromosome instability (CIN). About 25% of viable fetuses exhibit SCM/CIN (including chromosomal mosaicism confined to embryonic and extraembryonic tissues); in addition, up to 25% non-viable fetuses (spontaneous abortions) exhibit SCM at this development stage, as well. Later gestational periods are poorly addressed in terms of SCM. Nonetheless, cytogenetic analyses in the second and third trimester (prenatal diagnosis) show a significant decrease of SCM incidence as to cytogenetic studies of spontaneous and induced abortions. Therefore, one can suggest the existence of selective pressure against fetuses with SCM/CIN in early human ontogeny. The x-axis corresponds to the timeline from conception to birth, whereas the y-axis corresponds to the proportion of embryos/fetuses affected by SCM/CIN; the question marks fetal periods, which are poorly addressed in terms of SCM/CIN by molecular cytogenetic techniques.

Figure 2

Schematic representation of the bottleneck model for the explanation of selective pressure in fetuses with non-mosaic chromosomal aberrations (mainly, aneuploidy, and polyploidy), SCM and CIN throughout prenatal development. The bottleneck effect may be achieved both by the natural selection pressure and by programmed cell death.

Figure 3

Hypothetical role of SCM/CIN in aging. It appears that accumulation of somatic mutations (e.g., aneuploidy, alterations to chromosome structure, repeat length variations, intragenic sequence changes, etc.) interplays with cell senescence. The result of this interplay might produce either aging at the tissular level or tissue degeneration, which is likely to be responsible for aging of an organism, as a whole.