European Journal of Human Genetics (2015) 23, 559 & 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15 www.nature.com/ejhg offering insight into the evolutionary BOOK REVIEW nature of intercellular variability, a scenario in which environmental and other inter- The human genome: better to be actions, such as virus integration, for example, can act as a substrate for adaptation processes that give rise to new dynamic cellular phenotypes. .............................................. The authors go on to describe a striking parallelism between the basic mechanisms of species evolution and the development of fi Genetic Heterogeneity and Human Disease cancer cells. In cancer evolution, the rst Edited by: H Heng non-clonal, or punctuated, phase is driven by Price: $69.00/CHF59.00 a high level of karyotype heterogeneity, ................. whereas the second clonal phase (microevo- Alessandra Ferlini and Sergio Fini lution) witnesses the evolution of many cells that share similar karyotypes via accumula- .................................................................................... tion of gene mutations. From this perspective, and given the high multiple levels of the European Journal of Human Genetics (2015) 23, 559; doi:10.1038/ejhg.2015.2 genetic/epigenetic heterogeneity that exist in most cancers, genomic heterogeneity can be enome-wide studies have shed light on chromosomes, fragmentations, genome chaos viewed as the driving force behind many Gthe unexpectedly high content of wide- and so on, are known to contribute to the diseases, cancer in particular. spread constitutional (germline) variability. generation of somatic karyotype heterogeneity This intriguing vision of a genome broken The initial concept of a static and one- over the course of time. down into a myriad of elementary particles dimensional genome has been replaced by a In this context, Liehr et al discuss the that form a supermolecular complex, includ- complex and dynamic aggregate of biomole- clinical impact of the small supernumerary ing nucleic acids and proteins, organized in cules arranged in a functional, as well as marker chromosomes that are often present terms of space and time inside each cell topological, relationship. Indeed, genome in a mosaic condition, and frequently and essentially representing ‘bioinformation positioning in cells is far from random, and emerge in routine cytogenetics testing. The packages’, calls for a thorough review of the fi its spatial placement in the nucleus provides clinical signi cance of these abnormalities is central dogma of biology, as rightly pointed additional information. complicated by the presence of cryptic and out by Sgaramella in his contribution that fi The authors of this fascinating book go one tissue-speci c mosaicisms, as pointed out in closes the book. Furthermore, the articles in step further, extending this three-dimensional the contribution by Hulten et al,who ‘Genetic Heterogeneity and Human Disease’ idea of genome structure to four dimensions, describe the high frequency of low-grade provide an extensive reference ‘library’ for describing the concept of a four-dimensional trisomy 21 mosaicism in the general those who wish to study the specifictopics ‘ (4D) genome in which the DNA and the population ( we may all have a touch of covered in depth, and represent a valuable ’ other macromolecular components inside the Down Syndrome ), and by Iourov et al in source of information and clues for a wide nuclei vary over time at a somatic level. theirdiscussiononthesomaticcell audience of professionals in human genetics fi Expanding on this concept, and signi cantly genomics of brain disorders. They point to and biomedicine, highlighting the importance shifting the focus of the study of genome a greater frequency of neural aneuploidies of a large-scale innovative approach to the fi variability/instability, the authors take an in- as a newly identi ed feature of neuro- study of the meaning and implications of a fl depth look at non-clonal chromosome aber- degenerative diseases, re ecting on other 4D genome. ’ rations, which are often ignored in routine disorders hallmarked by aneuploidy such cytogenetics analysis but have potential links as chromosome syndromes and cancer. A Ferlini and S Fini are at to disease conditions. Indeed, several other The book takes into account a wide range The UOL of Medical Genetics, alterations, such as free chromatin released of factors, including stochastic elements University of Ferrara, Ferrara, Italy from interphase nuclei, incompletely packed that produce somatic genetic heterogeneity, E-mail: fl[email protected] or [email protected].