Consequences of aneuploidy in sickness and in health

Abstract

A link between aneuploidy and miscarriage or cancer in humans has been known for a long time. However, only in recent years the development of experimental models of whole-chromosome aneuploidy has allowed investigators to take a closer look at how aneuploidy affects individual cells. Collectively, recent studies using these models have shown that aneuploidy induces transcriptomic and proteomic changes, chromosomal instability, and adaptation. In this article, we discuss the findings from these recent studies and present current and emerging models on how aneuploidy may be deleterious in certain contexts, but beneficial in others.

Global Analysis of Gene Expression in Response to Whole-Chromosome Aneuploidy in Hexaploid Wheat

“…Aneuploidy, in which the copy number of one or more chromosomes deviates from the balanced multiple of a haploid complement, represents a large-effect mutation that gravely affects cellular physiology and has profound phenotypic consequences (Torres et al, 2008;Birchler and Veitia, 2012;Dodgson et al, 2016;Rutledge and Cimini, 2016). Apparently, all biological consequences of aneuploidy are rooted in dosage effects of genes encoded by the numerically altered chromosome(s); nevertheless, the mechanisms whereby a specific end phenotypic manifestation being brought about by aneuploidy can be due to indirect effects of the numerically altered chromosome(s) and, hence, can be extremely complex.…”

“…Model cellular aneuploid systems often concern only gain of chromosome(s), because the genetic background is either haploid or diploid, neither of which can usually sustain the loss of a whole chromosome (Rutledge and Cimini, 2016). For still mysterious reasons, plants in general are more tolerant to aneuploidy than animals.…”

“…Accumulated studies in model cellular systems and disparate organisms have established that aneuploidy can exert two broad types of impact on gene expression: (1) primary or cis-effects, that is, expression of the genes residing on the aneuploid chromosomes is altered due to dosage effects; and (2) secondary or trans-effects, that is, expression of a sizable portion of genes located on all the unvaried chromosomes is altered due to aneuploidy-induced activation and/or suppression of cellular pathways, a phenomenon dubbed the aneuploidy transcriptional response (Sheltzer et al, 2012;Birchler, 2014;Dürrbaum and Storchová, 2016). The molecular underpinnings of both the cis-and trans-effects on gene expression by aneuploidy remain to be fully understood (Birchler and Veitia, 2007;Dürrbaum and Storchová, 2016;Rutledge and Cimini, 2016). Meanwhile, dosage compensation also may occur, whereby the expression of certain genes located on some aneuploid chromosome(s) remains unchanged in spite of their copy number alterations (Guo and Birchler, 1994;Birchler et al, 2001;Hose et al, 2015;Gasch et al, 2016).…”

“…Consequently, the normal dosages of thousands of genes located on the aneuploid chromosome(s) are altered simultaneously, which produces profound effects on virtually all aspects of cellular physiology and often, but not always, impairs fitness (Torres et al, 2008;Williams and Amon, 2009;Rutledge and Cimini, 2016). Aneuploidy bears significant relevance to human health, as the condition is the leading cause of mental retardation and spontaneous abortion and a hallmark of cancer cells (Weaver and Cleveland, 2006).…”

INPP5E Preserves Genomic Stability through Regulation of Mitosis

“…Mitotic failure during embryonic growth leads to spontaneous abortion as well as a variety of developmental syndromes (31). After birth, chromosomal instability promotes carcinogenesis (32).…”