Aneuploidy in male Indian muntjac cells is limited to the Y2 chromosome

Vig, Baldev K.; Henderson, Amy

doi:10.1093/mutage/13.1.33

Cited by 5 publications

(3 citation statements)

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“…It is noteworthy that any potential loss of a single chromosome in Indian muntjac females would represent the loss of 1/3 of the haploid genome, which would seriously compromise cell viability. In agreement, previous work reported that chromosome missegregation and aneuploidy in Indian muntjac primary fibroblasts were essentially limited to the smallest Y 2 chromosome in males [ 47 ].…”

Section: Discussionsupporting

confidence: 90%

Chromosome Segregation Is Biased by Kinetochore Size

et al. 2018

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SummaryChromosome missegregation during mitosis or meiosis is a hallmark of cancer and the main cause of prenatal death in humans. The gain or loss of specific chromosomes is thought to be random, with cell viability being essentially determined by selection. Several established pathways including centrosome amplification, sister-chromatid cohesion defects, or a compromised spindle assembly checkpoint can lead to chromosome missegregation. However, how specific intrinsic features of the kinetochore—the critical chromosomal interface with spindle microtubules—impact chromosome segregation remains poorly understood. Here we used the unique cytological attributes of female Indian muntjac, the mammal with the lowest known chromosome number (2n = 6), to characterize and track individual chromosomes with distinct kinetochore size throughout mitosis. We show that centromere and kinetochore functional layers scale proportionally with centromere size. Measurement of intra-kinetochore distances, serial-section electron microscopy, and RNAi against key kinetochore proteins confirmed a standard structural and functional organization of the Indian muntjac kinetochores and revealed that microtubule binding capacity scales with kinetochore size. Surprisingly, we found that chromosome segregation in this species is not random. Chromosomes with larger kinetochores bi-oriented more efficiently and showed a 2-fold bias to congress to the equator in a motor-independent manner. Despite robust correction mechanisms during unperturbed mitosis, chromosomes with larger kinetochores were also strongly biased to establish erroneous merotelic attachments and missegregate during anaphase. This bias was impervious to the experimental attenuation of polar ejection forces on chromosome arms by RNAi against the chromokinesin Kif4a. Thus, kinetochore size is an important determinant of chromosome segregation fidelity.

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Section: Discussionsupporting

confidence: 90%

Chromosome Segregation Is Biased by Kinetochore Size

et al. 2018

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“…Conditions that readily induce aneuploidy in human and mouse cells only allow for loss or gain of the small sex chromosome Y2 in muntjac cells. Missegregation of the large chromosomes in muntjac is not tolerated due to gene dosage effects [27]. Most mammals must live with the occasional aneuploid cell, however, because they fully depend on spindle dynamics to detect and prevent chromosome missegregation [12,25].…”

Section: Coping With Merotelic Attachmentsmentioning

confidence: 99%

Merotelic attachments and non-homologous end joining are the basis of chromosomal instability

2010

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Although the large majority of solid tumors show a combination of mitotic spindle defects and chromosomal instability, little is known about the mechanisms that govern the initial steps in tumorigenesis. The recent report of spindle-induced DNA damage provides evidence for a single mechanism responsible for the most prominent genetic defects in chromosomal instability. Spindle-induced DNA damage is brought about by uncorrected merotelic attachments, which cause kinetochore distortion, chromosome breakage at the centromere, and possible activation of DNA damage repair pathways. Although merotelic attachments are common early in mitosis, some escape detection by the kinetochore pathway. As a consequence, a proportion of merotelic attachments gives rise to chromosome breakage in normal cells and in carcinomas. An intrinsic chromosome segregation defect might thus form the basis of tumor initiation. We propose a hypothesis in which merotelic attachments and chromosome breakage establish a feedback loop that results in relaxation of the spindle checkpoint and suppression of anti-proliferative pathways, thereby promoting carcinogenesis.

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“…Another insight emerging from these recent studies [7,14] is that there does not appear to be an obvious relationship between the rates of chromosome missegregation for certain chromosomes and the severity of the corresponding aneuploidy. An earlier study in male Indian muntjac cells showed that aneuploidies for the Y chromosomes (the Indian muntjac possesses two Y chromosomes, denoted Y1 and Y2) were the only aneuploidies observed in untreated cell populations, with aneuploidy for the Y2 chromosome (the smaller of the two) being the most common [15], suggesting that cells carrying aneuploidies for any of the other, larger chromosomes are unlikely to survive. Similarly, aneuploidy for chromosome 1 is almost never observed in human miscarriages [4], hinting to the possibility that the selective pressure against such aneuploidy is so In Indian muntjac (A), centromere-kinetochore size strongly correlates with the probability of a chromosome to missegregate during mitosis.…”

Section: Current Biologymentioning

confidence: 98%