Chromosome Inequality: Causes and Consequences of Non-Random Segregation Errors in Mitosis and Meiosis

Klaasen, Sjoerd J.; Kops, Geert J. P. L.

doi:10.3390/cells11223564

Cited by 15 publications

(11 citation statements)

References 139 publications

(190 reference statements)

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“…However, we noted a significant difference in parental age only between men with 47,XXY and controls and not between men with 47,XYY and controls; therefore, parental age did not explain the observed prevalence differences among genetic ancestry groups. Other nonrandom biological mechanisms contributing to nondisjunction may have a genetic or epigenetic basis with variations rooted in racial or ethnic ancestry . Alternatively, the cross-ancestry differences in prevalence could be secondary to sociodemographic factors, as enlistment in the US military requires conformation to a system of expectations that may be less attainable for minoritized individuals who also have physical, socioemotional, and learning differences that can be associated with SCAs .…”

Section: Discussionmentioning

confidence: 99%

Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort

Davis,

Teerlink,

Lynch

et al. 2024

JAMA Netw Open

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ImportanceThe reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry.ObjectivesTo determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls.Design, Setting, and ParticipantsThis cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023.ExposureGenomic identification of an additional X or Y chromosomeMain Outcomes and MeasuresOutcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio.ResultsOf 595 612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427 143 participants; 47,XYY: 625 of 427 143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean [SD], 4.30 [2.72] vs controls: mean [SD], 3.90 [2.47]; 47,XYY: mean [SD], 4.45 [2.90] vs controls: mean [SD], 3.82 [2.50]) and health care utilization (eg, median [IQR] outpatient encounters per year: 47,XXY, 22.6 [11.8-37.8] vs controls, 16.8 [9.4-28]; 47,XYY: 21.4 [12.4-33.8] vs controls: 17.0 [9.4-28.2]), while several measures of HRQOL were lower (eg, mean [SD] self-reported physical function: 47,XXY: 34.2 [12] vs control mean [SD] 37.8 [12.8]; 47,XYY: 36.3 [11.6] vs control 37.9 [12.8]). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median [IQR] encounters per year: 26.6 [14.9-43.2] vs 22.2 [11.3-36.0]) but lower Charlson Comorbidity Index scores (mean [SD]: 3.7 [2.7] vs 4.5 [4.1]).Conclusion and RelevanceIn this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.

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Section: Discussionmentioning

confidence: 99%

Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort

Davis,

Teerlink,

Lynch

et al. 2024

JAMA Netw Open

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“…Independent of the molecular underpinnings, the directionally asymmetric grip of the kinetochore suggests a previously unrecognized mechanism for promoting accuracy early in mitosis. The accuracy of mitosis is astounding, 73,74 and relies on a trial-and-error process where incorrect attachments lacking tension are released while correct tension-bearing attachments are stabilized. [8][9][10] The mechanisms proposed to explain this selectivity have focused primarily on plus end-attachments.…”

Section: Discussionmentioning

confidence: 99%

Kinetochores grip microtubules with directionally asymmetric strength

Larson,

Heitkamp,

Murray

et al. 2024

Preprint

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SUMMARYFor accurate mitosis, all chromosomes must achieve ‘bi-orientation’, with replicated sister chromatids coupled via kinetochores to the plus ends of opposing microtubules. However, kinetochores first bind the sides of microtubules and subsequently find plus ends by directed transport or when side-attached microtubules shorten and bring their ends to the kinetochores. Mitotic accuracy depends on the selective release of erroneous attachments and proposed mechanisms have focused mainly on plus-end attachments. Whether erroneous side-attachments are distinguished from correct side-attachments is unknown. Here we show that side-attached kinetochores are very sensitive to microtubule polarity, gripping six-fold more strongly when pulled toward plus versus minus ends. This directionally asymmetric grip correlates with changes in the axial arrangement of subcomplexes within the kinetochores, suggesting that internal architecture dictates attachment strength. We propose that the kinetochore’s directional grip promotes accuracy specifically during early mitosis, by stabilizing correct attachments even before both sisters have found plus ends.

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“…The malfunction of SAC genes allows cells to transit through mitosis prematurely, which inevitably leads to chromosomal instability and aneuploidy. 42 , 43 Accordingly, IPA pathway analysis predicted increased CIN in both LS mucUA and LS mucCRC ( Supplementary Table S9 ).…”

Section: Discussionmentioning

confidence: 99%

Mitotic abnormalities precede microsatellite instability in lynch syndrome-associated colorectal tumourigenesis

Pussila,

Laiho,

Törönen

et al. 2024

eBioMedicine

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Chromosome Inequality: Causes and Consequences of Non-Random Segregation Errors in Mitosis and Meiosis

Cited by 15 publications

References 139 publications

Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort

Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort

Kinetochores grip microtubules with directionally asymmetric strength

Mitotic abnormalities precede microsatellite instability in lynch syndrome-associated colorectal tumourigenesis

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