Small supernumerary marker chromosomes and the nuclear architecture of sperm – a study in a fertile and an infertile brother

Abstract

Small supernumerary marker chromosomes (sSMC) are found about four times more frequently in subfertile compared to the general population. The reason for this finding is still unclear. However, a connection of interphase architecture and genome function is suggested. And as we found in a previous study the presence of sSMC influences the nuclear architecture of peripheral blood cells and fibroblasts, we hypothesized that sSMC could have similar effects in sperm cells possibly leading to infertility. Here we applied for the first time 3-dimensional interphase fluorescence in situ hybridization (3D-FISH) to characterize the position of an extrachromosome with respect to its sister-and selected other chromosomes (6, 15, 18, 19, 21, X, and Y) in sperm. Two sSMC carrier brothers with the identical sSMC derived from chromosome 15 were studied. One of the brothers was fertile and the other brother was infertile. Deviations from the normal positioning of chromosomes 21 and Y were seen in both brothers and for chromosomes 19 and X only in the infertile brother. Most striking were high rates of nullisomy and/or disomy for chromosomes 15, including sSMC (15), and 18 exclusively seen in the infertile brother. Overall, further evidence is provided that sSMC influence the nuclear architecture of a cell, including sperm. Further studies are necessary in sperm of fertile and infertile sSMC carriers to elaborate if the detected aneuploidy like that seen in the infertile brother is due to sSMC presence and disturbance of nuclear architecture.

Spatial organization of fibroblast and spermatocyte nuclei with different B-chromosome content in Korean field mouse, Apodemus peninsulae (Rodentia, Muridae)

“…It remains an area of intense research. Studies of DNA distribution within nuclei range from the analysis of physical interactions between short DNA fragments (Yaffe and Tanay 2011; Dostie and Bickmore 2012) to mapping of chromosome territories (Lemke et al 2002;Manvelyan et al 2008;Cremer and Cremer 2010) and the influence of small supernumerary marker chromosomes on interphase architecture (Klein et al 2012;Karamysheva et al 2015). For many cell types non-random distribution of transcriptionally active and nonactive chromatin in nucleus is well described (Bickmore 2013).…”

Genetic dosage and position effect of small supernumerary marker chromosome (sSMC) in human sperm nuclei in infertile male patient

“…The positioning of sSMC has been described previously in a study of spermatozoa 52 and in another describing its localization in somatic cells 4 . In both reports, it was found that sSMCs were localized near to their sister chromosomes.…”

“…Moreover, we did not find any repositioning of the chromosome 15 centromere. Karamysheva et al 52 have found that in the spermatozoa of an infertile brother, sSMC(15) preferred colocalization with sex chromosomes more frequently than in the fertile brother. A similar finding was noted in our study with the repositioning of the sex chromosomes towards the periphery of the cell nucleus in sSMC + gametes, resulting in colocalization to the sSMC ( Fig.…”

Chromosomes in the DNA era: Perspectives in diagnostics and research

“…Accordingly, there is strong evidence that defined chromosomal positioning is a prerequisite for the correct functioning of living cells. Thus, the comparison of the chromosomal constitution in healthy and disease-affected human brains [29], of sperm in healthy and infertile individuals [30,31] or in leukemic and normal bone marrow [32,33] can enlighten the as yet not understood pathomechanisms of many human diseases. Additionally, the impact of extra chromosomes on the nuclear architecture has been studied using this technique in humans [34] and other species [35], in addition to the general position of chromosomes in species other than humans [36,37].…”