The in vitro survival of human monosomies and trisomies as embryonic stem cells

Abstract

Chromosomal aneuploidies are responsible for severe human genetic diseases. Aiming at creating models for such disorders, we have generated human embryonic stem cell (hESC) lines from pre-implantation genetic screened (PGS) embryos. The overall analysis of more than 400 aneuploid PGS embryos showed a similar risk of occurrence of monosomy or trisomy for any specific chromosome. However, the generation of hESCs from these embryos revealed a clear bias against monosomies in autosomes. Moreover, only specific trisomies showed a high chance of survival as hESC lines, enabling us to present another categorization of human aneuploidies. Our data suggest that chromosomal haploinsufficiency leads to lethality at very early stages of human development.

Gene expression analysis of induced pluripotent stem cells from aneuploid chromosomal syndromes

“…In recent years, several aneuploid human embryonic stem cell (ESC) lines have been established as models for studying human aneuploidy syndromes [12-15], which has expanded the scope of aneuploidy research, leading to investigations of other syndromes caused by the gain or loss of a chromosome. Compared with ESC models, induced pluripotent stem cell (iPSC) models, the successful reprogramming of differentiated human somatic cells into a pluripotent state, can be applied to more easily study human disease [16].…”

The high abortion cost of human reproduction

“…A rationale for such an improvement comes from studies comparing aneuploidy in very young embryos (cleavage stage and blastocysts) to conceptuses that spontaneously aborted after a pregnancy had been clinically detected. At the early embryo stages, monosomy (missing one homolog from one or more of the 23 pairs of homologous chromosomes) and trisomies (a extra chromosome at one or more of the 23 pairs of homologous chromosomes) were found to be equally common [16][17][18]. But among conceptuses that survive to clinical detection, and then abort, essentially no autosomal monosomies were observed (<<1%; [19][20][21][22]).…”

“…This study therefore eliminates any elevation in chromosomal abnormality rate that may be an artifact of: i) women using ART clinics not being a random sample of the population as a whole, and ii) chemical stimulation of the mother to ovulate multiple follicles during a single menstrual cycle. To guarantee fertilization, each egg was fertilized via intracytoplasmic sperm injection (ICSI), and then a cell from a 3-day old embryo was screened via FISH (fluorescence in situ hybridization) for ploidy level for nine chromosomes (13,16,18,21,22,15,17, X, and Y). Sampling a single cell from an embryo may produce an inaccurate estimate of the proportion of karyotypically abnormal embryos due to mosaicism, but in this study the researchers reanalyzed samples of embryos scored as karyotypically abnormal on day-3 (based on a single cell) again on day-5 (scoring every cell in the embryo) and found 92% concordance (i.e, 92% of all day-3 embryos scored as abnormal -by assay of a single cellwere also scored the same two days later when all cells were measured), so this potential problem was not substantial.…”

CIN and Aneuploidy: Different Concepts, Different Consequences

“…For instance, in humans, most types of systemic aneuploidy are embryonic lethal. [65] The major exceptions are the trisomy of chromosome 13, 18, and 21 (Patau's, Edward's, and Down's syndromes, respectively). However, these aneuploidies have a severe impact on development and life expectancy of the affected individuals: the median survival age of children with Edward's and Patau's syndrome is less than 2 weeks [66] and Down's syndrome individuals suffer from congenital disease, and mental retardation.…”