Written by Teresa Chiang, Richard M. Schultz, and Michael A. Lampson, Meiotic Origins of Maternal Age-Related Aneuploidy (cited below), focuses on a major category of chromosome mutations known as aneuploidy. As defined by An Introduction to Genetic Analysis (cited below), if the chromosome number of an individual differs from the wild type by part of a chromosome set, then this individual organism is considered an aneuploid. As I mentioned during our discussion in class, it is important to note that aneuploidy is not considered as just an extra chromosome. Rather, aneuploidy could be considered as both an extra chromosome or a missing chromosome. In other words, in a cell, aneuploidy is defined as the presence of an abnormal number of chromosomes. As stated by our article, what leads to aneuploidy in the egg and embryo in a female are chromosome segregation errors that mostly occur during meiosis 1. As also stated in our article, in other words, most human aneuploidies originate not from the sperm but rather the egg. Due to most chromosome segregation errors occurring during meiosis 1, aneuploidy is known to be the leading genetic cause of developmental disabilities and spontaneous abortions. There is a positive correlation found between the incidence of aneuploidy and women’s age such as if there is an increase in women’s age then there will be an increase in the incidence of aneuploidy observed.
To provide more relevant background information on our article’s subject matter, I think it is also important to include information regarding chromosomes and segregation in oocytes. An oocyte is a cell in an ovary that undergoes meiotic division to eventually form an ovum (mature reproductive cell found in a female). Meiosis consists of two rounds of cell divisions that will eventually create haploid gametes (n=23). The homologous chromosomes in which recombination and synapsis takes place occurs in prophase 1. At the end of meiosis l, these homologous chromosomes separate. On the other hand, at the end of meiosis ll, sister chromatids separate. As mentioned in the previous paragraph, the incorrect chromosomal separation leads to aneuploidy in the cell. Heterozygous centromeres indicate improper segregation after meiosis l (most trisomy disorders are due to errors specifically in meiosis l) whereas homologous centromeres indicate improper segregation after meiosis ll. As stated by our article and discussed during our lecture in class, meiosis in females begins during fetal development and stops at prophase 1 before birth and does not start again until prior to ovulation in adulthood. On the other hand, this process is fully activated throughout the lifetime in males after puberty.
Meiotic Origins of Maternal Age-Related Aneuploidy proposes several hypotheses pertaining to the cause of maternal age-related aneuploidy. The article reviews these three main possibilities: 1. Recombination errors in early meiosis- frequency and location, 2. Defective spindle assembly checkpoint (SAC) at meiosis 1, and 3. Deterioration of sister chromatid cohesion with age. The article discusses findings in each of the three possibilities that I just mentioned. In addition, the article suggests that the leading cause of age-related aneuploidy is the deterioration of cohesion with increasing maternal age.
The first possibility as just mentioned regards to recombination errors in early meiosis. As stated on page 2 of our article, meiotic recombination “results in the exchange of genetic material between chromatids of homologous chromosomes.” The human studies described in this article suggest that what may lead to aneuploidy are different recombination patterns. Their studies, based on the data collected by using both a mouse and human model as described on page 3, concluded that reduced recombination is associated with trisomy and that exchanges that are too close to either telomere or centromere are associated with trisomy.
The second possibility as mentioned before regards to defective spindle assembly checkpoint (SAC) at meiosis l. As I described in the relevant background information I included in this article review, since aneuploidy is directly related to chromosome segregation errors, the scientists looked at the first cell division. As stated by the article on page 3, the SAC functions in meiosis l as in mitosis. It delays anaphase until proper kinetochore-microtubule attachments are successfully formed. The three SAC proteins this article discussed were: MAD2L1, BUB1B, and TTK. As also described on page 3, these three SAC proteins localize to unattached kinetochores in meiosis l and come off once kinetochore-microtubule attachments form. This portion of the study also used the mouse model. Disrupting the three proteins listed above in mice resulted in both an earlier anaphase and an increased aneuploidy frequency.
The third and final possibility as mentioned before, had to do with the deterioration of sister chromatid cohesion with age. This section of the study also experimented with yeast which showed that only when the mitotic cohesion protein known as SCC1 is expressed before S phase, the sister chromatids are effectively held together. Therefore, this cohesion is established in the S phase. The results from mammalian cells that expressed GFP-tagged cohesion proteins, showed that chromatin-bound cohesions are stable from S phase through anaphase as described on page 4 in our article. The results from the mammalian cells show that mitotic cohesion is in fact established in S phase and remain bound to chromosomes until cleaved at anaphase. Furthermore, in yeast, based on the data collected, meiotic cohesion was seen similarly established in S phase. In addition, as seen in figure 2 on page 3, cohesion along chromosome arms keep bivalent together in meiosis l whereas sister chromatids’ centromere cohesion is held together in meiosis ll. A shift in chiasmata placement or premature bivalent separation in meiosis l may result in a defect in cohesion distal to crossover sites as also seen in figure 2B on page 3. On the other hands, premature separation of sister chromatids in meiosis ll may result in reduced centromere cohesion. Finally, this possibility also experimented with transgenic mice. They engineered the mice to test two critical parts of this hypothesis. These two being: 1. Whether new cohesion can be established after S phase, and 2. The stability of cohesins with age. The first part of this hypothesis was addressed by inserting TEV protease specific cleaving sites into the endogenous locus known as REC8. This experimental method could be visually seen in figure 3 on page 4. On the other hand, the second critical part of this hypothesis, stability of cohesin proteins, was tested by deleting the Smc1b gene in mice. The overall results from these two critical parts of the cohesin hypothesis suggests that “cohesins load onto chromosomes and establish cohesion only during fetal development, and he cohesion complexes, once loaded, remain functional until meiosis resumes” (page 4).
Overall, hypothesis #1, regarding recombination errors in early meiosis-frequency and location, is not highly accepted because recombination occurs at the onset of meiosis and is not age-dependent. Based on this, there is no obvious correlation between recombination errors, either in the frequency or positions of exchange, and age. A possible explanation to this, as we discussed during our presentation, may be that recombination errors make certain chromosomes more vulnerable to age-dependent deterioration of another process years later. Hypothesis #2, defective spindle assembly checkpoint (SAC) and meiosis l, was also not accepted due to no significant differences shown in the data the scientist collected. The results pertaining to this hypothesis suggested that the function of SAC in young and old oocytes in mice is too similar to conclude that there is a correlation in SAC function and an increase in age. Finally, hypothesis #3, deterioration of sister chromatid cohesion with age, was accepted. The data collected showed that a gradual loss of cohesin proteins from chromosomes, in mouse models, is a major factor in maternal-age related aneuploidy. However, it is important to note that it is crucial that more research need to be done to truly understand the mechanisms that exist to maintain cohesin complexes and to determine their timescale.
Although I found many strengths and weaknesses of this paper, Meiotic Origins of Maternal Age-Related Aneuploidy, one of the strengths that caught my attention the most was that they used a mouse model in one way or another in every single one of the three hypotheses that they tested. I absolutely loved that they used a mouse model to study age-related aneuploidy because of how similar they are to humans. Therefore, a lot of the data they collected from their study may be significantly beneficial to humans. Page 2 from this article described why the experimenters decided to use the mouse model. As stated on page 2, “The mouse is a good model for studying age-related aneuploidy because, as in humans, advanced maternal age is associated with an increase in aneuploidy incidence in naturally aged mice.” One weakness I found in this paper was that they did not discuss any other additional risk factors pertaining to an increased risk of aneuploidy. Although I understand that this paper focused on maternal age-related aneuploidy, I believe it would have been nice to include at least a brief description of other risk-factors to give the readers additional background knowledge. For instance, in a study performed by Young Kim, Jee Lee, Soo Kim, Sung Shim, and Dong Cha, Maternal age-specific rates of fetal chromosomal abnormalities in Korean pregnant women of advanced maternal age (cited below), included that environmental factors also increase the risk of aneuploidy in their introduction section. Therefore, even though that paper also focused on age-specific chromosomal abnormalities, they discussed other possible risk factors. Overall, I believe a bit more of background knowledge would have been beneficial to the readers.