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Sexually reproducing organisms produce gametes with half the somatic chromosome number to maintain genome size with each generation. This is achieved through meiosis, in which two rounds of chromosome segregation follow a single round of DNA replication. The first meiotic division separates maternal and paternal copies of each chromosome, but, in order for this segregation to occur properly, the homologous chromosomes must first pair with their correct partner and then become physically connected so that they orient together on the meiotic spindle.
Errors in homologous chromosome segregation are a leading cause of human aneuploidy. In human females, an estimated 10–30% of meioses experience errors in segregation that yield aneuploid oocytes, with most aneuploid conceptuses aborting before term. This means that aneuploidy is an important cause of pregnancy loss (35% of miscarriages and 4% of stillbirths). The number of aneuploid births approaches 0.3% [1–5], and many of these babies face devastating developmental disabilities and mental retardation. Some examples of human hereditary diseases caused by aneuploidies are Down, Klinefelter, Edwards and Turner syndromes .
A key task for researchers in meiosis is to identify and understand the mechanisms that direct the proper segregation of chromosomes, with the goal of explaining the various causes of aneuploidy. Sister chromatid cohesion and mechanisms that connect the homologous chromosomes in pairs (recombination and centromere interactions) provide the physical basis required for the chromosomes to correctly position at the spindle equator at metaphase I. In addition, meiotic segregation fidelity is ensured by cell-cycle control mechanisms, such as the spindle checkpoint, which monitors defective chromosome alignment to control the metaphase–anaphase transition. The four minireviews in this series provide a review of the function and regulation of important systems that play key roles in promoting proper meiotic chromosome segregation and have a significant impact on human health.
The first paper, by Susannah Rankin , explores the role of cohesins in tethering sister chromatids until the first meiotic cell division. This review provides an analysis of the potential roles for both mitotic cohesins and meiosis-specific cohesins. It also discusses the unique regulation of cohesin establishment and maintenance demanded by meiosis-specific chromosome behaviors, and the ways that regulators of cohesin may contribute to modulating various types of cohesin association with chromatin in response to meiotic cell-cycle progression.
The second review, by Christopher Sansam and Roberto Pezza , investigates meiotic recombination as a major mechanism providing the connection between homologous chromosomes that is required to facilitate their segregation at meiosis I. It focuses on the critical biochemical events of homologous recombination at early stages of meiotic prophase I. Special attention is paid to activities that promote formation of the joint molecules that are important for establishing both homologous-dependent pairing and for synapsis of the homologous chromosomes. The review describes current major challenges in elucidating the biochemical mechanism of recombination, the roles of recombinases, and their coordinated action with ancillary proteins.
In the third review, Emily Kurdzo and Dean Dawson  explore the roles that centromere–centromere pairing interactions may play in the proper segregation of homologous chromosome pairs in meiosis I. They describe experiments leading to the discovery of centromere pairing, and summarize new insights into the involvement of synaptonemal complex proteins in the generation and stabilization of these centromere-pairing interactions. The review also presents alternative models that may explain how centromere pairing could assist in proper orientation of both exchange and non-recombinant chromosomes on the meiotic spindle.
The last review in the series, by Gary Gorbsky , presents a historical perspective of discoveries giving rise to the concept of the spindle checkpoint, and contributions of meiotic and mitotic studies to defining the current view of the protein network that monitors defective chromosome alignment. This review includes an overview of protein interactions that contribute to the spindle checkpoint and how those are regulated by phosphorylation. Importantly, this review highlights the significance and challenges in our current understanding of checkpoint signaling in controlling complex meiotic divisions.
Roberto J. Pezza is an assistant member of the Oklahoma Medical Research Foundation, and an adjunct associate professor of the Department of Cell Biology, University of Oklahoma Health Science Center, USA. He obtained his PhD in Biochemistry from the Universidad Nacional de Cordoba, Argentina. After receiving post-doctoral training at the National Institutes of Health in Bethesda, MD, he was appointed an assistant member of the Oklahoma Medical Research Foundation in 2009 to further research on recombination and chromosome dynamics in mammalian meiosis. His research is important in delineating common causes of chromosome segregation errors that directly result in the large number and increasing incidence of birth defects associated with aneuploidy.