Insight into basis of chromosomal birth defects

23 September 2009

Meiosis is the process of cell division that halves the number of chromosomes per cell and in animals this process results in the production of gametes – sex cells. During the initial phase of meiosis homologous chromosome pairs align and one of each pair is subsequently separated into a different cell, resulting in a haploid cell. Failure of chromosomes to separate properly during the final stages of meiosis in the formation of human oocytes (egg cells) – a phenomenon that becomes increasingly common with advancing maternal age – causes aneuploidy (abnormal number of chromosomes) in the oocyte and any subsequent fetus. Many forms of aneuploidy are lethal, but the milder forms are a relatively common genetic cause of birth defects such as Down, Edwards and Patau syndromes.

Researchers at Florida State University studying chromosomal structural organisation in yeast have made a discovery that may explain why chromosomes fail to segregate properly (see press release). The pairing of homologous chromosomes is mediated by the synaptonemal complex (SC), which also plays an important role in meiotic recombination and genomic integrity. The importance of this complex is demonstrated by its conservation across species. Jin et al have shown that the absence of a protein Pds5 results in a failure of homologous chromosomes to pair and lead to formation of SC like complex between sister chromatids [Jin H et al. (2009) J Cell Biol. 186(5):713-25].

Previous studies have shown that Pds5 is required in maintaining cohesion between sister chromatids, an important step required prior to the assembly of the SC complex. To discover more about the role of Pds5 in this process, the researchers created yeast mutant cells in which the Pds5 protein was completely depleted specifically during meiosis. Surprisingly these mutant cells had only minor defects in sister chromatid cohesion, but homologous chromosomes failed to pair and an SC like structure formed between sister chromatids, resulting in them pairing instead. By investigating one of the factors that interacts with Pds5 they were also able to demonstrate a possible mechanism that lead to a disruption. The researchers suggest that Pds5 modulates the function of another protein, Rec8 in order facilitate the morphological changes in chromosomes which are required for normal segregation during meiosis, as well as other functions.

A number of other factors also interact with Pds5 and these are currently being investigated. The researchers hope “to achieve a comprehensive understanding of the molecular mechanisms behind chromosomal birth defects and see our research contribute to the creation of targeted interventions during meiosis" (see press release).

Comment: Whilst understanding the molecular mechanisms underlying human birth defects is important, any form of ‘targeted intervention’ during meiosis would not be practical or affordable for the vast majority of cases. Almost 95% of birth defects (the majority of which have genetic causes) occur in the developing world where high-tech prenatal genetic manipulation would certainly not be feasible. The PHG Foundation is currently embarking on a new project to reduce the suffering associated with birth defects in poorer countries by simple, practical measures to improve care and prevention.

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