Originally published as Genetics Published Articles Ahead of Print on January 21, 2007.

Genetics, Vol. 175, 1561-1569, April 2007, Copyright © 2007
doi:10.1534/genetics.106.068171

Mlh1 Deficiency in Zebrafish Results in Male Sterility and Aneuploid as Well as Triploid Progeny in Females

Harma Feitsma^*, Marcelo C. Leal, Peter B. Moens, Edwin Cuppen^*,1 and Rüdiger W. Schulz

^* Hubrecht Laboratory, Centre for Biomedical Genetics, 3584 CT, Utrecht, The Netherlands, Laboratory of Endocrinology, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands and Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada

¹ Corresponding author: Hubrecht Laboratory, Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
E-mail: ecuppen{at}niob.knaw.nl

In most eukaryotes, recombination of homologous chromosomes during meiosis is necessary for proper chromosome pairing and subsequent segregation. The molecular mechanisms of meiosis are still relatively unknown, but numerous genes are known to be involved, among which are many mismatch repair genes. One of them, mlh1, colocalizes with presumptive sites of crossing over, but its exact action remains unclear. We studied meiotic processes in a knockout line for mlh1 in zebrafish. Male mlh1 mutants are sterile and display an arrest in spermatogenesis at metaphase I, resulting in increased testis weight due to accumulation of prophase I spermatocytes. In contrast, females are fully fertile, but their progeny shows high rates of dysmorphology and mortality within the first days of development. SNP-based chromosome analysis shows that this is caused by aneuploidy, resulting from meiosis I chromosomal missegregation. Surprisingly, the small percentage of progeny that develops normally has a complete triploid genome, consisting of both sets of maternal and one set of paternal chromosomes. As adults, these triploid fish are infertile males with wild-type appearance. The frequency of triploid progeny of mlh1 mutant females is much higher than could be expected for random chromosome segregation. Together, these results show that multiple solutions exist for meiotic crossover/segregation problems.

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