Academic journal article Genetics

Crossover Distribution and Frequency Are Regulated by Him-5 in Caenorhabditis Elegans

Academic journal article Genetics

Crossover Distribution and Frequency Are Regulated by Him-5 in Caenorhabditis Elegans

Article excerpt

ABSTRACT Mutations in the him-5 gene in Caenorhabditis elegans strongly reduce the frequency of crossovers on the X chromosome, with lesser effects on the autosomes. him-5 mutants also show a change in crossover distribution on both the X and autosomes. These phenotypes are accompanied by a delayed entry into pachytene and premature desynapsis of the X chromosome. The nondisjunction, progression defects and desynapsis can be rescued by an exogenous source of double strand breaks (DSBs), indicating that the role of HIM-5 is to promote the formation of meiotic DSBs. Molecular cloning of the gene shows that the inferred HIM-5 product is a highly basic protein of 252 amino acids with no clear orthologs in other species, including other Caenorhabditis species. Although him-5 mutants are defective in segregation of the X chromosome, HIM-5 protein localizes preferentially to the autosomes. The mutant phenotypes and localization of him-5 are similar but not identical to the results seen with xnd-1, although unlike xnd-1, him-5 has no apparent effect on the acetylation of histone H2A on lysine 5 (H2AacK5). The localization of HIM-5 to the autosomes depends on the activities of both xnd-1 and him-17 allowing us to begin to establish pathways for the control of crossover distribution and frequency.

CROSSING over between homologous chromosomes during meiosis promotes genetic diversity by creating new combinations of alleles over generations. Crossovers also create physical connections between the homologs that ensure their proper alignment on the meiotic spindle and subsequent apposite segregation. Accordingly, homologous chromosomes require a crossover to prevent nondisjunction, and each of the events of meiosis I functions to promote this exchange.

A necessary early step in crossing over is the SPO11- dependent formation of double strand breaks (DSBs) (Keeney et al. 1997). In Saccharomyces cerevisiae, at least nine other proteins interact with SPO11 to regulate the recruitment and activation of SPO11 (Keeney and Neale 2006). These proteins that regulate the action of SPO11 are not highly conserved at the amino acid level, but recent studies have identified functional homologs of several of these components in mice (Cole et al. 2010; Kumar et al. 2010). Nevertheless, relatively little is known about the regulation of the SPO11 machinery in organisms other than S. cerevisiae.

Meiotic breaks occur preferentially in regions of open chromatin structure known as hotspots (Ohta et al. 1994; Wu and Lichten 1994). The pattern of crossovers and the recombination frequency vary among different chromosomes even within a species. One of the most distinctive patterns is seen in Caenorhabditis elegans, where the recombination rate on autosomes is repressed in the central region of each autosome, which contains a tight central cluster of genes. Instead crossovers occur preferentially on the chromosome arms where genes are widely spaced (Barnes et al. 1995). The X chromosome has a different pattern, in which genes are more uniformly spaced and the recombination frequency is relatively uniform across the chromosome at a rate that is intermediate between that of autosomal clusters and arms (Barnes et al. 1995; Rockman and Kruglyak 2009).

The genetic differences between the X chromosome and the autosomes during meiosis are also correlated with a variety of molecular and cytological differences seen in germline chromosomes. The X chromosome is transcriptionally repressed throughout most of germline development (Kelly et al. 2002) and histone modifications associated with closed and open chromatin configurations are enriched on the X and autosomes, respectively (Schaner and Kelly 2006). Furthermore, a number of mutations differentially affect crossover (CO) frequencies on the X chromosome vs. the autosomes. A subset of these genes, him-1, him-17, xnd- 1, and dpy-28, influences DSB formation and also has been implicated in the regulation of germline chromatin architecture (Hodgkin et al. …

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