Reducing the chromosome content in half

Meiosis is an essential part of the reproductive cycle in most eukaryotic organisms and is the process by which the chromosome number is divided precisely in half. Several steps are needed to accomplish this task and any defects in meiosis can be catastrophic because the oocyte or sperm receives an abnormal number of chromosomes. Defects such as these in humans are the leading cause of infertility in women and result in disorders such as Down's syndrome. Meiosis allows for conservation of chromosome number in the zygote by halving the number of chromosomes in the male and female gametes. New genotypes are created by the process of crossing over and chromosome segregation.

The meiotic divisions are composed of two parts. In meiosis I the number of chromosomes is halved. During prophase of meiosis I the homologous chromosomes pair and during the pachytene stage of prophase crossing over can occur. Crossing over is the process in which recombination occurs between homologous chromosomes. Crossing over during meiosis is very important because it promotes genetic variation and orients homologous chromosomes to ensure proper segregation. The synaptonemal complex (SC) is formed between the two homologous chromosomes. The formation of the SC and the pairing of the chromosomes ensure proper segregation of the homologous pairs of chromosomes. Non-disjunction occurs when the homologous pairs of chromosome do not separate in meiosis I and therefore one gamete gets two copies of the same chromosome.

Studies of meiosis in Drosophila

With the experimental benefits of Drosophila, we are able to isolate and characterize mutations that disrupt various steps in the meiotic program. We are concentrating on three of the most important aspects of meiosis: i) the initiation of meiotic recombination (DNA double-strand breaks), ii) the repair of these events as crossovers, and iii) the involvement of crossovers in the segregation of homologous chromosomes. (Crossovers direct segregation because they physically link homologous chromosomes together. On a meiotic spindle this leads to the precise splitting of the diploid genetic content into the haploid gametes.)

Brief summary of our view of meiosis (in Drosophila)

Based on the analysis of several meiotic mutants, our current understanding of the meiotic recombination pathway in Drosophila can be briefly summarized. First, pairing of homolgous chromosomes culminates in synapsis, where they are tightly held together by a meiosis-specific structure, the synaptonemal complex (SC). Synapsis of homologs requires the c(3)G and c(2)M gene products. In Drosophila, but not some other organisms, synapsis and SC formation are required for the normal initiation of meiotic recombination and crossover formation (that is, the subsequent events described next). Next, the initiation of recombination requires both of the mei-W68 and mei-P22 gene products to generate DSBs. We have been able to directly observe this process with antibodies to the MEI-P22 protein. Repair of the DSBs creates recombination intermediates like the Holliday junction. General and meiosis-specific DSB repair genes such as mei-41, okra and spnB are required for this process. In response to a double strand break a variant Histone H2A, HIS2AV, is phosphorylated. Using an antibody to this variant, we have detected this modification in Drosophila meiotic cells. Our studies show that at the sites of DSBs phophorylated HIS2AV accumulates and then rapidly disappears. In mutants that are defective in DNA repair HIS2AV phophorylation persists longer in meiosis. Finally, these intermediates are resolved into crossovers, a process that requires the mei-9 and mei-218 genes.