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The Case of the Missing Crossovers [Kleckner Lab]

The Case of the Missing Crossovers [Kleckner Lab]

Sexual reproduction involves the production of male and female gametes (e.g. sperm and egg) each of which carries a single complete set of chromosomes. In most organisms, this process is highly regular such that gametes with aberrant chromosome complements are very rare.  In striking contrast, human female gamete formation is dramatically error-prone, often yielding eggs with aberrant chromosome complements (“aneuploidy”). Moreover, the frequency of aneuploidy increases dramatically with maternal age, ultimately affecting more than half of all eggs in women over 40. These aneuploidies, when propagated into zygotes after fertilization, result in pregnancy termination, implantation failures or genetic birth defects, e.g. Down syndrome.

In the current issue of Cell, MCB’s Kleckner laboratory, in collaboration with the Wang/Zhang, Hassold/Hunt and Zickler laboratories, identify a female-specific defect in germline chromosomal events which plays a central causative role for the high level of female germline aneuploidy. (Shunxin Wang, Terry Hassold, Patricia Hunt, Martin A. White, Denise Zickler, Nancy Kleckner, Liangran Zhang; Inefficient crossover maturation underlies elevated aneuploidy in human female, meiosis, Cell (PDF), March 9, 2017. Wang and Zhang initiated this work when they were post-doctoral fellows in the Kleckner laboratory and continued the analysis after they established their own laboratory in Shandong, China.

The Wang et al. consortium analyzed human male and female gamete formation with respect to the key process of meiotic crossing-over. Meiosis is the specialized cellular program by which a diploid germ cell, carrying both maternal and paternal copies of each chromosome, gives rise to haploid cells (and eventually gametes), carrying only one copy of each chromosome (either maternal or paternal). Crossing-over, which comprises the reciprocal exchange of DNA segments (and thus chromosome segments) between the maternal and paternal homologs, is a central feature of the meiotic program. Crossovers increase genetic diversity by mixing genes between the two parental genomes. However, Wang and colleagues were interested in crossing-over for a different reason: crossovers also play a direct role in meiotic chromosome segregation.

Because of this role, as a universal feature of meiosis, every pair of homologs nearly always acquires at least one crossover. Additionally, when more than one crossover is present, they tend to be evenly spaced along the chromosomes. Since crossovers occur at different positions in different individual nuclei, this phenomenon represents an interesting case of spatial patterning in a biological system.

Wang et al., carried out a detailed comparison of crossover patterns in human male and female meiosis. By analyzing single-cell images of molecular crossover complexes along organized meiotic chromosomes, they discovered that human female meiosis has a specific defect in crossover formation and that this defect plays a major role in the elevated level of human female aneuploidy. In brief, among recombinational interactions that are initiated and normally should mature into crossovers, ~25% actually fail to do so.  In effect, ~25% of crossovers are “subtracted” from the arrays that would normally have occurred. The result of this effect is an increase in the frequency of homolog pairs that lack even a single crossover or have atypical arrays of crossovers, both of which effects can compromise the chromosome segregation process. No such subtraction effect is present in human male meiosis or in other studied organisms. Additional analyses show that the identified phenomenon, termed “female-specific crossover maturation inefficiency,” plays a major role in the elevated level of maternally-derived chromosome aberrations during human sexual reproduction, via both direct and indirect consequences.

The above conclusions emerged by application of a mathematical model, developed by the Kleckner laboratory in collaboration with John Hutchinson of SEAS. Spatial patterning of crossovers requires communication along the lengths of the chromosomes.  Such patterning is a common feature of physical systems, where the requisite communication is provided by redistribution of mechanical stress. In brief, a large array of precursor events is set up; these precursors come under stress; the most sensitive precursor goes critical to give the event of interest (e.g. a crossover) with accompanying local relief of stress; and ensuing redistribution of that change away from the nucleation site creates a spatial domain of reduced stress that disfavors occurrence of subsequent events in the vicinity of the first. As more and more events occur in such a system, they fill in the holes between prior events, leading to an evenly spaced array. The Hutchinson/Kleckner model does a very good job of explaining known crossover patterns and of revealing previously unknown features and peculiarities of such patterns, as in the case of human female meiosis. A major challenge is to understand whether the biological pattern actually involves, via this type of physical effect, or whether the analogous outcome is achieved solely via more active processes.

The new findings of Wang et al. also raise an interesting additional question: why is human female meiosis specifically afflicted by inefficient crossover maturation? An intriguing possibility, raised also by previous studies, is the paradoxical possibility that aneuploidy may confer an evolutionary advantage. Warburton suggested, in 1987, that since aneuploidy usually results in pregnancy termination, it will increase the time between viable pregnancies, thus conserving maternal resources for existing young children. (Reproductive Loss: How Much is Preventable? Warburton, D. N. Engl. J. Med. 1987; 316: 158–160) Additionally, age-dependent aneuploidy will reduce the probability that older women will have pregnancies that come to term. This may free them to use their resources for other important activities, e.g. serving as grandmothers, or simply to avoid the continuing risk of additional pregnancies.

Overall, the paper of Wang et al. is of interest because it demonstrates how an investigation into basic cellular processes can have unexpected implications for disease research and for our broader understanding of the human condition/evolution.

 by Shunxin Wang, Terry Hassold, Patricia Hunt, Martin A. White, Denise Zickler, Nancy Kleckner, Liangran Zhang

Cell (PDF)

(top l to bottom r) Shunxin Wang, Martin White, Nancy Kleckner, and Liangran Zhang; (not shown) Terry Hassold, Patricia Hunt, and Denise Zickler

(top l to bottom r) Shunxin Wang, Martin White, Nancy Kleckner, and Liangran Zhang; (not shown) Terry Hassold, Patricia Hunt, and Denise Zickler