Genome diversification occurs in the germline of sexually reproducing organisms. Our understanding the processes that drive diversification as well as those that safeguard genome stability is limited due to the requirements for single cell genomics as well as access to the human germline. In humans, reproduction is surprisingly inefficient, especially in females, where a baseline of 20% of human eggs contain a chromosome error (aneuploidy). Aneuploidies results in preclinical and clinical pregnancy losses and are the leading cause of congenital disorders in human. Recently, we have developed new technologies that allow us to probe the human germline directly to explore the incidence and molecular mechanisms that cause the high rate of chromosome errors (aneuploidy). Our findings reveal that chromosome errors in human eggs follows a U curve and shape fertility rates across reproductive life span in human females (1). Such errors are chromosome-specific and suggest that the high rate of pregnancy loss may be an evolutionary stable strategy in human females. The molecular causes of chromosomal aging in eggs includes cohesion loss that increases with female age (1, 2).
More recently, we have identified a mechanism that can explain the high rate of pregnancy losse that occur independently of maternal age- gross chromosomal rearrangements (GCR). We observe that 10% of human eggs contain a GCR larger than 10 Mbp and that this results in both embryonic arrest during the preimplantation stages as well as embryos with that contain GCRs in the inner cell mass that gives rise to the fetus. The breakpoints for GCRs include common fragile sites and in particular meiotic recombination hotspots (30x). 28% of the GCRs involve an entire chromosome arm and we find that meiotic recombination is common in pericentromeric regions. We propose that recombination between non-allelic sequences drive both reciprocal translocations between non-homologous chromosomes as well as intrachromosomal deletions around centromeres that result in whole arm loss. suggesting that the defective repair of programmed double-strand breaks induced during fetal life cause problems in adult eggs and conceptions.