Human chromosome nondisjunction leads to an extraordinary frequency of aneuploidy: an estimated 10-25% of all human conceptions have too many or too few chromosomes. This chromosome error is the leading cause of pregnancy loss, mental retardation and birth defects. Despite this clinical significance, little is known about the causes and associated risk factors for nondisjunction. For the past 15 years, we have investigated trisomy 21, the leading cause of Down syndrome (DS), as a model to understand human nondisjunction. We have built an unprecedented resource of infants with DS and their parents, including biological samples, epidemiological and clinical data. We have shown that altered recombination patterns along the nondisjoined chromosome are risks for nondisjunction, and for the first time, have shown such patterns differ significantly by the age of the oocyte. In this proposal, we will focus on the pattern of recombination among the rest of the chromosomes to determine whether the observed effect on chromosome 21 is due to transacting or cis-acting factors. We will examine two basic properties of inter-individual variation in recombination among oocytes with nondisjoined chromosomes 21 and their siblings: 1) rate of genome-wide recombination and 2) preferred sites of recombination throughout the genome. Results will provide insight into the cause of altered recombination, a risk factor that significantly increases susceptibility for nondisjunction in humans. For example, evidence for a transacting factor that influences recombination suggests either genetic factors or environmental factors that have their effect in-utero during early oogenesis. Based on these results, we will be able to focus/re-focus our search for risk factors in the context of maternal age and recombination patterns. Thus, we will increase the power to dissect the susceptibility of human nondisjunction into its individual liability factors. Once identified, we can determine if such factors can be altered to ensure proper chromosome segregation during oogenesis, one of the most significant processes in our species.
Human chromosome nondisjunction is the leading cause of pregnancy loss, mental retardation and birth defects. In this proposal, we will focus on one important molecular risk factor, altered recombination. We will test the hypothesis the altered recombination patterns observed along the nondisjoined chromosome in oocytes are dictated by trans-acting factors. If true, treatment endpoints can be considered to ensure proper chromosome segregation during oogenesis, one of the most significant processes in our species.
| Oliver, Tiffany Renee; Middlebrooks, Candace; Harden, Ariel et al. (2016) Variation in the Zinc Finger of PRDM9 is Associated with the Absence of Recombination along Nondisjoined Chromosomes 21 of Maternal Origin. J Down Syndr Chromosom Abnorm 2: |
| Middlebrooks, Candace D; Mukhopadhyay, Nandita; Tinker, Stuart W et al. (2014) Evidence for dysregulation of genome-wide recombination in oocytes with nondisjoined chromosomes 21. Hum Mol Genet 23:408-17 |
| Oliver, Tiffany Renee; Tinker, Stuart W; Allen, Emily Graves et al. (2012) Altered patterns of multiple recombinant events are associated with nondisjunction of chromosome 21. Hum Genet 131:1039-46 |
| Chowdhury, Reshmi; Bois, Philippe R J; Feingold, Eleanor et al. (2009) Genetic analysis of variation in human meiotic recombination. PLoS Genet 5:e1000648 |
