RESEARCH INTERESTS
One of the most exciting findings in human genetics has been the recognition that unstable trinucleotide repeats contribute to more than four dozen genetic disorders, including myotonic muscular dystrophy, amyotrophic lateral sclerosis (Lou Gehrig's disease) and Huntington’s disease. With collaborators, Nelson described the first of these unstable DNA sequences, a polymorphic CGG trinucleotide repeat in the FMR1 gene found to be enlarged in people with fragile X syndrome, the most common form of inherited intellectual disability and autism. The mechanism by which this mutation leads to disease is through loss of function of the FMR1 gene product due to diminished expression accompanied by aberrant methylation of the gene. The FMR1 gene product is an RNA binding protein that interacts with complexes of RNA and ribosomes. It regulates the translation of hundreds of mRNAs. The Nelson group focuses on dissecting the function(s) of FMR1 and its paralogs FXR1 and FXR2. Understanding factors that lead to DNA instability of this sequence is also a key interest.

The Nelson group also studies disorders found in people with smaller expansions of the FMR1 CGG repeat, known as premutation carriers (55-200 repeats). Males with CGG repeat lengths in this range are at risk for a late-onset neurodegenerative disorder termed FXTAS. FXTAS is distinct from fragile X syndrome; individuals are cognitively unaffected until their 6th or 7th decade, but then show neuronal degeneration accompanied by neuronal nuclear inclusions that stain with ubiquitin on autopsy. The Nelson group has utilized models in flies and mice to investigate the hypothesis that a gain of function through RNA toxicity is responsible for neuronal dysfunction and death. Fly models allowed identification and characterization of modifiers, and mouse models showed definitively that the CGG repeat was both necessary and sufficient to affect mammalian neurons. The group is also studying fragile X-associated primary ovarian insufficiency, (FXPOI) a disorder resulting in early menopause found in some female carriers of the premutation. Using mouse models, the group has improved understanding of the mechanism of ovarian insufficiency. Identifying genetic modifiers in both FXTAS and FXPOI is a goal for potential therapies. The group has demonstrated roles for several RNA-binding proteins including TDP-43 and alterations in 5-hydroxymethylcytosine, suggesting widespread dysregulation of gene expression.

The Nelson group was involved in numerous aspects of the Human Genome Project, with key input into the mapping and sequencing of the human X chromosome, and participation in several other sequencing projects, from fruit fly to Rhesus monkey. Dr. Nelson's group identified gene mutations in other disorders such as Incontinentia Pigmenti and FRAXE intellectual disability. He also has interest in the genetic contribution to common disorders such as cancer, and has investigated the potential role of common variants in genes involved in DNA repair in human disease.