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Most genes in a diploid organism are thought to be expressed and regulated equally by the two parental alleles. However, a subset of genes referred to as monoallelically-expressed genes are expressed preferentially only on the maternal or paternal allele. Monoallelically-expressed genes include imprinted genes, which express either the maternal or paternal allele p referentially, as well as random monoallelic genes that choose to express one allele at random. Examples of in vivo random monoallelic genes include X-linked genes in females, immunoglobulins in B cells, clustered protocadherins, and olfactory receptors. However, these examples generally are thought to be rare in the mammalian genome and confined to a few genes that have a uniquely clustered organization in the genome. In this dissertation, new genome-wide analysis methods were developed to reveal the lands cape of epigenetic allelic effects in the mous e. Chapter 2 details the discovery of novel, noncanonical genomic imprinting effects that are enriched uniquely in the brain. Chapter 3 details the development of new genomics and statistical methods to identif y genes that express their alleles differentially in vivo through nongenetic mechanisms. This novel screening strategy was applied to reveal the landscape of epigenetic allelic effects in the mouse brain at different ages and to p rofile different tissue types. The dissertation describes the discovery of diverse forms of nongenetic differential allelic expression in mouse, macaque, and human brains, and demonstrates that these effects interact with heterozygous mutations and shape genetic architecture at the allelic and cellular level in vivo. The results challenge current thinking in the fields of genetics and epigenetic by revealing a new landscape of epigenetic allelic effects in vivo, and describe new mechanisms that may shape phenotypic variation and susceptibility to disease. Although the functions of these allelic effects are unknown, and the regulatory mechanisms involved have yet to be defined, the future of the field is discussed.

Although vascularized composite allografts (VCAs) have been performed clinically for a variety of indications, potential complications from long-term immunosuppression and graft-versus-host disease remain important barriers to widespread applications. Recently it has been demonstrated that VCAs incorporating a vascularized long bone in a rat model provide concurrent vascularized bone marrow transplantation that, itself, functions to establish hematopoietic chimerism and donor-specific tolerance following non-myeloablative conditioning of recipients. Advances such as this, which aim to improve the safety profile of tolerance induction, will help usher in an era of wider clinical VCA application for nonlife-saving reconstructions.

There is an increasing awareness about the importance of translation from basic scientific findings into practical application for efficiently improving human health, especially in the pharmaceutical industry. In the field of neurorehabilitation, however, the bench-to-bedside process continues to be developing, and thus most of the therapeutic interventions have encountered barriers during exploration of evidence-based effectiveness. Despite this immaturity, constraint-induced movement therapy (CIT), a well-evidenced treatment evolved from research in nonhuman primates, is suggested to be an ideal paradigm of translational research in the field of neurorehabilitation. This article reviews the evolvement of CIT with regards to its behavioral efficacy and neuroimaging evidence through the translation roadmap developed by the National Institutes of Health. We also discuss prospects for the application of combined interventions, such as stem cell therapy or pharmaceutical prescription, with appropriate screening of patients beforehand, as well as an efficient delivery mode after the treatment. To achieve such goals and consolidate evidenced-based neurorehabilitation, we provide a framework for applications into the translational research of other therapeutic interventions aside from CIT.