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Hershman, Steven Gregory

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Hershman

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Steven Gregory

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Hershman, Steven Gregory
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    The Emergence of 'Us and Them' in 80 Lines of Code: Modeling Group Genesis in Homogeneous Populations
    (SAGE Publications, 2014) Gray, Kurt; Rand, David G.; Ert, Eyal; Lewis, Kevin; Hershman, Steven Gregory; Norton, Michael
    Psychological explanations of group genesis often require population heterogeneity in identity or other characteristics, whether deep (e.g., religion) or superficial (e.g., eye color). We use game-theoretical agent-based models to explore group genesis in homogeneous populations and find robust group formation with just two basic principles: reciprocity and transitivity. These emergent groups demonstrate in-group cooperation and out-group defection, even though agents lack common identity. Group formation increases individual payoffs, and group structure is robust to varying levels of reciprocity and transitivity. Increasing population size increases group size more than group number, and manipulating baseline trust in a population has predictable effects on group genesis. An interactive online demonstration enables first-hand exploration of the parameter space (www.mpmlab.org/groups), and available source code (supplementary materials) provides a guide to implementing psychological agent-based models.
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    Personal Genomics and Mitochondrial Disease
    (2013-09-30) Hershman, Steven Gregory; Mootha, Vamsi Krishna; Berry, Gerard; MacArthur, Daniel; Slaugenhaupt, Susan; Church, George; McCarroll, Steven
    Mitochondrial diseases involving dysfunction of the respiratory chain are the most common inborn errors of metabolism. Mitochondria are found in all cell types besides red blood cells; consequently, patients can present with any symptom in any organ at any age. These diseases are genetically heterogeneous, and exhibit maternal, autosomal dominant, autosomal recessive and X-linked modes of inheritance. Historically, clinical genetic evaluation of mitochondrial disease has been limited to sequencing of the mitochondrial DNA (mtDNA) or several candidate genes. As human genome sequencing transformed from a research grade effort costing $250,000 to a clinical test orderable by doctors for under $10,000, it has become practical for researchers to sequence individual patients. This thesis describes our experiences in applying "MitoExome" sequencing of the mtDNA and exons of >1000 nuclear genes encoding mitochondrial proteins in ~200 patients with suspected mitochondrial disease. In 42 infants, we found that 55% harbored pathogenic mtDNA variants or compound heterozygous mutations in candidate genes. The pathogenicity of two nuclear genes not previously linked to disease, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. In an additional two unrelated children presenting with Leigh syndrome and combined OXPHOS deficiency, we identified compound heterozygous mutations in MTFMT. Patient fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of MTFMT. Furthermore, patient fibroblasts have dramatically reduced fMet-\(tRNA^{Met}\) levels and an abnormal formylation profile of mitochondrially translated \(COX_1\). These results demonstrate that MTFMT is critical for human mitochondrial translation. Lastly, to facilitate evaluation of copy number variants (CNVs), we developed a web-interface that integrates CNV calling with genetic and phenotypic information. Additional diagnoses are suggested and in a male with ataxia, neuropathy, azoospermia, and hearing loss we found a deletion compounded with a missense variant in D-bifunctional protein, \(HSD_{17}B_4\), a peroxisomal enzyme that catalyzes beta-oxidation of very long chain fatty acids. Retrospective review of metabolic testing from this patient revealed alterations of long- and very-long chain fatty acid metabolism consistent with a peroxisomal disorder. This work expands the molecular basis of mitochondrial disease and has implications for clinical genomics.