Genetic Research Cycle in Human Disease

The major focus in Dr. Gusella’s laboratory, and by extension the rest of the Center for Human Genetic Research at the MGH continues to be the pursuit of the genetic research cycle in a variety of human disorders. This cycle involves: a) using patient samples/phenotypes (clinical, biochemical, molecular, etc.) to relate differences in human genotype with phenotypic variation (normal variation, disease causative differences, predisposing variants, modifying genes, developmental variants, determinants of response to therapy, “physiologic genomics”), b) using biochemistry, cell biology, lower organisms and especially mouse modeling to understand mechanisms and interactions operative in both disease and normal physiology, c) using genetics in the mouse and other organisms as a powerful route to lead the way to genes that may be important in humans for either normal biology or disease pathogenesis, and d) pursuing translational efforts to use the genetic findings to deliver better diagnostics, management and treatment to patients. In addition to collaborating widely to facilitate the genetic research cycle for members of other departments, including genetic studies of diabetes and endocrine dysfunction, Dr. Gusella’s laboratory investigates inherited nervous system disorders such as Huntington’s disease, Parkinson’s disease, autism, familial dysautonomia, and neurofibromatosis. Of particular relevance to diabetes are the findings that mouse models of HD expressing expanded polyglutamine protein develop diabetic symptoms, that human cells from HD patients show clear disruptions in control of energy metabolism, and that even in the normal population CAG size range, huntingtin appears to be a negative regulator of ATP production. Our recent work has involved the use of patient derived iPS cells to define phenotypes associated with the HD mutation, incuding clear disruptions in the control of energy metabolism that correlate with the length of the CAG repeat mutation. We have also pursued genome-wide associtation studies on the sensitized genetic background of HD and identified genetic factors that modify the pathogenesis of the disease. Our future directions include defining the relationship between the HD mutation, modifiers and regulation of energy metabolism in both human cells and in mouse and lower organism models being studied in the lab.


1. Lee JM, Galkina EI, Levantovsky RM, Fossale E, Anne Anderson M, Gillis T, Srinidhi Mysore J, Coser KR, Shioda T, Zhang B, Furia MD, Derry J, Kohane IS, Seong IS, Wheeler VC, Gusella JF, MacDonald ME. Dominant effects of the Huntington’s disease HTT CAG repeat length are captured in gene-expression data sets by a continuous analysis mathematical modeling strategy. Hum Mol Genet. 2013 Aug 15;22(16):3227-38. PubMed Central PMCID: PMC3723309.

2. Ernst C, Marshall CR, Shen Y, Metcalfe K, Rosenfeld J, Hodge JC, Torres A, Blumenthal I, Chiang C, Pillalamarri V, Crapper L, Diallo AB, Ruderfer D, Pereira S, Sklar P, Purcell S, Wildin RS, Spencer AC, Quade BF, Harris DJ, Lemyre E, Wu BL, Stavropoulos DJ, Geraghty MT, Shaffer LG, Morton CC, Scherer SW, Gusella JF, Talkowski ME. Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity. Arch Gen Psychiatry. 2012 Dec;69(12):1238-46. PubMed Central PMCID: PMC3590016.

3. HD iPSC Consortium. Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell. 2012 Aug 3;11(2):264-78. PubMed Central PMCID: PMC3804072.

4. Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z, Martinet D, Shen Y, Valsesia A, Beckmann ND, Thorleifsson G, Belfiore M, Bouquillon S, Campion D,, Gusella JF, Gustafsson O, Metspalu A, Scherer SW, Stefansson K, Blakemore AI, Beckmann JS, Froguel P. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature. 2011 Aug 31;478(7367):97-102. PubMed Central PMCID: PMC3637175.

5. Fossale E, Seong IS, Coser KR, Shioda T, Kohane IS, Wheeler VC, Gusella JF, MacDonald ME, Lee JM. Differential effects of the Huntington’s disease CAG mutation in striatum and cerebellum are quantitative not qualitative. Hum Mol Genet. 2011;20(21):4258-67. PubMed Central PMCID: PMC3188996.

6. James MF, Han S, Polizzano C, Plotkin SR, Manning BD, Stemmer-Rachamimov AO, Gusella JF, Ramesh V. NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol. 2009 Aug;29(15):4250-61. PubMed Central PMCID: PMC2715803.

7. Lee JM, Ivanova EV, Seong IS, Cashorali T, Kohane I, Gusella JF, MacDonald ME. Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. PLoS Genet. 2007 Aug;3(8):e135. PubMed Central PMCID: PMC1950164.