Alessandra Chesi, PhD
Assistant Professor of Pathology and Laboratory MedicinePerelman School of Medicine at the University of Pennsylvania
Contact InformationPerelman School of Medicine at the University of Pennsylvania
Department of Pathology and Laboratory Medicine
Stellar-Chance Laboratories, Rm. 605A
422 Curie Blvd.
Philadelphia, PA 19104
Specialty Division
Cancer and Immunobiology
Research Expertise
Research Interests:
Our lab's goal is to translate genetics findings from GWAS and sequencing studies of human neurodegenerative disorders into molecular mechanisms of disease, with the aim of identifying actionable target genes.
Keywords:
Neurogenetics, bioinformatics, 3D genomics, Alzheimer's disease, Parkinson's disease, neurodegeneration, iPSC-derived neural cells
Techniques:
Capture C, ATAC-seq, ChIP-seq, RNA-seq, CRISPR/Cas9
Research Summary:
Genetic studies have provided a wealth of variants associated with human complex traits, but are not able to pinpoint the underlying target genes and molecular mechanisms. We are interested in finding the target genes for several brain-related disorders, such as Alzheimer's, Parkinson's and other neurodegenerative disease. To do this, we use a combined wet-bench/bioinformatic approach, leveraging cutting-edge genomics and epigenetic techniques such as Capture C, ATAC-seq, ChIP-seq, and RNA-seq plus custom analysis pipelines and methods to perform a “variant-to-gene mapping” campaign for these disorders. We follow up candidate culprit variant-gene pairs by CRISPR/Cas9 editing and functional studies in appropriate cellular models of neurodegeneration, such as iPSC-derived neurons (cortical, dopaminergic, etc.), microglia, astrocytes, co-cultures and cerebral organoids (“brain in a dish”). Our ultimate goal is drug discovery for the identified target genes/molecular pathways, utilizing our cellular models of neurodegeneration for drug screens and leveraging system biology approaches.
Rotation Projects:
Please contact Dr. Chesi to discuss possible rotation projects.
Graduate Groups
Cell and Molecular Biology
Education
M.Sc. (Physics), University of Pisa, Italy, 2002
PhD (Structural and Functional Genomics), International School for Advanced Studies (SISSA/ISAS), Trieste, Italy, 2007
Specialty Certification
Postgraduate Training
Postdoctoral Fellow, Cell & Developmental Biology, University of Pennsylvania, 2008-11
Postdoctoral Fellow, Genetics, Stanford University, 2012
Awards and Honors
CBM/WARTSILA Prize for Outstanding Doctoral Dissertation in Genomics, 2007
Second Prize, Center for Neurodegenerative Disease Research Retreat Poster Contest, 2008
Postdoctoral Fellowship, Parkinson’s Disease Foundation, 2008-10
ASN (Italian National Scientific Qualification in Genetics at the Associate Professor level), 2017-26
Memberships and Professional Organizations
American Society for Bone Mineral Research, 2015-present
American Society for Human Genetics, 2015-present
Web Links
Selected Publications
3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity
Trang KB, Pahl MC, Pippin JA, Su C, Littleton SH, Sharma P, Kulkarni NN, Ghanem LR, Terry NA, O'Brien JM, Wagley Y, Hankenson KD, Jermusyk A, Hoskins JW, Amundadottir LT, Xu M, Brown KM, Anderson SA, Yang W, Titchenell PM, Seale P, Cook L, Levings MK, Zemel BS, Chesi A, Wells AD, Grant SFA. medRxiv [Preprint]. 2024 Feb 5:2023.08.30.23294092. doi: 10.1101/2023.08.30.23294092. PMID: 37693606; PMCID: PMC10491377.
Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes
Bradfield JP, Kember RL, Ulrich A, Balkiyarova Z, Alyass A, Aris IM, Bell JA, Broadaway KA, Chen Z, Chai JF, Davies NM, Fernandez-Orth D, Bustamante M, Fore R, Ganguli A, Heiskala A, Hottenga JJ, Íñiguez C, Kobes S, Leinonen J, Lowry E, Lyytikainen LP, Mahajan A, Pitkänen N, Schnurr TM, Have CT, Strachan DP, Thiering E, Vogelezang S, Wade KH, Wang CA, Wong A, Holm LA, Chesi A, et al. Genome Biol 25(1):22, Jan 2024. doi: 10.1186/s13059-023-03136-z. PMID: 38229171; PMCID: PMC10790528.
Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains
Guo L, Mann JR, Mauna JC, Copley KE, Wang H, Rubien JD, Odeh HM, Lin J, Lee BL, Ganser L, Robinson E, Kim KM, Murthy AC, Paul T, Portz B, Gleixner AM, Diaz Z, Carey JL, Smirnov A, Padilla G, Lavorando E, Espy C, Shang Y, Huang EJ, Chesi A, Fawzi NL, Myong S, Donnelly CJ, Shorter J. bioRxiv [Preprint]. 2023 Sep 4:2023.09.04.555754. doi: 10.1101/2023.09.04.555754. PMID: 37732211; PMCID: PMC10508739.
Perturbation of the insomnia WDR90 GWAS locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q
Sonti S, Littleton SH, Pahl MC, Zimmerman AJ, Chesi A, Palermo J, Lasconi C, Brown EB, Pippin JA, Wells AD, Doldur-Balli F, Pack AI, Gehrman PR, Keene AC, Grant SFA. bioRxiv [Preprint] 2023 Aug 18:2023.08.17.553739. doi: 10.1101/2023.08.17.553739. PMID: 37645863; PMCID: PMC10462147.
Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis
Medina-Gomez C#, Mullin BH#, Chesi A#, Prijatelj V, Kemp JP, Shochat-Carvalho C, Trajanoska K, Wang C, Joro R, Evans TE, Schraut KE, Li-Gao R, Ahluwalia TS, Zillikens MC, Zhu K, Mook-Kanamori DO, Evans DS, Nethander M, Knol MJ, Thorleifsson G, Prokic I, Zemel B, Broer L, McGuigan FE, van Schoor NM, Reppe S, Pawlak MA, Ralston SH, van der Velde N, Lorentzon M, Stefansson K, Adams HHH, Wilson SG, Ikram MA, Walsh JP, Lakka TA, Gautvik KM, Wilson JF, Orwoll ES, van Duijn CM, Bønnelykke K, Uitterlinden AG, Styrkársdóttir U, Akesson KE, Spector TD, Tobias JH, Ohlsson C, Felix JF, Bisgaard H, Grant SFA, Richards JB, Evans DM, van der Eerden B, van de Peppel J, Ackert-Bicknell C, Karasik D, Kague E, Rivadeneira F. Commun Biol 6(1):691, Jul 2023. doi: 10.1038/s42003-023-04869-0. PMID: 37402774; PMCID: PMC10319806.
Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep
Palermo J, Chesi A, Zimmerman A, Sonti S, Pahl MC, Lasconi C, Brown EB, Pippin JA, Wells AD, Doldur-Balli F, Mazzotti DR, Pack AI, Gehrman PR, Grant SFA, Keene AC. Sci Adv 9(1):eabq0844, Jan 2023. doi: 10.1126/sciadv.abq0844. Epub 2023 Jan 6. PMID: 36608130; PMCID: PMC9821868.
A saturated map of common genetic variants associated with human height
Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S, Graff M, Eliasen AU, Jiang Y, Raghavan S, Miao J, Arias JD, Graham SE, Mukamel RE, Spracklen CN, Yin X, Chen SH, Ferreira T, Highland HH, Ji Y, Karaderi T, Lin K, Lüll K, Malden DE, Medina-Gomez C, Machado M, Moore A, Rüeger S, Sim X, Vrieze S, Ahluwalia TS, Akiyama M, Allison MA, Alvarez M, Andersen MK, Ani A, Appadurai V, Arbeeva L, Bhaskar S, Bielak LF, Bollepalli S, Bonnycastle LL, Bork-Jensen J, Bradfield JP, Bradford Y, Braund PS, Brody JA, Burgdorf KS, Cade BE, Cai H, Cai Q, Campbell A, Cañadas-Garre M, Catamo E, Chai JF, Chai X, Chang LC, Chang YC, Chen CH, Chesi A, et al. Nature 610(7933):704-712, Oct 2022. doi: 10.1038/s41586-022-05275-y. Epub 2022 Oct 12. PMID: 36224396; PMCID: PMC9605867.
A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
Ramdas S, Judd J, Graham SE, Kanoni S, Wang Y, Surakka I, Wenz B, Clarke SL, Chesi A, Wells A, et al. Am J Hum Genet 109(8):1366-1387, Aug 2022. doi: 10.1016/j.ajhg.2022.06.012. PMID: 35931049; PMCID: PMC9388392.
Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types
Pahl MC, Le Coz C, Su C, Sharma P, Thomas RM, Pippin JA, Cruz Cabrera E, Johnson ME, Leonard ME, Lu S, Chesi A, Sullivan KE, Romberg N, Grant SFA, Wells AD. Genome Biol 23(1):125, Jun 2022. doi: 10.1186/s13059-022-02691-1. PMID: 35659055; PMCID: PMC9164584.
Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits
Lasconi C, Pahl MC, Pippin JA, Su C, Johnson ME, Chesi A, Boehm K, Manduchi E, Ou K, Golson ML, Wells AD, Kaestner KH, Grant SFA. Sleep 45(8):zsac109, Aug 2022. doi: 10.1093/sleep/zsac109. PMID: 35537191; PMCID: PMC9366645.
