About

Jessica Butts, Ph.D., is an Assistant Professor and Principal Investigator in the Department of Bioengineering and the Neuroengineering Initiative at Rice University. She completed her Ph.D. in Bioengineering at the University of California – San Francisco and Berkeley in 2018. Following her doctoral studies, she was an HHMI Postdoctoral Associate in the Department of Molecular and Human Genetics at Baylor College of Medicine in the Huda Zoghbi Lab from 2019 to 2023. Her research focuses on the brainstem, with particular interest in understanding how neurons differentiate using multi-omics approaches. Dr. Butts combines her expertise in bioengineering and neuroengineering to investigate fundamental questions about neuronal development and function. Outside of her professional work, she enjoys running, cooking, exploring new restaurants, watching Formula 1 racing, and maintaining saltwater aquariums.

Research topics

• Biology
• Neuroscience
• Genetics
• Cell biology
• Anatomy
• Surgery
• Medicine

Selected publications

• Rare heterozygous missense variants in VSX2 are associated with retinal detachment

  PLoS Genetics · 2026-02-03

  articleOpen access

  Retinal detachment (RD) is a sight-threatening emergency requiring urgent intervention to prevent permanent vision loss. While both environmental and genetic risk factors contribute to RD, its complete genetic architecture remains unknown. Here, we performed the largest whole genome sequencing-based case-control study in RD to date, including data from 7,276 RD cases and 236,741 controls in the UK Biobank. Through variant- and gene-level association analyses, we identified VSX2 as a genetic determinant of RD risk while confirming established associations including FAT3, RDH5, and COL2A1. Gene-level collapsing analysis revealed that rare heterozygous missense variants in VSX2 confer a 2.8-fold increased risk of RD (p = 2.4x10-10; odds ratio (OR) = 2.8; 95% confidence interval (CI): [2.1, 3.7]). One missense variant in this gene, p.Glu218Asp, demonstrated a particularly strong effect size (p = 9.3x10-10; OR = 5.9; 95% CI: [3.7, 9.4]). Replication analyses in two additional cohorts, totaling 1,331 cases and 52,355 controls strengthened both the gene- and variant-level associations even further (p = 1.4x10-10 and 1.1x10-11, respectively). Other contributory heterozygous variants included previously reported pathogenic homozygous variants for anophthalmia and microphthalmia. These findings thus reveal a previously unknown gene dosage curve for VSX2, where homozygous mutations cause severe developmental eye disorders and heterozygous mutations cause adult-onset retinal detachment. Extending this observation, we found a significant enrichment for other known recessive Mendelian eye disease genes among nominally significant (p < 0.05) genes associated with RD in the collapsing analysis. This work provides a compelling example of how heterozygous variants in recessive disease genes can be associated with less severe clinical phenotypes.

  PublisherDOI

• Notch signaling in neurogenesis

  Development · 2025-05-15 · 12 citations

  reviewSenior author

  The Notch signaling pathway plays a crucial role in neurogenesis by regulating cell fate specification. However, its complexity poses challenges in uncovering the mechanisms underlying these decisions. This Review explores the intricacies of the Notch pathway, including its diverse activation mechanisms and the influence of post-translational modifications of Notch receptors and ligands on pathway outcomes. We discuss how Notch signaling regulates embryonic neurogenesis via interactions with proneural genes and with other signaling pathways. We also examine the role of Notch in adult neurogenesis, and the therapeutic potential of leveraging Notch signaling to reprogram glia in the adult brain. Lastly, we highlight emerging technologies that measure Notch dynamics and discuss remaining knowledge gaps. Together, these insights underscore the multifaceted role of Notch signaling and outline key directions for future research.

  PublisherDOI

• Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease

  Cell Reports · 2025-03-01 · 12 citations

  articleOpen access

  ). Notably, ITSN1 haploinsufficiency has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, we find that loss of the ITSN1 ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity and motor deficits, and in vitro assays further suggest a physical interaction between ITSN1 and α-synuclein. These results firmly establish ITSN1 as a PD risk gene with an effect size exceeding previously established loci, implicate vesicular trafficking dysfunction in PD pathogenesis, and potentially open new avenues for therapeutic development.

  PublisherOA PDFDOI

• Diverse ancestral representation improves genetic intolerance metrics

  Nature Communications · 2025-03-18 · 6 citations

  articleOpen access

  The unprecedented scale of genomic databases has revolutionized our ability to identify regions in the human genome intolerant to variation-regions often implicated in disease. However, these datasets remain constrained by limited ancestral diversity. Here, we analyze whole-exome sequencing data from 460,551 UK Biobank and 125,748 Genome Aggregation Database (gnomAD) participants across multiple ancestries to test several key intolerance metrics, including the Residual Variance Intolerance Score (RVIS), Missense Tolerance Ratio (MTR), and Loss-of-Function Observed/Expected ratio (LOF O/E). We demonstrate that increasing ancestral representation, rather than sample size alone, critically drives their performance. Scores trained on variation observed in African and Admixed American ancestral groups show higher resolution in detecting haploinsufficient and neurodevelopmental disease risk genes compared to scores trained on European ancestry groups. Most strikingly, MTR trained on 43,000 multi-ancestry exomes demonstrates greater predictive power than when trained on a nearly 10-fold larger dataset of 440,000 non-Finnish European exomes. We further find that European ancestry group-based scores are likely approaching saturation. These findings highlight the need for enhanced population representation in genomic resources to fully realize the potential of precision medicine and drug discovery. Ancestry group-specific scores are publicly available through an interactive portal: http://intolerance.public.cgr.astrazeneca.com/ .

  PublisherOA PDFDOI

• A single-cell transcriptomic map of the developing Atoh1 lineage identifies neural fate decisions and neuronal diversity in the hindbrain

  Developmental Cell · 2024-08-01 · 20 citations

  articleOpen access1st authorCorresponding

  Proneural transcription factors establish molecular cascades to orchestrate neuronal diversity. One such transcription factor, Atonal homolog 1 (Atoh1), gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although Atoh1 lineage neurons have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA sequencing and ATOH1 DNA binding in Atoh1 lineage neurons of the developing mouse hindbrain. This high-resolution dataset identified markers for specific brainstem nuclei and demonstrated that transcriptionally heterogeneous progenitors require ATOH1 for proper migration. Moreover, we identified a sizable population of proliferating unipolar brush cell progenitors in the mouse Atoh1 lineage, previously described in humans as the origin of one medulloblastoma subtype. Collectively, our data provide insights into the developing mouse hindbrain and markers for functional assessment of understudied neuronal populations.

  PublisherDOI

• Diverse ancestral representation improves genetic intolerance metrics

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-06

  preprintOpen access

  Summary Rapidly expanding genomic databases have enabled the identification of regions in the human genome intolerant to variation and thus likely relevant to human disease. However, despite their unprecedented scale, these datasets remain constrained by limited ancestral diversity. Here, we systematically evaluate how genetic diversity impacts gene- and sub-genic intolerance metrics by analyzing whole-exome sequencing data from 460,551 UK Biobank participants and 125,748 gnomAD participants across diverse ancestral backgrounds. Through comprehensive analysis of randomly sampled datasets with varying ancestral compositions, we demonstrate that genetic diversity, rather than sample size alone, drives the performance of intolerance metrics in identifying functionally critical genes and genic sub-regions. Notably, scores trained on variation observed in African and Admixed American ancestral groups showed superior resolution in detecting neurodevelopmental disease risk genes and haploinsufficient genes compared to scores trained on variation observed in European ancestry cohorts. Most strikingly, the Missense Tolerance Ratio (MTR) trained on 43,000 multi-ancestry exomes demonstrated greater predictive power than when trained on a nearly 10-fold larger dataset of 440,000 non-Finnish European exomes, indicating that European ancestry-based scores are approaching saturation. These findings establish ancestral diversity as the fundamental determinant for advancing intolerance metrics and underscore the urgent scientific and ethical imperative for enhanced population representation in genomic resources to fully realize the potential of precision medicine and drug discovery.

  PublisherOA PDFDOI

• Haploinsufficiency of <i>ITSN1</i> is associated with Parkinson’s disease

  medRxiv · 2024-07-27 · 2 citations

  preprintOpen access

  Abstract Background Despite its significant heritability, the genetic underpinnings of Parkinson disease (PD) remain incompletely understood, particularly the role of rare variants. Advances in population-scale sequencing now provide an unprecedented opportunity to uncover additional large-effect rare genetic risk factors and expand our understanding of disease mechanisms. Methods We leveraged whole-genome sequence data with linked electronic health records from 490,560 UK Biobank participants, identifying 3,809 PD cases and 247,101 controls without a neurological disorder. We performed both variant-and gene-level association analyses to identify novel genetic associations with PD. We analyzed two additional independent case-control cohorts for replication (totaling 3,739 cases and 58,156 controls). Additionally, we performed functional validation of a novel PD association in a human synuclein-expressing Drosophila model. Findings In the UK Biobank, we replicated associations in well-established loci including GBA1 and LRRK2. We also identified a novel association between protein-truncating variants (PTVs) in ITSN1 and an increased risk of PD, with an effect size exceeding those of established loci (Fisher’s Exact Test: p=6.1x10 -7 ; Odds ratio [95% confidence interval] = 10.53 [5.20, 21.34]). We replicated the ITSN1 risk signal in a meta-analysis across all cohorts (Cochran-Mantel-Haenszel test p=5.7x10 -9 ; Odds ratio [95% confidence interval] = 9.20 [4.66, 16.70]). In Drosophila , haploinsufficiency of the ITSN1 ortholog ( Dap160 ) exacerbated α-synuclein-induced compound eye degeneration and motor deficits. Interpretation We establish ITSN1 as a novel risk gene for PD, with PTVs substantially increasing disease risk. ITSN1 encodes a scaffold protein involved in synaptic vesicle endocytosis, a critical pathway increasingly recognized in PD pathogenesis. Our findings highlight the power of large-scale sequencing coupled with preclinical functional modeling to identify rare variant associations and elucidate disease mechanisms.

  PublisherOA PDFDOI

• <i>Atoh1</i> drives the heterogeneity of the pontine nuclei neurons and promotes their differentiation

  Science Advances · 2023 · 9 citations

  • Biology
  • Neuroscience
  • Cell biology

  missense mutations.

  PublisherOA PDFDOI

• List of contributors

  Elsevier eBooks · 2022-12-02

  book-chapter
  PublisherDOI

• Spinal interneurons and cell transplantation

  Elsevier eBooks · 2022-12-02 · 3 citations

  book-chapter
  PublisherDOI

Frequent coauthors

• Huda Y. Zoghbi

  Baylor College of Medicine

  36 shared

• Ryan S. Dhindsa

  AstraZeneca (Brazil)

  29 shared

• Sih‐Rong Wu

  Universidad Católica de Santa Fe

  24 shared

• Jean‐Pierre Revelli

  Lexicon Pharmaceuticals (United States)

  24 shared

• Mark A. Durham

  Baylor College of Medicine

  24 shared

• Todd C. McDevitt

  Gladstone Institutes

  22 shared

• Olivier Saulnier

  Hospital for Sick Children

  20 shared

• Michael D. Taylor

  Baylor College of Medicine

  20 shared

Labs

• Butts LabPI

Education

• PhD, Bioegnineering

  University of California, San Francisco

• Bachelors of Science, Biomedical Engineering

  Washington University in St. Louis

  2013

Awards & honors

• NSF Graduate Research fellowship (2015 – 2018)
• NINDS F32 National Research Service Award (2020 – 2022)