Functional Genomics and Neurogenetics

September 6-13, 2025

 

 

Director: Daniel Geschwind

University of California Los Angeles, USA

 

Faculty:

Kristen Brennand, Yale University, New Haven, USA

Goncalo Castelo Branco, Karolinska Institute, Stockholm, Sweden

Jonathan Flint, University of California Los Angeles, USA

Daniel Geschwind, University of California Los Angeles, USA

Botond Roska, Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland

Olga Troyanskaya, Princeton University, USA

 

We are in the midst of a revolution in biology that is based on advances in genetic and genomic technology, empowered by advances in computer science. In addition to identifying specific factors that cause human brain disorders, genetics and genomics now provide an extraordinarily powerful tool kit for understanding nervous system function in health and disease. There have been many major recent advances. This includes molecular-systems methods that permit dynamic measurement of gene products in a highly parallel manner, coupled with an underlying systems-level knowledge of the organization of these gene products to provide a more integrative understanding of nervous system function. By permitting us to view specific gene products in the context of all others, we can use these rapidly evolving approaches to discover previously unexplored biology, develop new hypotheses and rank these hypotheses based on quantitative reasoning.

Specific tools for gene identification include whole exome and whole genome sequencing and genetic association studies, single cell and bulk tissue RNA sequencing for measuring virtually all direct forms of gene products, their post-transcriptional regulation, and a plethora of allied methods for investigating epigenetic regulation, as well as a plethora of epigenetic methods, ranging from single cell cut and tag and ATAC-seq to bulk chromatin conformation profiling by Hi-C and related methods. Advances in model organism genetics and in vitro modelling based on stem cell biology provide experimental platforms for neurobiological investigation and hypothesis testing at both low and high throughput. Further, genomic and genetic approaches can be used to vastly amplify the value of these model systems, from transcriptional and epigenetic profiling to providing catalogues of cell types and cell type-specific changes to move towards understanding circuit function. Lastly, a number of high throughput assays, ranging from arrayed and pooled CRISPR screening approaches to multiple parallel reporter assays, permit genome-wide functional screening.

In this Advanced Course, we will introduce these platforms and address some of the major challenges inherent in connecting different levels of analysis, from genes to pathways to cells and circuits, that are required to understand how genetic variation ultimately leads to behavioural and cognitive phenotypes. Examples of specific topics that will be addressed include Nextgen sequencing, genetic association and eQTL analysis, single cell and multi-scale analyses from genomics and transcriptomics, methods for measuring chromatin structure and related epigenetic landscapes, especially focusing on single cell analytic methods, IPSC-derived in vitro systems, and methods for systems-level analysis, such as gene networks and focused applications of machine learning. The Faculty has pioneered research in these areas and will cover several major disease areas, ranging from neuropsychiatric disorders such as autism and schizophrenia to neurodegenerative diseases.

 

Daniel H. Geschwind

Understanding neurodevelopmental disorders via integrative genomics and neurobiology

Our laboratory works at the interface of genetics and neuroscience, integrating gene discovery with computational and functional genomics and experimental validation in model systems. Our goal is to develop new therapeutics based on an improved understanding of disease mechanisms. I will provide an introduction and overview of the approaches. My portions of this Advanced Course will touch address several of the major challenges facing modern neurogenetics, some of which will attempt to tie together information from some of the other lectures based on the logical flow of moving from finding loci, to finding genes, to uncovering biological function. A major focus of my lectures will be high throughput biology and data integration,  including multiple parallel reporter assays (MPRA) and CRISPR validation and screening. I will cover our work using 3D chromatin structure, epigenetic annotations, MPRA and eQTL to characterize the functional consequences of disease-related variation, ranging from the regulatory elements to the target genes (moving from loci to genes). Another key topic that I will cover will be using co-expression networks to build functional models, identify disease drivers and perform drug screening. I will discuss our work applying gene networks to a complex neurodevelopmental disorder, autism spectrum disorder (ASD), and neurodegenerative conditions to uncover how diverse sets of genes and mutations converge on specific biological processes and brain circuits and how this can inform disease modelling in vitro. I will also describe the power and challenges of using gene co-expression networks for drug screening via proof of principle experiments in several contexts.

 

Kristen Brennand

Using stem cells to explore the genetics underlying brain disease.

Each person’s distinct genetics and environment predispose them to some phenotypes and confer resilience to others. How do all the individual variants across the genetic landscape combine to yield larger phenotypic impacts in aggregate? How does genetic variation govern the penetrance of deleterious mutations, variable expressivity, and pleiotropy? What is the role of the environment across the lifespan? Understanding how these elements interact will advance our knowledge of human development, ageing, health, and disease. Our functional genomics approach integrates human-induced pluripotent stem cell models with CRISPR-based genome engineering to introduce and reverse genetic variation, yielding precision models that can be combined with genetic and pharmacological screens. With this approach, we demonstrated that diverse risk variants share downstream convergent impacts and that when added together, their combinatorial perturbations yield novel non-additive outcomes that cannot yet be predicted by individual manipulations alone. We seek to understand the genetic regulation of phenotype and how developmental, cellular, and environmental contexts impact it. Thus, rather than just characterize the impact of trait-associated variants, we seek to uncover modifiers that alter it. For example, we study how genotype-phenotype relationships vary across people and dynamic conditions. Our goal is to decipher the frameworks that buffer genetic risk in order to confer biological resilience and promote healthy development. We are uniquely positioned to answer critical questions: How does the environment impact genetic regulation? Why are there marked sex effects across many human traits and diseases? What are the molecular mechanisms of resilience whereby individuals with high genetic risk show no clinical manifestation of disease? Understanding the basic biology governing the complex interplay between genetic variants and the environment will springboard the development of novel, personalized approaches to improve health and prevent disease.

 

Jonathan Flint

Human and model organism complex trait genetics

These presentations introduce current issues in human and model organism complex trait genetics. For human genetics, the focus will be on how identifying genes involved in common human diseases, which include psychiatric diseases, had to overcome ignorance about their underlying genetic architecture. Assumptions about the number of loci, the size of their contribution to disease, and their location in the genome (assumed to be within genes) all turned out to be incorrect. As a picture emerged of polygenicity, of thousands of loci of small effect, lying in regulatory regions of the genome, new approaches have been developed to use this information to explore the biology of behaviour.  Examples from the work on studying schizophrenia and major depressive disorder to illustrate the current state of knowledge will be used.  The presentations on model organism genetics review the use of inbred strains, primarily mouse and rat, but true for any species in which animals can be rendered inbred, to identify loci contributing to the behavioural variation. The ability to manipulate the genome and to design breeding experiments has been able to overcome some of the obstacles that make gene identification difficult in human genetics and provides novel ways of exploring the neurobiology of behaviour.

 

Goncalo Castelo Branco

Single-cell transcriptomics and epigenomics: focus of oligodendroglia

Our laboratory focuses on the molecular mechanisms regulating epigenomic and transcriptomic states of oligodendroglia, which are targeted in demyelinating diseases such as multiple sclerosis (MS). Our long-term goal is to build a solid platform of convergent knowledge and know-how leading to epigenetic based-therapies to induce regeneration/remyelination and prevent neuroinflammation in MS. Using open-end and candidate-based multidisciplinary approaches, we combine state-of-the-art technologies, including single-cell, spatial transcriptomics and epigenomics, CRISPR-based screens in human IPSCs-derived oligodendroglia and other technologies, with the analysis of rodent models of disease and human MS patient archival tissue. In my lectures in this Advanced Course, I will focus on three themes: 1) Epigenetics from a neurodevelopment perspective; 2) Historical perspective and current status of single-cell and spatially-resolved transcriptomics and epigenomics technologies; 3) Oligodendroglia in development and multiple sclerosis: insights from single cell and spatial transcriptomics and epigenomics.