The Genetics Podcast

This week on The Genetics Podcast, Patrick is joined by Dr. David Hallett, Chief Scientific Officer at Recursion. They discuss the biggest shifts in drug discovery over Dave's three-decade career, where AI is genuinely transforming the field today versus where the hype outruns the reality, and how Recursion's perturbational maps have uncovered and validated a novel neurodegeneration target. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Dave 01:57 The biggest shifts in drug discovery over three decades 06:39 Where AI is delivering real wins across drug discovery today 12:19 How AI-assisted trial simulation reveals which eligibility criteria to relax 14:46 The three biggest reasons drug programs fail in the clinic 18:20 How Recursion's perturbational maps uncover new drug targets 24:58 A four-step framework for validating a novel drug target 28:44 How Recursion balances deep therapeutic focus with partnership breadth 30:52 Why AI can't shortcut clinical trials, and what proof of real impact looks like 34:57 The skills scientists need most in the AI era, and why trusting AI outputs starts with trusting the data 39:52 Closing remarks Find out more: Recursion ( https://www.recursion.com/ )

This week on The Genetics Podcast, Patrick is joined by Dr. Danny Miller, Assistant Professor of Pediatrics and of Laboratory Medicine and Pathology at the University of Washington and Attending Physician at Seattle Children's Hospital. They discuss the case for making long-read sequencing the first genetic test every patient receives, the reference dataset his lab is building from the 1000 Genomes Project to resolve structural variants, publicly available methylation signatures as biomarkers for diagnosis and treatment response, and his vision for genome-informed care from newborn screening through the NICU. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Danny 01:41 The case for long-read sequencing as first-line genetic testing 02:52 Current barriers to wider use of long-read sequencing 04:14 Building a long-read reference dataset from 1000 Genomes for variant filtering 06:47 How long-read sequencing can solve a missed diagnosis 08:12 The clinical case for complete telomere-to-telomere genomes 10:39 What it will take to shift the clinical genetics status quo 12:06 Making methylation signatures public to diagnose disease and track therapy 15:58 Danny's path from programming and finance into clinical genetics 18:19 Danny's lived experience with deafness and achondroplasia, and how it shapes his approach to genetic counseling 21:46 Danny's optimism about AI in genomics and worry about AI in education 27:15 The path to making genomes a routine part of the medical record 29:47 The vision of same-day newborn genomic data guiding NICU treatment decisions 34:31 Closing remarks Find out more: Miller Lab ( https://millerlaboratory.com/ )

This week on The Genetics Podcast, Patrick is joined by Dr. Brent Richards, CEO and Founder of 5 Prime Sciences and Professor of Human Genetics, Epidemiology, and Medicine at McGill University. They discuss how to triangulate different types of genetic evidence to validate a drug target, why herd psychology often drives which targets get funded, why strong genetic support didn't save the Zeus IL-6 trial, and how collider bias can distort genetically stratified clinical trials. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Brent 01:43 How company size shapes access to genetic drug discovery tools 04:10 Brent's framework for triangulating different types of genetic evidence 06:50 The herd psychology behind which drug targets get funded 10:01 Potential reasons the Zeus IL-6 trial failed despite strong genetic evidence 12:49 What a gold standard genetic evidence package actually looks like 17:13 Closing the data gap with diverse genomes and systematic pipelines 19:03 The diabetes patient story that drove Brent into drug development and balancing academia with industry 25:39 Why obesity went from a drug development graveyard to its biggest frontier 29:13 How collider bias can distort genetic risk trial results 38:20 Where to go deeper on advanced genetic drug discovery concepts 40:11 Closing remarks Find out more: 5PrimeSciences’ symposium on human genetics at ASHG2026 in October

This week on The Genetics Podcast, Patrick is joined by Dr. Andrew Jackson, Programme Leader at the MRC Human Genetics Unit at the University of Edinburgh. They discuss how his lab discovered that gain-of-function DNMT3A mutations cause both microcephalic dwarfism and an accelerated aging syndrome, and what that reveals about the shared biology of growth and aging. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Andrew 01:34 The origins of Andrew's work linking brain size and aging 02:54 The genetics of mammalian size range and epigenetic factors regulating growth 05:02 How DNMT3A mutations causing dwarfism led to discovering an accelerated aging syndrome 09:46 Cell number rather than cell size as the shared driver of growth and aging 13:07 Whether brain size within humans actually predicts cognitive ability 15:20 Why intellectual disability has far more known genes than dwarfism 19:26 Discovering ribonuclease H2's role in DNA repair, and its unexpected link to cancer 23:35 Why studying rare monogenic diseases reveals broader biology 26:59 Andrew's next research questions on aging, cancer, and mutation biology 28:42 Why humans, model organisms, and cell assays each have a role 31:00 Somatic mosaicism's growing role in aging and disease beyond cancer 36:11 Closing remarks Find out more: Mentioned studies from Andrew’s lab: https://www.nature.com/articles/s41588-026-02633-8 https://www.nature.com/articles/s41588-018-0274-x

This week on The Genetics Podcast, Patrick is joined by Stevie Ringel, co-founder of Nome and founder of the Kizuna Foundation. They discuss Stevie's own ultra-rare disease diagnosis and shaped his path to founding Kizuna Foundation and Nome, how Nome's AI agents help scientists navigate the operational complexity of small-batch drug development, the technical and business model advantages underpinning Nome's accuracy, and what it will take to build a sustainable funding model for ultra-rare disease. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Stevie 01:37 Stevie's inherited retinal disease (IRD) diagnosis and subsequent path into genomics 03:16 Why Stevie founded Kizuna Foundation and why ultra-rare drug development is so operationally complex 06:27 The origin story of Nome and using AI to automate the operational work 10:09 The inspiration for the name “Nome” and who the company is built to serve 12:44 The biggest blockers to program speed 15:07 How AI and scale can bring down the cost of gene therapy manufacturing 18:01 FDA signals and global regulatory competition 19:33 Priority review vouchers and why Nome stays out of molecule IP 20:33 Nome's AI and review process for patient reports and its expansion to health systems 25:04 Nome's agent architecture and the data behind its accuracy 28:17 Why delivery remains gene therapy's biggest bottleneck and approaches for solving it 31:34 The case for a new capital model in rare disease drug development 33:25 What’s next for Nome as they advance preclinical programs 34:25 Nome’s focus on process excellence across therapeutic modalities 36:34 Closing remarks Find out more: Nome

This week on The Genetics Podcast, Patrick is joined by Dr. Jagesh Shah, Chief Scientific Officer at Mirai Bio. They discuss why delivery is a central bottleneck holding back nucleic acid medicines, how Mirai's lipid nanoparticle (LNP) platform is built to reach tissues like adipocytes and T cells, and the machine learning feedback loop the company uses to engineer LNP formulations. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Jagesh 01:40 Why delivery is the main bottleneck for gene therapies 03:42 Easier vs harder tissues to target for delivery 06:40 Overview of Mirai's modular delivery platform 09:02 Comparing viral vectors and lipid nanoparticles (LNPs) 12:18 Different approaches for targeting adipocytes and T cells with LNPs 15:49 Mirai's machine learning (ML) feedback loop for optimizing LNP formulation 20:50 Why lipid chemistry is still hard for ML to learn and factors affecting LNP tropism 24:35 Jagesh's path from academia to Mirai 27:23 Mirai's platform business model and how it lowers risk 29:13 What industry partnerships with Mirai look like 31:41 Mirai's next frontier of delivery to muscle tissue and the brain 34:40 Cargo size and immunogenicity of LNPs vs AAV 36:00 Why the field needs to close the regulatory pace gap 37:19 Closing remarks Find out more: Mirai Bio

This week on The Genetics Podcast, Patrick is joined by Sharon Terry, President & CEO of Genetic Alliance. They discuss how Sharon established a layperson-led biobank, her long-term work on rare diseases and patient advocacy, and her program to bring genetic technology to patients in low- to middle-income countries. We’re re-running this episode for its enduring lessons on patient advocacy, rare disease parenting, communication, and citizen science. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Sharon and a discussion of the personal experience with rare disease that started her journey 03:47 Reasons Sharon decided to establish the first layperson-led biobank 05:34 Challenges with setting up the biobank infrastructure 07:00 Balancing financial factors in a non-profit organization 09:30 Recent patterns and future insight into rare disease drug discovery framework and regulation 15:32 Barriers to widespread collaboration and cooperation in rare disease research, and why it should be approached from a public health perspective 18:12 Background and experiences from the iHope Genetic Health program in low- to middle-income countries 24:44 Sharon’s perspective on challenges with the Genetic Information Non-discrimination Act 28:49 Sharon’s lessons learned in her patient advocacy and policy work, and her hopes for future legislation 33:04 Sharon’s hopes for improved access to genetic testing and treatment for children in underserved communities 34:34 How Sharon learned about rare diseases and genetics as a “homeschooling mom without a degree” 37:54 Insights into how elements of spirituality can support advocacy work 40:18 Closing remarks

This week on The Genetics Podcast, Patrick is joined by Dr. Carl Anderson, Senior Group Leader and Head of the Human Genetics Programme at the Wellcome Sanger Institute, where he leads the Genomics of Inflammation and Immunity Group. They discuss IBDVerse, the single-cell atlas Carl's team built to map genetic effects on gene regulation across gut cell types, how coding and non-coding variants converge on shared biological pathways in inflammatory bowel disease, and Carl's vision for longitudinal multi-omics cohorts built around the sickest and most underrepresented hospital patients. Show Notes 0:00 Intro to The Genetics Podcast 00:58 Welcome to Carl 02:05 The origins of IBDVerse and mapping genetic effects on gene regulation across gut cell types in IBD 05:43 How anti-TNFs and newer genetically-supported IBD drugs have reshaped treatment 08:04 Genetic versus environmental contributions to IBD 09:53 Using single-cell data to uncover IBD disease subtypes 13:22 Drug sequencing and immunogenicity in treatment response 16:52 The backstory of building the IBDVerse atlas at scale 20:29 How coding and non-coding IBD variants converge on the same genes and pathways 23:38 The case for pathway-specific polygenic risk scores 28:17 Building a longitudinal multi-omics dataset to predict IBD progression and drug response 30:08 Why Sanger's next cohort targets sick and underrepresented patients rather than healthy volunteers 34:07 What Carl looks for when interviewing PhD students and faculty candidates 39:20 A call to junior scientists and closing remarks Find out more: IBDverse study

This week on The Genetics Podcast, Patrick is joined by Dr. Pradeep Natarajan, Director of Preventive Cardiology at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. They discuss the discovery of clonal hematopoiesis as a driver of cardiovascular disease, the inflammatory mechanisms and emerging therapies targeting it, the growing clinical case for polygenic risk scores, and Pradeep's upcoming move to lead cardiometabolic and human genetics research at Amgen. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Pradeep 01:30 The origin story of clonal hematopoiesis (CH) as a cardiovascular risk factor 09:41 CH mutations such as TET2 that are linked to cardiovascular disease 12:27 Evidence tying inflammation to CH and drugs that could target it 16:49 TenSixteen Bio’s strategy for targeting CH and the challenge of finding the right patients 21:33 Trajectory of CH across age and somatic mosaicism beyond blood 26:44 How polygenic risk scores fill a gap in cardiovascular risk prediction 34:49 The future clinical applications of polygenic risk scores 39:20 The challenge of standardizing polygenic risk scores for clinical and regulatory use 42:27 Pradeep's move to pharmaceutical company Amgen and his reasons for it 46:23 Closing remarks Find out more: Clonal hematopoiesis paper

This week on The Genetics Podcast, Patrick is joined by Dr. Christopher Walsh, Professor of Pediatrics and Neurology at Harvard Medical School, Chief of Genetics and Genomics at Boston Children's Hospital, and HHMI Investigator. They discuss his path from neurobiology to human genetics, how somatic mosaicism in the brain drives disease from epilepsy to Alzheimer's, and what this reveals about new therapeutic targets for neurodegeneration. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Chris 01:18 Chris’ path from neurobiology to human genetics 04:55 How collaboration and mentorship have shaped Chris' career 06:59 Somatic mosaicism and genetic mutations in the brain, from epilepsy to Alzheimer’s 13:56 Repurposing cancer therapeutics and targeting DNA damage as new approaches to Alzheimer's 15:29 A shared pattern of DNA damage across neurodegenerative diseases and the mechanism behind it 19:36 How healthy neurons accumulate mutations with age and what that means for the brain 23:21 How mutation rates and patterns vary across cell types 26:23 How genome quality control and synaptic pruning may explain both brain development and neurodegeneration 30:33 Why some people maintain a healthy brain into old age 33:57 Chris’ advice for early-career scientists on pursuing goals 36:43 Closing remarks Find out more: https://walshlab.org/

This week on The Genetics Podcast, Patrick is joined by Yentli Soto Albrecht, physician-scientist in training and founder of CureC9. They discuss how losing her father to C9orf72 ALS, and later learning her own genetic risk, reshaped the direction of her career. The conversation explores the biology linking the C9 repeat expansion to ALS and FTD, and how CureC9 is removing barriers across biomarkers, therapeutics, and patient samples to accelerate progress toward a cure. Show Notes 0:00 Intro to The Genetics Podcast 00:58 Welcome to Yentli 02:34 How Yentli's father's C9 ALS diagnosis and her own genetic risk led her to pivot her research career toward curing it 06:41 The biology of the C9orf72 repeat expansion and how TDP-43 dysregulation links it to ALS and FTD 11:40 Therapeutic strategies targeting TDP-43 pathology in ALS and FTD 15:35 The state of biomarkers for ALS and FTD, and why C9-FTD trials lag behind ALS 22:08 How Yentli is lowering barriers for biomarker, cell line, and drug development through CureC9 30:40 Call for collaborators and where to follow Yentli 32:59 Closing remarks Find out more: CureC9

This week on The Genetics Podcast, we're re-airing our conversation with Eric Green, Founder and CEO of Trace Neuroscience, Co-Founder and Chief Scientific Officer at Maze Therapeutics, and Adjunct Clinical Assistant Professor at Stanford University School of Medicine. Patrick and Eric discuss Eric's transition from cardiology to entrepreneurship, the role of highly focused biotechs in creating precision therapies, and the development of high-impact gene therapies for people with amyotrophic lateral sclerosis (ALS). We're revisiting this episode following Trace Neuroscience's recent announcement that the first patient has been dosed with its antisense oligonucleotide (ASO) designed to restore UNC13A function in ALS. Show Notes 0:00 Intro to The Genetics Podcast 02:03 Welcome to Eric, his background in cardiology, and how he got into biotech 06:23 Eric’s experience incubating and spinning out early-stage companies with Third Rock Ventures and developing Maze Therapeutics 09:13 Eric’s decision to transition from academia to the world of biotech 11:24 Building Maze Therapeutics and Eric’s focus on and genetic modifiers to discover new drugs 15:09 The growth of therapeutic modalities in the context of genetics and gene therapies 16:48 What led Eric to launch Trace Neuroscience to develop ALS therapies 28:35 The process of getting Trace’s ALS therapies into the clinic 32:22 The identification of therapeutic value in low odds ratio genes 35:58 Eric’s view on the APOA1 gene target and its major effect size in kidney disease 40:03 How best to integrate genetics and genetic discovery into small and medium biotechs 41:50 Closing remarks Find out more Trace Neuroscience https://www.businesswire.com/news/home/20260622451252/en/Trace-Neuroscience-Initiates-Global-Clinical-Development-Program-for-TRCN-1023-an-Antisense-Oligonucleotide-Designed-to-Restore-UNC13A-Function-for-the-Treatment-of-ALS

This week on The Genetics Podcast, Patrick is joined by Dr. Timothy Yu, Associate Professor of Pediatrics at Harvard Medical School and Physician/Researcher at Boston Children’s Hospital. They discuss how one child’s hidden genetic mutation led Tim into individualized ASO medicine, what it takes to develop n-of-1 therapies, and how new regulatory frameworks could expand treatment options for children with ultra-rare genetic disease. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Tim 02:05 How uncovering the genetic mutation underlying an ultra-rare disease led Tim into personalized ASO medicine 07:38 Challenges in developing a custom ASO 12:25 How Tim’s team has scaled individualized ASO therapies to reach more than 50 patients worldwide 16:18 Measuring clinical benefit in n-of-1 therapies with natural history data, wearables, and biomarkers 20:24 How the N-of-1 Collaborative helps rare disease researchers share infrastructure 24:28 Comparing ASOs, base editing, and prime editing for individualized rare disease therapies 30:06 Finding scalable models for n-of-1 therapies in newborn genetic disease 33:52 The potential impact of the FDA’s Plausible Mechanism framework on bespoke therapies 36:58 Connecting rapid newborn genome sequencing to earlier treatment for rare genetic disease 42:10 Closing remarks

This week on The Genetics Podcast, Patrick is joined by Dr. Cara Altimus, CEO of BD², and Dr. Benjamin Neale, Associate Professor at Harvard Medical School and Massachusetts General Hospital. They discuss how rare variant discovery is opening new routes into bipolar disorder biology, how BD² is combining genetics with longitudinal multimodal data, and how patient priorities are shaping a research model focused on faster diagnosis and more precise treatments. Show Notes 0:00 Intro to The Genetics Podcast 00:58 Welcome to Cara and Ben 01:57 The origin and aims of BD2 04:20 Major knowledge gaps in bipolar disorder genetics 06:43 Using genetics and deep phenotyping to map bipolar disorder biology 13:47 Why bipolar disorder genetics needs both scale and deep clinical data 17:32 Finding the most predictive data for bipolar disorder biology and care 19:19 The search for scalable biomarkers in bipolar disorder 21:35 How BD² is building a bridge from discovery to clinical trials 26:48 Why bipolar diagnosis takes years and what patients want research to solve 33:08 How BD² is looking to other programs as inspiration to build a new research model 35:31 What overlapping risk genes reveal across bipolar disorder, schizophrenia, and autism 37:40 How rare variants could de-risk precision psychiatry trials 41:25 How BD² is scaling from early milestones to global funder momentum 45:04 Closing remarks Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link Find out more: BD2

This week on The Genetics Podcast, Patrick is joined by Dr. Angela Bradshaw, Director for Research at Alzheimer Europe and honorary lecturer at the University of Glasgow. Following a series of recent episodes exploring Alzheimer’s disease research, we’re revisiting this conversation to bring in an essential patient advocacy and nonprofit perspective on the field. Patrick and Angela discuss how Alzheimer Europe partners in and supports pan-European dementia research, the heterogeneity of dementia and Alzheimer’s disease, the future of potential new gene therapies, and the critical role advocacy organizations play in ensuring research reflects the needs and priorities of patient communities. Show Notes 0:00 Intro to The Genetics Podcast 01:27 Welcome to Angela and how she joined Alzheimer Europe 06:06 The biggest priorities and areas of focus for dementia and Alzheimer’s Disease (AD) research 10:10 Biomarkers for dementia and how early in disease development they can be utilized 12:40 The heterogeneity of dementia and AD and current understanding of subtypes and treatment journeys 17:20 The challenges of diagnosis, early identifiers, and the integration of genetics 18:53 Angela’s view on the latest breakthrough therapies 22:50 Partnering in and supporting dementia research efforts across 30+ European countries 29:15 Reimbursement frameworks and shared regulations across different countries 33:40 Angela’s thoughts on the near future of gene therapies for AD and dementia 38:04 Why Angela spent 50 hours travelling the length of Australia by bus 41:26 Closing remarks Find out more Alzheimer Europe Please consider rating and reviewing us on your chosen podcast listening platform!

This week on The Genetics Podcast, Patrick is joined by Salvador Rico, Chief Medical Officer at Encoded Therapeutics. With Encoded’s Dravet syndrome gene therapy program recently reaching major clinical and regulatory milestones, we’re revisiting this conversation on Salvador’s journey into drug development, his work on gene therapy for X-linked myotubular myopathy, and the fundamental challenges and exciting advances shaping the future of genetic medicine. Show Notes 0:00 Intro to The Genetics Podcast 01:27 Welcome to Salvador and how he became involved in drug development 11:29 Frustrations and rewards of the genetics field 14:27 Salvador’s study on gene therapy for patients with X-linked myotubular myopathy (XLMTM) 20:13 Risk of liver issues in gene therapy trials and attempts to mitigate them 24:50 Encoded Therapeutics‘ approach to drug discovery and what motivated Salvador to join the team 27:50 Steps towards therapeutic targeting of gene regulatory elements 30:32 Advantages of different methods for drug delivery 32:59 DNA- versus RNA-based therapy 35:24 Insights from approaches in other fields, including psychiatry 37:03 Considerations for using natural history studies 41:00 Expectations and goals for Encoded Therapeutics’ current and upcoming studies 43:45 Closing remarks Find out more Encoded Therapeutics New clinical data

This week on The Genetics Podcast, Patrick is joined by Dr. Vincent Dion, Group Leader at the UK Dementia Research Institute at Cardiff University. They discuss how repeat expansions drive Huntington’s disease and other neurological disorders, why DNA repair can sometimes worsen these mutations over time, and how CRISPR nickase editing could offer a new way to shrink disease-causing repeats rather than simply silence them. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Vincent 01:45 Working on origins-of-life chemistry in Stanley Miller’s lab 03:56 Vincent’s path to genetics 06:00 How somatic repeat expansion drives Huntington’s disease 09:40 Therapeutic strategies for Huntington’s disease 15:29 Using gene editing to shrink repeat expansions 18:31 Optimizing CRISPR nickase delivery and expression for repeat expansion editing 25:15 Moving gene editing from academic research toward a first-in-human trial 27:31 Clinical trial challenges for Huntington’s gene therapies and uniQure’s early data 30:47 Epigenetic regulation of repeat instability in neurodegenerative disease 33:14 How basic science breakthroughs like CRISPR become transformative biology tools 34:55 How academic couples navigate the two-body problem when building research careers 39:39 Developing biomarkers to measure whether DNA-targeting therapies are working 42:17 Closing remarks Please consider rating and reviewing us on your chosen podcast listening platform!

This week on The Genetics Podcast, Patrick is joined by Dr. Paul Valdmanis, Associate Professor at the University of Washington. They discuss the impact of APOE4 on risk in Alzheimer’s disease, how long-read sequencing is uncovering hidden genetic variation in Alzheimer’s and ALS, and what rare variants and cryptic splicing can teach us about neurodegeneration. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Paul 01:40 Long-read sequencing and ancestry-specific APOE4 risk in Alzheimer’s disease 04:20 Key findings from Paul’s study on a protective APOE4-linked variant in Alzheimer’s disease 10:58 What rare PSEN1 and PSEN2 variants reveal about Alzheimer’s disease biology 14:38 Disease-specific genetic mechanisms in ALS versus Alzheimer’s 17:14 Precision therapies for neurodegenerative disease 18:35 Choosing therapeutic targets in the neurodegenerative disease cascade 20:21 Landscape of ALS and Alzheimer’s therapies 23:48 Lessons from liver-directed gene therapy on microRNA toxicity, cancer risk, and brain delivery challenges 29:12 Using long-read sequencing to uncover tandem repeat expansions missed by conventional genomics 33:26 Findings from a study of long-read sequencing on ancient genomes 38:06 Closing remarks Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link Find out more: APOE study Ancestry study

This week on The Genetics Podcast, Patrick is joined by Dr. Bin Yu, CDSS Chancellor’s Distinguished Professor at UC Berkeley. They discuss how different statistical approaches, from linear models to random forests, can be used to study complex genetic traits, recent findings on epistasis in cardiomyopathy, and how improving robustness and reproducibility can lead to more reliable scientific conclusions. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Bin 01:47 Linear models as the foundation of genetic analysis 05:34 Using random forests and stability to identify gene–gene interactions beyond linear models 11:05 How iterative feature weighting in random forests improves detection of gene interactions 13:10 Using GWAS to prioritize features in high-dimensional genetic data 15:06 Applying stable interaction models to hypertrophic cardiomyopathy in UK Biobank 20:47 Biological insights from gene–gene interactions in cardiomyopathy and evidence for indirect epistasis 23:25 Scaling discovery of epistatic interactions with better data and integrated experimental validation 27:21 The predictability, computability, and stability (PCS) framework for data science 30:06 How Bin’s early life during the Chinese Cultural Revolution shaped her 32:54 Balancing AI-driven productivity with human reasoning and scientific thinking 35:23 Developing the ability to read people through observation, listening, and real-world interaction 38:03 Closing remarks Find out more: Epistasis in cardiac hypertrophy study https://vdsbook.com/

This week on The Genetics Podcast, Patrick is joined by Dr. Sarah Marzi, Senior Lecturer at King's College London and group leader at the UK Dementia Research Institute. They discuss the impact of genes and environment on neurodegenerative disease, including: how APOE genotype shapes microglial function, how cell type-specific epigenomics of postmortem brain tissue is revealing the role of microglia and oligodendrocytes in Alzheimer's disease, and how pesticide exposure drives selective dopaminergic neuron loss and neuroinflammation in Parkinson's. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Sarah 02:13 Environmental contributions to Parkinson’s disease and ALS 05:01 The role of microglia in Alzheimer’s disease and findings from a study on APOE variants in a mouse model 12:50 APOE4 effects on lipid accumulation, microglial activation, and vitamin D receptor signaling 14:20 Building a multi-omic atlas of the Alzheimer’s brain 18:01 Overview of the pathological cascade of events in the Alzheimer’s brain 20:31 Anti-amyloid therapies, early intervention, and combination treatment strategies 22:24 Rotenone exposure and microglial immune activation in Parkinson’s disease 29:24 Dopaminergic neuron vulnerability to pesticide exposure and mitochondrial dysfunction 31:04 Familial Parkinson’s genes, polygenic Alzheimer’s risk, and genetically targeted clinical trials 33:13 Polygenic risk and microglial cell state regulation in Alzheimer’s disease 34:13 Defining cell states in single cell RNA sequencing 35:30 Oligodendrocyte epigenetic and transcriptional changes in Alzheimer’s disease 37:23 Sarah’s most memorable hiking adventures 38:58 Closing remarks Find out more: Alzheimer’s APOE microglia xenotransplantation study Rotenone exposure Parkinson’s study