The Genetics Podcast

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
01:48 Working on origins-of-life chemistry in Stanley Miller’s lab
04:13 Vincent’s path to genetics 
06:29 How somatic repeat expansion drives Huntington’s disease 
10:26 Therapeutic strategies for Huntington’s disease
16:53 Using gene editing to shrink repeat expansions
20:16 Optimizing CRISPR nickase delivery and expression for repeat expansion editing
27:32 Moving gene editing from academic research toward a first-in-human trial
29:55 Clinical trial challenges for Huntington’s gene therapies and uniQure’s early data
33:33 Epigenetic regulation of repeat instability in neurodegenerative disease
34:51 How basic science breakthroughs like CRISPR become transformative biology tools
37:52 How academic couples navigate the two-body problem when building research careers
43:02 Developing biomarkers to measure whether DNA-targeting therapies are working
45:54 Closing remarks
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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
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https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link
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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
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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

This week on The Genetics Podcast, Patrick is joined by Lindsey Wahlstrom, Co-Founder and Chief Momatologist of Rona’s FUN LAB, Jimi Olaghere, sickle cell disease patient advocate and early CRISPR gene therapy trial participant, and Rachel Smith, Vice President and Head of Rare and Genetic Diseases at Parexel. They discuss the realities of developing and delivering advanced therapies in rare disease, how funding models, regulation, and trial design shape access and outcomes, and why embedding patient experience early is critical to building therapies that are not only effective but scalable, accessible, and meaningful for patients and families.

Show Notes: 
0:00 Intro to The Genetics Podcast
01:00 Welcome to guests and what Rare Disease Day means to them
08:09 Balancing hope with funding, pricing, and access in advanced therapies
11:48 Why patient access must be built into drug development from day one
14:20 Patient engagement, community readiness, and the realities of trial participation
17:49 Why early patient input is still inconsistent and often treated as a checkbox
23:20 Designing trials around what actually matters to patients and families
26:53 Navigating regulators, payers, and trial design constraints in rare disease therapies
36:02 Redefining success in gene therapy around access, scalability, and real patient benefit
43:27 Closing remarks