The Genetics Podcast

This week on The Genetics Podcast, Patrick is joined by Dr. Andrea Ganna, Associate Professor at the Institute for Molecular Medicine Finland (FIMM). They discuss the promise and limits of polygenic risk scores for disease prediction and clinical trials, how large-scale electronic health records and AI models could transform medical research and healthcare planning, what Finland’s national health data infrastructure enables for population-scale studies, and how genetics can be used to strengthen trial emulation in observational data.
Show Notes: 
0:00 Intro to The Genetics Podcast
00:59 Welcome to Andrea
01:51 Andrea’s research focuses, including polygenic scores in biobanks and AI applications 
03:02 Complementarity between polygenic scores and electronic health record–derived risk signals across biobanks
04:47 Using polygenic risk scores for prognostic versus predictive enrichment in clinical trials
10:28 Limitations and opportunities of using AI models on large-scale electronic health records
15:47 Legal, data infrastructure, and privacy barriers to building AI models on health records
18:04 Choosing model architectures for healthcare AI 
19:47 Using AI and multi-omics data to integrate biological knowledge and the challenge of learning causality
21:43 How removing genetic effects from proteins improves disease prediction and highlights the role of environment
24:42 Finland’s health data ecosystem and national biobanks
28:11 Using genetics to improve trial emulation in biobank data and observational studies
33:42 Closing remarks
Find out more:
Trial emulation study

Polygenic scores study

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This week on The Genetics Podcast, Patrick is joined by Dr. Anna Lindstrand, Professor and Consultant in Clinical Genetics and Genomics at the Karolinska Institute. They discuss how Sweden has scaled whole genome sequencing as a first-line test for rare disease, what long-read sequencing adds to clinical diagnostics, how national genomic infrastructure can accelerate translation into precision medicine, and where prevention and adult genomic screening may fit into the future of healthcare.
Show Notes
0:00 Intro to The Genetics Podcast
00:59 Welcome to Anna
01:34 Choosing between whole genome, exome, panels, and long-read sequencing in clinical practice
04:05 Evaluating long-read sequencing in the clinic 
06:37 What long-read sequencing adds to diagnostic yield
09:15 The role of RNA sequencing, proteomics, and methylation profiling as complementary tools in clinical genomics
13:07 Building a coordinated national infrastructure for clinical genomics and rare disease research in Sweden
18:20 The shift toward precision therapeutics and new standards for clinical actionability
23:18 Using national genomic data and registries to make Sweden trial-ready for precision therapies
27:01 Moving beyond monogenic models to capture polygenic and borderline signals in clinical genomics
30:44 Genomics for prevention including adult screening and pharmacogenomics
36:23 Anna’s research priorities for the next phase of genomic medicine and structural variant discovery
38:32 Closing remarks
Find out more:
Long-read sequencing study

Moving beyond monogenic disease paper

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This week on The Genetics Podcast, Patrick is joined by Dr. Matthew Goldstein, CEO of jscreen. They discuss his journey from physician-scientist and biotech founder to leading a national nonprofit focused on preventive genetic screening, how a personal tragedy reshaped his mission around carrier screening and access, and what it will take to close the gap between the promise of genomics and its real-world implementation in healthcare.
Show Notes: 
0:00 Intro to The Genetics Podcast
00:58 Welcome to Matthew
01:41 Matthew’s path from an MD-PhD to founding a personalized cancer vaccine biotech
09:06 From personal tragedy to leading jscreen to expand access to reproductive carrier screening 
17:11 Purpose, grief, and how Matthew has led jscreen in honor of his daughter
20:38 The implementation gap between genomic potential and real-world preventive screening 
23:33 Nonprofit models, reimbursement barriers, and building sustainable access to preventive genetic screening
28:27 Lessons from the Jewish community’s experience with Tay-Sachs and gaps in understanding
33:05 Preconception carrier screening and the role of community in preventive health
38:04 Closing remarks
Find out more: jscreen

This week on The Genetics Podcast, Patrick is joined by Dr. Ryan Dhindsa, Assistant Professor at the Baylor College of Medicine and PI at Texas Children’s Hospital, and Dr. Caleb Lareau, PI at Memorial Sloan Kettering Cancer Center and Assistant Professor of Computational Biology and Medicine at Weill Cornell Medicine. They discuss how a Twitter DM sparked a multi-year collaboration to extract Epstein–Barr virus signals from large-scale human genomic datasets, how measuring viral persistence in UK Biobank data reveals insights into autoimmune disease risk and host genetic control, and what this work means for understanding the long-term impact of chronic viral infections on human health.
Show Notes: 
0:00 Intro to The Genetics Podcast
00:59 Welcome to Ryan and Caleb
01:58 How a Twitter DM led to a long-term collaboration
03:10 Rescuing Epstein–Barr virus (EBV) sequences from human whole genome data 
04:45 Quantifying EBV persistence in UK Biobank, validating the signal, and uncovering links to autoimmune disease
12:00 Computational virology, chronic viral effects on human disease, and extending the approach to the broader human virome
16:59 Design considerations for population genomics programs to better capture chronic viral effects on human disease
21:30 Genetic, viral strain, and environmental factors that shape EBV persistence and immune control
26:09 Future directions for EBV research and expanding beyond European ancestry cohorts
29:46 Focus areas of Ryan’s research including rare variant genetics, neurological disease mechanisms, and pediatric population genomics
33:49 Focus areas of Caleb’s research including the human virome and expanding sequencing technologies to detect uncharacterized nucleic acids
37:03 Where genomic “dark matter” may underlie unexplained cancer and severe disease
38:46 Gaps in non-coding variant interpretation and incomplete penetrance in unsolved genetic disease
42:01 Closing remarks
Find out more:
Ryan’s research group

Caleb’s research group

This week on The Genetics Podcast, Patrick is joined by Dr. Nicky Whiffin, Associate Professor and Wellcome Career Development Fellow at the Big Data Institute, University of Oxford. They discuss the discovery of a new neurodevelopmental syndrome caused by mutations in the small nuclear RNA gene RNU4-2, what this reveals about the non-coding genome and the spliceosome, and how large-scale genome sequencing is reshaping diagnosis, variant interpretation, and the future of genetic medicine.
Show Notes: 
0:00 Intro to The Genetics Podcast
00:59 Welcome to Nicky
02:09 Overview of the non-coding genome and its functional elements
03:59 How small nuclear RNAs drive splicing and exon recognition
04:54 Overview of the major and minor spliceosomes and the role of small nuclear RNAs in intron removal
06:34 Discovery of recurrent de novo RNU4-2 mutations in developmental disorders through large-scale genomics data
12:18 Growth of patient advocacy groups and global networks following the discovery of ReNU syndrome
14:43 Potential for antisense oligonucleotide therapies for ReNU syndrome
16:06 Clinical endpoints, treatment timing, and biomarker development for ReNU
18:32 Impact of RNU4-2 discovery on exome design, genome sequencing adoption, and targeted testing strategies
19:52 Distinct dominant, recessive, and retinal phenotypes arising from variants within RNU4-2
22:15 Open questions on mutation rates and selection in spliceosomal small nuclear RNAs
25:25  Limits of non-coding variant discovery and the unresolved genetic burden in developmental disorders
29:52 Therapeutic upregulation strategies targeting untranslated regions in haploinsufficiency 
33:40 The MRC Centre of Research Excellence in Therapeutic Genomics’ approach to scalable genetic medicines
35:54 Long-term prospects and delivery challenges for gene editing approaches 
36:56 Newborn genome screening, actionability debates, and implications for rare disease diagnosis
40:25 Population genomics insights from unascertained newborn genome sequencing cohorts
42:04 Closing remarks
Find out more: ReNU discovery paper