Koen Rademaker

Koen Rademaker

Spatial biology and gene expression research in neurodevelopmental disease @ Bayraktar lab, Wellcome Sanger Institute.

A developmental human brain spatial transcriptomic atlas of autism susceptibility genes identifies convergence in thalamic circuits

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Authors

Alexander Aivazidis 1,*, Fani Memi1,*, Koen Rademaker1,*, Mahmoud Koko1, Kenny Roberts1, Andrew Trinh1, Robert Petryszak1, Vitalii Kleshchevnikov1, Liz Tuck1, Steven Lisgo2, Tong Li1, Stanislaw Makarchuk1, Tomasz J. Nowakowski3, Hilary C. Martin1, Omer Ali Bayraktar1

Affiliations

  1. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
  2. Human Developmental Biology Resource, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
  3. University of California San Francisco, San Francisco, CA, USA

* Contributed equally

Abstract

Mapping how genes converge on specific brain cell types and neural circuits is critical to understand the complex genetics underlying autism. Rare loss-of-function mutations strongly predispose susceptibility to autism and additionally developmental and intellectual disabilities in over 10% of cases. Single cell transcriptomic atlases of developing human brains have implicated enrichment of these genes in cortical neuron subtypes, yet these atlases lack crucial resolution to characterise the cellular architecture of spatially demarcated and functionally distinct brain regions. Here, we present the first spatio-temporal autism gene expression atlas of 250 susceptibility genes, in which over 10 million single cells were profiled using 10x Genomics Xenium from six midgestation individuals. We identified five highly spatially regionalised gene programs, and discovered novel convergence in the thalamus and germinal zones. We additionally implicate developing thalamic and cortical neuronal cell types, and progenitor cell populations. These findings implicate the thalamus as a major hub of autism susceptibility in the developing human brain. Overall, we demonstrate the potential to spatially survey expression of trait-associated genes in crucial tissues and developmental stages to understand genetic pathologies.