New techniques to decipher autism’s complexity

Following an initial focus on genetic risk for psychiatric disorders widely distributed in the human population, contemporary studies increasingly emphasize the role of rare de novo somatic mutation in both coding and regulatory regions of the genome. In this issue, our newsletter highlights the promise and challenges of these advances. De novo mutation in autism spectrum disorder (ASD) was first convincingly shown using exome- and other-directed sequencing strategies. Here, in our first paper, technical advance using ultra-deep whole genome sequencing reveals the prevalence of mosaic somatic mutation in the cortex of ASD patients and controls (Rodin, Dou et al 2021). Alongside the advances in sequencing chemistry and data analytics that better define mutation, the consequential altered phenotype is being directly assessed by recombineering the human risk genes in a growing number of models. To illustrate the speed of advance in phenotyping, we focus secondly on a recent study where the growing power of CRISPR-based gene engineering is employed to systematically alter multiple risk loci and assess phenotypic mechanisms in mouse embryos (Jin et al 2020). In this pioneering study the authors focused on de novo mutation occurring within coding regions predicted to be highly penetrant. These papers and the comments of our Board members emphasize the continued rapid advance linking both germ line and de novo mutation to phenotype in human neurodevelopmental disorders.

-Ron McKay, PhD, Chief Editor
Lieber Institute for Brain Development

-Venkata S. Mattay, MD
Managing Editor

-Michele Solis, PhD
Science Writer

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Editorial Board

Fred ‘Rusty’ Gage, PhD
President, The Salk Institute for Biological Studies

Daniel Geschwind, MD, PhD
Professor, UCLA School of Medicine

Elizabeth Grove, PhD
Professor, University of Chicago

Jürgen Knoblich, PhD
Interim Scientific Director, Institute of Molecular Biotechnology, Austrian Academy of Sciences

Arnold Kriegstein, MD
Professor, UCSF

Pat Levitt, PhD
Professor, Keck School of Medicine of USC

Mu-Ming Poo, PhD
Director, Institute of Neuroscience, Chinese Academy of Sciences

John Rubenstein, MD, PhD
Professor of Psychiatry, UCSF

Nenad Sestan, MD, PhD
Professor, Yale University

Flora Vaccarino, MD
Professor, Yale University

Chris Walsh, MD, PhD
Chief, Division of Genetics & Genomics, Boston Children’s Hospital

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