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Gustav Smith, MD, PhD

Gustav Smith

Associate professor

Gustav Smith, MD, PhD

A genomic mutational constraint map using variation in 76,156 human genomes

Author

  • S. Chen
  • L. Groop
  • O. Melander
  • P.M. Nilsson
  • J. Gustav Smith
  • D.G. MacArthur
  • K.J. Karczewski

Summary, in English

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders 1–4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)—the largest public open-access human genome allele frequency reference dataset—and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.

Department/s

  • Translational Muscle Research
  • Cardiovascular Research - Hypertension
  • EpiHealth: Epidemiology for Health
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • MultiPark: Multidisciplinary research focused on Parkinson´s disease
  • Internal Medicine - Epidemiology
  • WCMM-Wallenberg Centre for Molecular Medicine
  • Heart Failure and Mechanical Support
  • Cardiovascular Epigenetics
  • Cardiology
  • Molecular Epidemiology and Cardiology

Publishing year

2024

Language

English

Pages

92-100

Publication/Series

Nature

Volume

625

Issue

7993

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medical Genetics

Keywords

  • Chromosome Mapping
  • Gene Frequency
  • Genetic Variation
  • Genome, Human
  • Genomics
  • Humans
  • Mutation
  • allele
  • DNA
  • gene expression
  • genome
  • mutation
  • protein
  • triangulation
  • article
  • gene frequency
  • genetic variation
  • human
  • human genome
  • natural selection
  • open reading frame
  • chromosomal mapping
  • genetics
  • genomics

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension
  • Internal Medicine - Epidemiology
  • Heart Failure and Mechanical Support
  • Cardiovascular Epigenetics
  • Molecular Epidemiology and Cardiology

ISBN/ISSN/Other

  • ISSN: 0028-0836