Relating pathogenic loss-of function mutations in humans to their evolutionary fitness costs

  1. Ipsita Agarwal  Is a corresponding author
  2. Zachary L Fuller
  3. Simon R Myers
  4. Molly Przeworski
  1. Columbia University, United States
  2. University of Oxford, United Kingdom

Abstract

Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in 'mutation intolerant' genes. We show how such observations can be interpreted in light of a model of mutation-selection balance, and use the model to relate the pathogenic consequences of LOF mutations at present-day to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,318 autosomal and 679 X-linked genes from exome sequences in 56,855 individuals. Estimated fitness costs for the loss of a gene copy are typically above 1%; they tend to be largest for X-linked genes, whether or not they have a Y homolog, followed by autosomal genes and genes in the pseudoautosomal region. We then compare inferred fitness effects for all possible de novo LOF mutations to those of de novo mutations identified in individuals diagnosed with one of six severe, complex diseases or developmental disorders. Probands carry an excess of mutations with estimated fitness effects above 10%; as we show by simulation, when sampled in the population, such highly deleterious mutations are typically only a couple of generations old. Moreover, the proportion of highly deleterious mutations carried by probands reflects the typical age of onset of the disease. The study design also has a discernible influence: a greater proportion of highly deleterious mutations is detected in pedigree than case-control studies, and for autism, in simplex than multiplex families and in female versus male probands. Thus, anchoring observations in human genetics to a population genetic model allows us to learn about the fitness effects of mutations identified by different mapping strategies and for different traits.

Data availability

All source data are freely available to researchers, with sources listed in Table S4. Code for simulations, and output is available at https://github.com/zfuller5280/MutationSelection and https://github.com/agarwal-i/loss-of-function-fitness-effects. Estimates of fitness costs of LOF mutations are provided as Table S2.

Article and author information

Author details

  1. Ipsita Agarwal

    Department of Biological Sciences, Columbia University, New York, United States
    For correspondence
    ia2337@columbia.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8537-0008
  2. Zachary L Fuller

    Department of Biological Sciences, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4765-9227
  3. Simon R Myers

    Department of Statistics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  4. Molly Przeworski

    Department of Systems Biology, Columbia University, New York, United States
    Competing interests
    Molly Przeworski, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5369-9009

Funding

National Institutes of Health (GM121372)

  • Molly Przeworski

National Institutes of Health (HG011432)

  • Molly Przeworski

National Institutes of Health (GM128318)

  • Zachary L Fuller

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. George H Perry, Pennsylvania State University, United States

Version history

  1. Preprint posted: August 12, 2022 (view preprint)
  2. Received: September 1, 2022
  3. Accepted: January 16, 2023
  4. Accepted Manuscript published: January 17, 2023 (version 1)
  5. Version of Record published: February 17, 2023 (version 2)

Copyright

© 2023, Agarwal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,670
    Page views
  • 303
    Downloads
  • 12
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ipsita Agarwal
  2. Zachary L Fuller
  3. Simon R Myers
  4. Molly Przeworski
(2023)
Relating pathogenic loss-of function mutations in humans to their evolutionary fitness costs
eLife 12:e83172.
https://doi.org/10.7554/eLife.83172

Share this article

https://doi.org/10.7554/eLife.83172

Further reading

    1. Evolutionary Biology
    Zhiliang Zhang, Zhifei Zhang ... Guoxiang Li
    Research Article

    Biologically-controlled mineralization producing organic-inorganic composites (hard skeletons) by metazoan biomineralizers has been an evolutionary innovation since the earliest Cambrian. Among them, linguliform brachiopods are one of the key invertebrates that secrete calcium phosphate minerals to build their shells. One of the most distinct shell structures is the organo-phosphatic cylindrical column exclusive to phosphatic-shelled brachiopods, including both crown and stem groups. However, the complexity, diversity, and biomineralization processes of these microscopic columns are far from clear in brachiopod ancestors. Here, exquisitely well-preserved columnar shell ultrastructures are reported for the first time in the earliest eoobolids Latusobolus xiaoyangbaensis gen. et sp. nov. and Eoobolus acutulus sp. nov. from the Cambrian Series 2 Shuijingtuo Formation of South China. The hierarchical shell architectures, epithelial cell moulds, and the shape and size of cylindrical columns are scrutinised in these new species. Their calcium phosphate-based biomineralized shells are mainly composed of stacked sandwich columnar units. The secretion and construction of the stacked sandwich model of columnar architecture, which played a significant role in the evolution of linguliforms, is highly biologically controlled and organic-matrix mediated. Furthermore, a continuous transformation of anatomic features resulting from the growth of diverse columnar shells is revealed between Eoobolidae, Lingulellotretidae, and Acrotretida, shedding new light on the evolutionary growth and adaptive innovation of biomineralized columnar architecture among early phosphatic-shelled brachiopods during the Cambrian explosion.

    1. Developmental Biology
    2. Evolutionary Biology
    Eman Hijaze, Tsvia Gildor ... Smadar Ben-Tabou de-Leon
    Research Article

    Biomineralization had apparently evolved independently in different phyla, using distinct minerals, organic scaffolds, and gene regulatory networks (GRNs). However, diverse eukaryotes from unicellular organisms, through echinoderms to vertebrates, use the actomyosin network during biomineralization. Specifically, the actomyosin remodeling protein, Rho-associated coiled-coil kinase (ROCK) regulates cell differentiation and gene expression in vertebrates’ biomineralizing cells, yet, little is known on ROCK’s role in invertebrates’ biomineralization. Here, we reveal that ROCK controls the formation, growth, and morphology of the calcite spicules in the sea urchin larva. ROCK expression is elevated in the sea urchin skeletogenic cells downstream of the Vascular Endothelial Growth Factor (VEGF) signaling. ROCK inhibition leads to skeletal loss and disrupts skeletogenic gene expression. ROCK inhibition after spicule formation reduces the spicule elongation rate and induces ectopic spicule branching. Similar skeletogenic phenotypes are observed when ROCK is inhibited in a skeletogenic cell culture, indicating that these phenotypes are due to ROCK activity specifically in the skeletogenic cells. Reduced skeletal growth and enhanced branching are also observed under direct perturbations of the actomyosin network. We propose that ROCK and the actomyosin machinery were employed independently, downstream of distinct GRNs, to regulate biomineral growth and morphology in Eukaryotes.