Association mapping from sequencing reads using k-mers

  1. Atif Rahman  Is a corresponding author
  2. Ingileif Hallgrímsdóttir
  3. Michael Eisen
  4. Lior Pachter  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Howard Hughes Medical Institute, University of California, Berkeley, United States

Abstract

Genome wide association studies (GWAS) rely on microarrays, or more recently mapping of sequencing reads, to genotype individuals. The reliance on prior sequencing of a reference genome limits the scope of association studies, and also precludes mapping associations outside of the reference. We present an alignment free method for association studies of categorical phenotypes based on counting k-mers in whole-genome sequencing reads, testing for associations directly between k-mers and the trait of interest, and local assembly of the statistically significant k-mers to identify sequence differences. An analysis of the 1000 genomes data show that sequences identified by our method largely agree with results obtained using the standard approach. However, unlike standard GWAS, our method identifies associations with structural variations and sites not present in the reference genome. We also demonstrate that population stratification can be inferred from k-mers. Finally, application to an E.coli dataset on ampicillin resistance validates the approach.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 5.

The following previously published data sets were used

Article and author information

Author details

  1. Atif Rahman

    Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, United States
    For correspondence
    atif@cse.buet.ac.bd
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1805-3971
  2. Ingileif Hallgrímsdóttir

    Department of Statistics, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael Eisen

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7528-738X
  4. Lior Pachter

    Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, United States
    For correspondence
    lpachter@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (NIH R21 HG006583)

  • Atif Rahman
  • Ingileif Hallgrímsdóttir
  • Michael Eisen
  • Lior Pachter

Fulbright Science and Technology Fellowship (15093630)

  • Atif Rahman

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

Copyright

© 2018, Rahman 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

  • 13,907
    views
  • 1,176
    downloads
  • 98
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Atif Rahman
  2. Ingileif Hallgrímsdóttir
  3. Michael Eisen
  4. Lior Pachter
(2018)
Association mapping from sequencing reads using k-mers
eLife 7:e32920.
https://doi.org/10.7554/eLife.32920

Share this article

https://doi.org/10.7554/eLife.32920

Further reading

    1. Epidemiology and Global Health
    2. Microbiology and Infectious Disease
    Gillian AM Tarr, Linda Chui ... Tim A McAllister
    Research Article

    Several areas of the world suffer a notably high incidence of Shiga toxin-producing Escherichia coli. To assess the impact of persistent cross-species transmission systems on the epidemiology of E. coli O157:H7 in Alberta, Canada, we sequenced and assembled E. coli O157:H7 isolates originating from collocated cattle and human populations, 2007–2015. We constructed a timed phylogeny using BEAST2 using a structured coalescent model. We then extended the tree with human isolates through 2019 to assess the long-term disease impact of locally persistent lineages. During 2007–2015, we estimated that 88.5% of human lineages arose from cattle lineages. We identified 11 persistent lineages local to Alberta, which were associated with 38.0% (95% CI 29.3%, 47.3%) of human isolates. During the later period, six locally persistent lineages continued to be associated with human illness, including 74.7% (95% CI 68.3%, 80.3%) of reported cases in 2018 and 2019. Our study identified multiple locally evolving lineages transmitted between cattle and humans persistently associated with E. coli O157:H7 illnesses for up to 13 y. Locally persistent lineages may be a principal cause of the high incidence of E. coli O157:H7 in locations such as Alberta and provide opportunities for focused control efforts.

    1. Epidemiology and Global Health
    Riccardo Spott, Mathias W Pletz ... Christian Brandt
    Research Article

    Given the rapid cross-country spread of SARS-CoV-2 and the resulting difficulty in tracking lineage spread, we investigated the potential of combining mobile service data and fine-granular metadata (such as postal codes and genomic data) to advance integrated genomic surveillance of the pandemic in the federal state of Thuringia, Germany. We sequenced over 6500 SARS-CoV-2 Alpha genomes (B.1.1.7) across 7 months within Thuringia while collecting patients’ isolation dates and postal codes. Our dataset is complemented by over 66,000 publicly available German Alpha genomes and mobile service data for Thuringia. We identified the existence and spread of nine persistent mutation variants within the Alpha lineage, seven of which formed separate phylogenetic clusters with different spreading patterns in Thuringia. The remaining two are subclusters. Mobile service data can indicate these clusters’ spread and highlight a potential sampling bias, especially of low-prevalence variants. Thereby, mobile service data can be used either retrospectively to assess surveillance coverage and efficiency from already collected data or to actively guide part of a surveillance sampling process to districts where these variants are expected to emerge. The latter concept was successfully implemented as a proof-of-concept for a mobility-guided sampling strategy in response to the surveillance of Omicron sublineage BQ.1.1. The combination of mobile service data and SARS-CoV-2 surveillance by genome sequencing is a valuable tool for more targeted and responsive surveillance.