Association mapping from sequencing reads using k-mers
- University of California, Berkeley, United States
- 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.
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1000 Genomes : A Deep Catalog of Human Genetic Variationhttp://www.internationalgenome.org/data.
Article and author information
Author details
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.
Reviewing Editor
- Jonathan Flint, University of California, Los Angeles, United States
Version history
- Received: October 18, 2017
- Accepted: June 8, 2018
- Accepted Manuscript published: June 13, 2018 (version 1)
- Version of Record published: July 13, 2018 (version 2)
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.
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Association mapping from sequencing reads using k-mers
eLife 7:e32920.
https://doi.org/10.7554/eLife.32920
Further reading
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- Epidemiology and Global Health
Background:
In most of the world, the mammography screening programmes were paused at the start of the pandemic, whilst mammography screening continued in Denmark. We examined the mammography screening participation during the COVID-19 pandemic in Denmark.
Methods:
The study population comprised all women aged 50–69 years old invited to participate in mammography screening from 2016 to 2021 in Denmark based on data from the Danish Quality Database for Mammography Screening in combination with population-based registries. Using a generalised linear model, we estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) of mammography screening participation within 90, 180, and 365 d since invitation during the pandemic in comparison with the previous years adjusting for age, year and month of invitation.
Results:
The study comprised 1,828,791 invitations among 847,766 women. Before the pandemic, 80.2% of invitations resulted in participation in mammography screening within 90 d, 82.7% within 180 d, and 83.1% within 365 d. At the start of the pandemic, the participation in screening within 90 d was reduced to 69.9% for those invited in pre-lockdown and to 76.5% for those invited in first lockdown. Extending the length of follow-up time to 365 d only a minor overall reduction was observed (PR = 0.94; 95% CI: 0.93–0.95 in pre-lockdown and PR = 0.97; 95% CI: 0.96–0.97 in first lockdown). A lower participation was, however, seen among immigrants and among women with a low income.
Conclusions:
The short-term participation in mammography screening was reduced at the start of the pandemic, whilst only a minor reduction in the overall participation was observed with longer follow-up time, indicating that women postponed screening. Some groups of women, nonetheless, had a lower participation, indicating that the social inequity in screening participation was exacerbated during the pandemic.
Funding:
The study was funded by the Danish Cancer Society Scientific Committee (grant number R321-A17417) and the Danish regions.
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- Epidemiology and Global Health
- Genetics and Genomics
Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is partially maintained among repeated serial samples from the same host, it can transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.
