Population genomics of intrapatient HIV-1 evolution

  1. Fabio Zanini
  2. Johanna Brodin
  3. Lina Thebo
  4. Christa Lanz
  5. Göran Bratt
  6. Jan Albert
  7. Richard A Neher  Is a corresponding author
  1. Max Planck Institute for Developmental Biology, Germany
  2. Karolinska Institute, Sweden
  3. Stockholm South General Hospital, Sweden
  4. Karolinska Institutet, Sweden

Abstract

Many microbial populations rapidly adapt to changing environments with multiple variants competing for survival. To quantify such complex evolutionary dynamics in vivo, time resolved and genome wide data including rare variants are essential. We performed whole-genome deep sequencing of HIV-1 populations in 9 untreated patients, with 6-12 longitudinal samples per patient spanning 5-8 years of infection. The data can be accessed and explored via an interactive web application. We show that patterns of minor diversity are reproducible between patients and mirror global HIV-1 diversity, suggesting a universal landscape of fitness costs that control diversity. Reversions towards the ancestral HIV-1 sequence are observed throughout infection and account for almost one third of all sequence changes. Reversion rates depend strongly on conservation. Frequent recombination limits linkage disequilibrium to about 100bp in most of the genome, but strong hitch-hiking due to short range linkage limits diversity.

Article and author information

Author details

  1. Fabio Zanini

    Evolutionary Dynamics and Biophysics, Max Planck Institute for Developmental Biology, Tübingen, Germany
    Competing interests
    No competing interests declared.
  2. Johanna Brodin

    Department of Microbiology Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  3. Lina Thebo

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  4. Christa Lanz

    Evolutionary Dynamics and Biophysics, Max Planck Institute for Developmental Biology, Tübingen, Germany
    Competing interests
    No competing interests declared.
  5. Göran Bratt

    Department of Clinical Science and Education, Stockholm South General Hospital, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  6. Jan Albert

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  7. Richard A Neher

    Evolutionary Dynamics and Biophysics, Max Planck Institute for Developmental Biology, Tübingen, Germany
    For correspondence
    richard.neher@tuebingen.mpg.de
    Competing interests
    Richard A Neher, Reviewing editor, eLife.

Reviewing Editor

  1. Arup K Chakraborty, Massachusetts Institute of Technology, United States

Ethics

Human subjects: The study was carried out according to the Declaration of Helsinki. Ethical approval was granted by the Regional Ethical Review board in Stockholm, Sweden (Dnr 2012/505-31/12). Patients participating in the study gave written and oral informed consent to participate.

Version history

  1. Received: September 1, 2015
  2. Accepted: December 8, 2015
  3. Accepted Manuscript published: December 10, 2015 (version 1)
  4. Version of Record published: January 8, 2016 (version 2)

Copyright

© 2015, Zanini 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

  • 9,239
    views
  • 1,431
    downloads
  • 202
    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. Fabio Zanini
  2. Johanna Brodin
  3. Lina Thebo
  4. Christa Lanz
  5. Göran Bratt
  6. Jan Albert
  7. Richard A Neher
(2015)
Population genomics of intrapatient HIV-1 evolution
eLife 4:e11282.
https://doi.org/10.7554/eLife.11282

Share this article

https://doi.org/10.7554/eLife.11282

Further reading

    1. Genetics and Genomics
    Tiechao Ruan, Ruixi Zhou ... Ying Shen
    Research Article

    IQ motif-containing proteins can be recognized by calmodulin (CaM) and are essential for many biological processes. However, the role of IQ motif-containing proteins in spermatogenesis is largely unknown. In this study, we identified a loss-of-function mutation in the novel gene IQ motif-containing H (IQCH) in a Chinese family with male infertility characterized by a cracked flagellar axoneme and abnormal mitochondrial structure. To verify the function of IQCH, Iqch knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the Iqch KO male mice exhibited impaired fertility, which was related to deficient acrosome activity and abnormal structures of the axoneme and mitochondria, mirroring the patient phenotypes. Mechanistically, IQCH can bind to CaM and subsequently regulate the expression of RNA-binding proteins (especially HNRPAB), which are indispensable for spermatogenesis. Overall, this study revealed the function of IQCH, expanded the role of IQ motif-containing proteins in reproductive processes, and provided important guidance for genetic counseling and genetic diagnosis of male infertility.

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Ardalan Naseri, Degui Zhi, Shaojie Zhang
    Research Article Updated

    Runs-of-homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 single nucleotide polymorphisms (SNPs) and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended human leukocyte antigen (HLA) region and autoimmune disorders. We found an association between a diplotype covering the homeostatic iron regulator (HFE) gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (p-value = 1.82 × 10−11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.