hmmIBD: software to infer pairwise identity by descent between haploid genotypes

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Abstract

Background

A number of recent malaria studies have used identity by descent (IBD) to study epidemiological processes relevant to malaria control. In this paper, a software package, hmmIBD, is introduced for estimating pairwise IBD between haploid genomes, such as those of the malaria parasite, sampled from one or two populations. Source code is freely available.

Methods

The performance of hmmIBD was verified using simulated data and benchmarked against an existing method for detecting IBD within populations. Code for all tests is freely available. The utility of hmmIBD for detecting IBD across populations was demonstrated using Plasmodium falciparum data from Cambodia and Ghana.

Results

Alongside an existing method, hmmIBD was highly accurate, sensitive and specific. It is fast, requiring only 70 s on average to analyse 50 whole genome sequences on a laptop computer, and scales linearly in the number of pairwise comparisons. Treatment of different populations under hmmIBD improves detection of IBD across populations.

Conclusion

Fast and accurate software for detecting IBD in malaria parasite genetic data sampled from one or two populations is presented. The latter will likely be a useful feature for malaria elimination efforts, since it could facilitate identification of imported malaria cases. Software is robust to possible misspecification of the genotyping error and the recombination rate. However, exclusion of data in regions whose rates vary greatly from their genome-wide average is recommended.

Electronic supplementary material

The online version of this article (10.1186/s12936-018-2349-7) contains supplementary material, which is available to authorized users.

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Most cited references 9

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Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.

John Wootton, Xiaorong Feng, Michael Ferdig … (2002)

Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt and at least four CQR founder events. This disequilibrium and its decay rate in the pfcrt-flanking region are consistent with strong directional selective sweeps occurring over only approximately 20-80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.

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Modeling malaria genomics reveals transmission decline and rebound in Senegal.

Rachel Daniels, Stephen F. Schaffner, Edward A Wenger … (2015)

To study the effects of malaria-control interventions on parasite population genomics, we examined a set of 1,007 samples of the malaria parasite Plasmodium falciparum collected in Thiès, Senegal between 2006 and 2013. The parasite samples were genotyped using a molecular barcode of 24 SNPs. About 35% of the samples grouped into subsets with identical barcodes, varying in size by year and sometimes persisting across years. The barcodes also formed networks of related groups. Analysis of 164 completely sequenced parasites revealed extensive sharing of genomic regions. In at least two cases we found first-generation recombinant offspring of parents whose genomes are similar or identical to genomes also present in the sample. An epidemiological model that tracks parasite genotypes can reproduce the observed pattern of barcode subsets. Quantification of likelihoods in the model strongly suggests a reduction of transmission from 2006-2010 with a significant rebound in 2012-2013. The reduced transmission and rebound were confirmed directly by incidence data from Thiès. These findings imply that intensive intervention to control malaria results in rapid and dramatic changes in parasite population genomics. The results also suggest that genomics combined with epidemiological modeling may afford prompt, continuous, and cost-effective tracking of progress toward malaria elimination.

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Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance

Gustavo Cerqueira, Ian Cheeseman, Steve Schaffner … (2017)

Background Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001–2014). Results We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance. Conclusions This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1204-4) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Stephen F. Schaffner:

ORCID: http://orcid.org/0000-0001-6699-3568

sfs@broadinstitute.org

Journal

Journal ID (nlm-ta): Malar J

Journal ID (iso-abbrev): Malar. J

Title: Malaria Journal

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2875

Publication date (Electronic): 15 May 2018

Publication date PMC-release: 15 May 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 196

Affiliations

[1 ]GRID grid.66859.34, Infectious Disease and Microbiome Program, , Broad Institute of MIT and Harvard, ; Cambridge, MA 02142 USA

[2 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology and Center for Communicable Disease Dynamics, , Harvard T. H. Chan School of Public Health, ; Boston, MA 02115 USA

[3 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Immunology and Infectious Diseases, , Harvard T. H. Chan School of Public Health, ; Boston, MA 02115 USA

[4 ]Present Address: Institute for Disease Modeling, Bellevue, WA USA

Author information

Stephen F. Schaffner http://orcid.org/0000-0001-6699-3568

Article

Publisher ID: 2349

DOI: 10.1186/s12936-018-2349-7

PMC ID: 5952413

PubMed ID: 29764422

SO-VID: 888cf7e8-2c56-43ba-81eb-392b166548ed

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 February 2018

Date accepted : 7 May 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;

Award ID: OPP1053604

Award Recipient : Dyann F. Wirth

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: U19AI110818

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: identity by descent,hidden markov model,malaria,haploid,plasmodium falciparum

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: identity by descent, hidden markov model, malaria, haploid, plasmodium falciparum

hmmIBD: software to infer pairwise identity by descent between haploid genotypes

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Abstract

Background

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Electronic supplementary material

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Malaria vaccine development

Most cited references 9

Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.

Modeling malaria genomics reveals transmission decline and rebound in Senegal.

Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance

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