# Harnessing the power of experimental genetic crosses and systems genetics to probe drug resistance in malaria

> **NIH NIH P01** · UNIVERSITY OF NOTRE DAME · 2021 · $2,004,499

## Abstract

ABSTRACT
Genetic crosses coupled with linkage mapping have provided an outstandingly successful approach for
locating the genetic determinants of biomedically important traits such as drug resistance and host specificity in
P. falciparum malaria. Plasmodium crosses were originally conducted using chimpanzees, but crosses using
these primates are now no longer possible. The overall goal of this Program Project grant (P01) is to leverage
cutting edge technology that enables us to stage Plasmodium falciparum experimental genetic crosses and
isolate large numbers of unique recombinant progeny. We do this using a human-liver chimeric mouse infused
with human red blood cells (the FRG huHep/huRBC mouse). We will use this technology to address the
emerging health threat posed by the emergence and spread of artemisinin resistant (ART-R) and more
recently piperaquine resistant parasites.
There has been much fanfare recently about the identification of coding mutations in the kelch13 gene that are
strongly associated with ART-R. However, very little is known about the function of this gene and how
mutations in kelch13 generate a wide range of resistance levels and fitness effects, and how these effects are
compensated by other structural or regulatory changes in the genome. Furthermore, there is evidence of ART-
R without mutations in kelch13, and that particular genetic backgrounds are permissive for ART-R. We will use
targeted experimental genetic crosses to (i) dissect the genetic complexity of ART-R, (ii) clarify the role of
kelch13, (iii) define the regulators and partner genes that control ART-R, and (iv) determine the genetic basis
of emerging piperaquine resistance.
The project is based in three locations (Notre Dame, Seattle and San Antonio), each with one Research
Project supported by a Core facility, with an Administrative Core in Notre Dame. The three research Cores
support the tasks of each of the three individual Research Projects, and rely on each other for the generation
of progeny lines, sequencing and complementary data analysis. Each Research Project has its own stand-
alone research questions, but the flow of information and reagents among projects significantly enhances the
potential for discovery that fully leverages the P01 framework. Genetic crosses will be conducted by Core A,
while RP01 will increase our understanding of the fundamental aspects of sexual recombination and Mendelian
genetics in P. falciparum, allowing us to further optimize methods for generating recombinant progeny. The
recombinant progeny will be characterized for drug resistance and competitive growth phenotypes by RP02
and for variation in transcript, protein and metabolite abundance by RP03, with support from Core C. The
phenotype, sequence and systems genetic data will be integrated by Core B, which will both conduct analyses
and ensure that the archived data will be accessible to all three Research Projects.

## Key facts

- **NIH application ID:** 10216641
- **Project number:** 5P01AI127338-05
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Michael T Ferdig
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,004,499
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216641

## Citation

> US National Institutes of Health, RePORTER application 10216641, Harnessing the power of experimental genetic crosses and systems genetics to probe drug resistance in malaria (5P01AI127338-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216641. Licensed CC0.

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