# Peaks to genes: Fine mapping of QTLs and functional analysis

> **NIH NIH P01** · UNIVERSITY OF NOTRE DAME · 2024 · $506,232

## Abstract

PROJECT SUMMARY
Linkage mapping using genetic crosses results in identification of quantitative trait locus (QTL) regions
that may contain tens to hundreds of genes. Identification of the causative genes therefore requires
careful prioritization of candidate loci, followed by gene manipulation studies to validate the best
candidates, and ultimately to determine the causative mutations. Core B will play a critical role in this
program project, interfacing with RP01-03 for QTL location, candidate gene prioritization and candidate
validation phases of each project. Bulk segregant analysis for QTL location. In the first funding period,
we refined methods for rapid mapping of genes underlying QTL using Bulk Segregant Approaches
(BSA) that utilize deep sequencing of F2 progeny populations. Core B will sequence and analyze BSA
experiments conducted by RP01, RP02 and RP03 to determine the QTLs underlying traits of interest.
QTL mapping of P. falciparum typically maps reads to the 3D7 reference sequence, but this limits our
ability to localize QTLs to core genome regions. We will generate long-read (nanopore) reference
sequences for the parental parasites, which allows accurate mapping across the whole genome.
Candidate gene prioritization: Identifying the genes and mutations that underlie traits of interest is a
central issue in QTL mapping. Core B will develop and implement bioinformatic and experimental
approaches to prioritize candidate genes. We will utilize information from genomic analyses of P.
falciparum populations, computation predictions of SNP functionality, as well as information from P.
falciparum piggyBac mutagenesis libraries, and rodent malaria (P. berghei) knockout studies. We will
also utilize information from expression QTL (eQTL) analyses (RP03), and use nanopore long read
sequences to investigate structural variants that may underly phenotypes of interest. Candidate gene
validation: We will deploy systematic CRISPR/Cas9 gene editing to determine the loci and specific
mutations underlying parasite phenotypes. This will initially use SNP editing to determine causative
mutations. We can also use conditional knockouts or conditional protein mislocalization (knock
sideways) strategies to examine the role of candidate resistance loci. Where haplotypes contain several
causative mutations, we will edit these individually or in combination to examine whether SNPs act
additively or epistatically to determine phenotype. These validation experiments will be conducted in
close collaboration with projects RP01, RP02 and RP03: Core B will generate the edited parasites,
while the projects will conduct the phenotyping experiments to examine links between phenotype and
genotype. These studies will (a) develop efficient computational and experimental approaches for rapid
identification of genes and causative mutations following QTL location (peaks to genes) and (b)
generate gene edited parasite lines, sequence data and bioinformatic tools that will be...

## Key facts

- **NIH application ID:** 10863150
- **Project number:** 2P01AI127338-06A1
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Tim J Anderson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $506,232
- **Award type:** 2
- **Project period:** 2017-08-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863150

## Citation

> US National Institutes of Health, RePORTER application 10863150, Peaks to genes: Fine mapping of QTLs and functional analysis (2P01AI127338-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10863150. Licensed CC0.

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