# Noncoding DNA regulatory elements and Anopheles vector biology

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $347,513

## Abstract

SUMMARY –The highest global malaria prevalence is in Africa, where the most important vectors are members
of the Anopheles gambiae species complex, including the widespread Anopheles coluzzii. Our long-term goal is
to dissect the natural genetic differences among mosquitoes that underlie malaria transmission, including
differences in malaria susceptibility, ecological adaptation, biting behavior, and insecticide resistance. The
objective of this project is to identify the genetic and functional mechanisms of the known major genomic control
region for natural A. coluzzii susceptibility to wild P. falciparum. This locus is located in a large region of
noncoding DNA on chromosome arm 2L. Frequent alleles in the wild population at this locus strongly influence
susceptible or resistant malaria infection outcomes. The central hypothesis is that genetic polymorphism of
noncoding regulatory elements explains this locus, and therefore an important fraction of vector genetic variation
for P. falciparum infection in nature. The rationale is based on the observation that noncoding genetic
polymorphisms control >90% of phenotypic variation in animals, while protein-coding sequence polymorphism
contributes little to phenotypic variation. The most important noncoding regulatory elements, enhancers, are
responsible for the majority of phenotypic variation. Enhancers are regions ~1 kb in size that modulate target
gene expression levels independent of their distance or physical orientation to the targets. Enhancers cannot be
predicted by sequence signatures, but require functional assays for detection. In an R21 project, we used a high-
throughput functional assay to generate the first comprehensive genome-wide map of enhancers in A. coluzzii,
as well as maps of the other noncoding regulatory elements, microRNAs and long noncoding RNAs (miRNAs
and lncRNAs). Our specific aims will leverage these new genomic resources to study the influence of natural
genetic variation in enhancers and other noncoding regulatory elements for malaria infection outcome: Aim 1)
Genetically resolve the major natural locus regulating wild malaria infection; Aim 2) Prioritize the candidate
noncoding and coding elements within the locus by testing correlation with infection in a wild mosquito panel;
Aim 3) Identify functional mechanisms underlying genetic control of malaria infection. This project is significant
because it will determine for the first time the genetic and functional mechanisms underlying the major genomic
control region for malaria infection of Anopheles in nature. The proposed project is innovative because the effect
of genetic variation of noncoding elements, thought to be the main source of phenotypic variation, has barely
been examined in any species, especially in malaria vector mosquitoes, and no mechanism of genetic control
over vector competence for Plasmodium in nature is currently known. The results are expected to lead to new
malaria control tools rooted in the ...

## Key facts

- **NIH application ID:** 10328247
- **Project number:** 5R01AI145999-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Michelle M Riehle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $347,513
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328247

## Citation

> US National Institutes of Health, RePORTER application 10328247, Noncoding DNA regulatory elements and Anopheles vector biology (5R01AI145999-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10328247. Licensed CC0.

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