Epigenetic regulation of neo-sex chromosomes in filarial parasites

Filarial nematodes (filariae) are a major cause of morbidity and mortality in the tropics. The two major anthelminthic drugs used to eradicated filarial disease are contraindicated in regions where Loa loa is co- endemic. Lineage-specific therapies would be an important tool, one that can come only from “knowing one’s enemy,” by developing a better understanding of their essential biological traits. Filariae are diverse roundworms that are all obligate vertebrate parasites vectored by blood-feeding arthropods. They are related to the widely studied species Caenorhabditis elegans (in the same taxonomic order, Rhabditida), and much of what we know about filarial nematodes is based on the study of C. elegans. However, many genes in filarial nematodes have no known function and >20% are not in C. elegans, such that studies directly focusing on filarial nematodes are needed. Because of their unique combination of attributes, these studies will also further our general understanding of genome evolution. Some filarial species, including the most medically important ones, have experienced recent fusions of their ancestral X (sex) chromosome with distinct autosomes. These X:autosome fusions also created new Y chromosomes that are derived from the unfused autosomal homolog. These neo-Y chromosomes have persisted and become highly differentiated in a relatively short time period. While neo-Y chromosomes are found in many other taxa, they are not found in Caenorhabditis or many other nematodes, which are XX-XO with X dosage-based sex determination. Neo-Y chromosomes are also not typically found in organisms with holocentric chromosomes, like nematodes. Therefore, filarial nematodes have differing characteristics for the study of sex chromosome evolution than has previously been examined. One goal of the proposed research is to determine whether known mechanisms of sex chromosome regulation in C. elegans apply to all or part of the fused chromosomes of filarial species like Brugia malayi, a causative agent of lymphatic filariasis. As these new sex chromosomes are of relatively recent origin, they offer an opportunity to examine the process of X-Y differentiation in an animal with holocentric chromosomes. Another goal is to determine the impact of sex chromosome-autosome fusions on the reproductive gene repertoire of filarial species. Success in either will reveal both general aspects of chromosome evolution and potential vulnerabilities that could lead to therapeutic interventions. The research proposed is a collaboration between an investigator with deep experience in the area of filarial genomics, computational biology, and genome evolution and another who has long worked in the area of Caenorhabditis genomics, reproductive biology, and evolution. Project Number: 1R21AI190325-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Julie Dunning Hotopp | Institution: UNIVERSITY OF MARYLAND BALTIMORE, BALTIMORE, MD | Award Amount: $440,211 | Activity Code: R21 | Study Section: Genetic Variation and Evolution Study Section[GVE] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19032501A1