PUBLICATION
Phenotype to genotype: A new and rapid approach using whole-genome sequencing
- Authors
- Feltes, M., Zimin, A.V., Angel, S., Pansari, N., Hensley, M.R., Anderson, J.L., Shen, M.C., Klemek, M., Shen, Y., Ginde, V.S., Kozan, H., Le, N.V., Truong, V.P., Wilson, M.H., Salzberg, S.L., Farber, S.A.
- ID
- ZDB-PUB-250715-8
- Date
- 2025
- Source
- PLoS Genetics 21: e1011702e1011702 (Journal)
- Registered Authors
- Farber, Steven, Feltes, McKenna, Shen, Meng-Chieh
- Keywords
- none
- MeSH Terms
-
- Zea mays/genetics
- Mutation
- Zebrafish/genetics
- Animals
- Apolipoproteins B/genetics
- Apolipoproteins B/metabolism
- Whole Genome Sequencing*/methods
- Algorithms
- Phenotype
- Chromosome Mapping/methods
- Genotype
- Zebrafish Proteins/genetics
- PubMed
- 40658698 Full text @ PLoS Genet.
Citation
Feltes, M., Zimin, A.V., Angel, S., Pansari, N., Hensley, M.R., Anderson, J.L., Shen, M.C., Klemek, M., Shen, Y., Ginde, V.S., Kozan, H., Le, N.V., Truong, V.P., Wilson, M.H., Salzberg, S.L., Farber, S.A. (2025) Phenotype to genotype: A new and rapid approach using whole-genome sequencing. PLoS Genetics. 21:e1011702e1011702.
Abstract
Forward genetic screening is a powerful approach to assign functions to genes and can be used to elucidate the many genes whose functions remain unknown. A key step in forward genetic screening is mapping: identification of the gene causing the phenotype. Existing mapping methods use a bioinformatic mapping-by-sequencing approach based on allelic frequency calculations that often identify large genomic regions which contain an intractable number of candidate genes for testing. Here, we describe WheresWalker, a modern mapping-by-sequencing algorithm that identifies a mutation-containing interval and then supports positional cloning to shrink the interval, which drastically reduces the number of potential candidates, allowing for extremely rapid mutation identification. We validated this method using mutants from a forward genetic mutagenesis screen in zebrafish for modifiers of ApoB-lipoprotein metabolism. WheresWalker correctly mapped and identified novel zebrafish mutations in mttp, apobb.1, and mia2 genes, as well as a previously published mutation in maize. Further, we used WheresWalker to identify a previously unappreciated ApoB-lipoprotein metabolism-modifying locus, slc3a2a.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping