Familial/idiopathic-type scoliosis (IS) accounts for 80% of all human spinal curvature and affects 3%-4% of the pediatric population. The deformity imposes a substantial cost on the healthcare system through physician care, bracing treatments, and spinal fusion surgeries. Efforts to identify causative factors have failed so far, due to variability within human pedigrees, and the lack of an animal genetic model with a similar phenotype. Despite many efforts, no causative genes have been discovered for this syndrome. The proposed research uses two closely related species of teleosts each having mutants with idiopathic-type curvature similar to humans. These animals are the first models to demonstrate spinal curvature that is not induced nor caused by congenital malformation of the vertebrae. It is well established that humans and fish share many genes with similar tissue and temporal expression characteristics, and comparisons between human and fish genomes have proven to be valuable for understanding the genetics of human diseases. The combined analysis in these two highly-tractable, laboratory models will identify candidate genes for idiopathic-type curvature to be tested for association with IS in human pedigrees (see letter of collaboration from Dr. Nancy Miller). The identification of genes associated with human IS could allow for effective screening, facilitating early curve detection and treatment, mitigating curve progression before surgery is necessary. Understanding physiological mechanisms can suggest novel therapeutic interventions. Objectives: (1) To identify genes involved in the idiopathic-type curvature phenotype using two closely related model teleosts, the first non-induced animal models for IS. (2) To investigate the complex genetic architecture of idiopathic-type curvature in a comprehensive pedigree of the curveback mutant. Hypothesis: Candidate genes discovered in either of these models will help elucidate the genetic causes and physiological pathways leading to the deformity in humans. Research plan: We will use guppy and medaka mapping crosses combined with a high- density genetic map and a fully-annotated, complete genome sequence for medaka, to identify candidate genes for spinal deformities in these highly syntenic, model genetic teleosts. We will use a comprehensive, multi-generation pedigree for a detailed analysis of inheritance of the curveback phenotype. The curveback guppy presents several opportunities for discovering genes that cause idiopathic-type spinal curvature: a multi-generation curveback pedigree based on sib-mating with over 1500 normal and curved individuals, most of which have been preserved for genotyping;mapping cross comprising 129 BC offspring of which an average of 48% have curves of variable magnitude, and 175 F2s (a total of 16.5% of 127 adult F2s are curved;the distribution of curve magnitude is variable);189 expressed sequence tag (EST)-based single nucleotide polymorphisms (SNPs), and 839 random genomic SNPs, designed for high-throughput genotyping;recessive phenotype;and QTL study based on 84 BC offspring screened for 189 EST-based SNPs. The ESTs markers have been mapped to positions on the medaka genome using the BLAST algorithm. Therefore, synteny between guppy and medaka has been confirmed, and therefore the fully-annotated medaka sequence can be used to identify candidate genes for guppy curveback. The wavy medaka mutant also presents several opportunities and resources for mapping genes responsible for idiopathic-type scoliosis: the wavy lineage has been inbred for more than 60 years;a fully-annotated genome is available;and a genetic linkage map has been described, based on 232 microsatellite markers;a full range of genomic tools are available for medaka, including transgenics and gene knockout libraries. We have completed an extensive mapping cross of 437 F2 offspring from one family, 103 of which exhibit curvature. Using microsatellite markers, we have performed an initial coarse-scan of approximately one half of the medaka genome and identified a candidate locus for association with curvature. Our proposed research will use the extensive mapping cross and the genomic resources available for medaka to fine-map candidate genes for idiopathic- type spinal curvature. Public Health Relevance: Human idiopathic-type scoliosis (IS) is a debilitating disease, affecting 3%-4% of the global pediatric population. The genetic basis is unknown. The proposed research offers a highly innovative approach to mapping genes associated with IS, using the first animal models known to exhibit idiopathic-type curvature similar to humans. How the IS phenotype arises in model teleosts is a worthwhile basic science pursuit that may lead to greater understanding of the molecular and cellular mechanisms in humans. Identification of genes associated with idiopathic-type spinal curvature could allow for effective screening to facilitate early curve detection in humans and suggest new therapeutic approaches.