Abstract
BackgroundUnderstanding complex networks that modulate development in humans is hampered by genetic and phenotypic heterogeneity within and between populations. Here we present a method that exploits natural variation in highly diverse mouse genetic reference panels in which genetic and environmental factors can be tightly controlled. The aim of our study is to test a cross-species genetic mapping strategy, which compares data of gene mapping in human patients with functional data obtained by QTL mapping in recombinant inbred mouse strains in order to prioritize human disease candidate genes.MethodologyWe exploit evolutionary conservation of developmental phenotypes to discover gene variants that influence brain development in humans. We studied corpus callosum volume in a recombinant inbred mouse panel (C57BL/6J×DBA/2J, BXD strains) using high-field strength MRI technology. We aligned mouse mapping results for this neuro-anatomical phenotype with genetic data from patients with abnormal corpus callosum (ACC) development.Principal FindingsFrom the 61 syndromes which involve an ACC, 51 human candidate genes have been identified. Through interval mapping, we identified a single significant QTL on mouse chromosome 7 for corpus callosum volume with a QTL peak located between 25.5 and 26.7 Mb. Comparing the genes in this mouse QTL region with those associated with human syndromes (involving ACC) and those covered by copy number variations (CNV) yielded a single overlap, namely HNRPU in humans and Hnrpul1 in mice. Further analysis of corpus callosum volume in BXD strains revealed that the corpus callosum was significantly larger in BXD mice with a B genotype at the Hnrpul1 locus than in BXD mice with a D genotype at Hnrpul1 (F = 22.48, p<9.87*10−5).ConclusionThis approach that exploits highly diverse mouse strains provides an efficient and effective translational bridge to study the etiology of human developmental disorders, such as autism and schizophrenia.
Highlights
The corpus callosum is the fibrous structure that connects both hemispheres of the cortex in all placental mammals [1,2]
Further analysis of corpus callosum volume in BXD strains revealed that the corpus callosum was significantly larger in BXD mice with a B genotype at the Hnrpul1 locus than in BXD mice with a D genotype at Hnrpul1 (F = 22.48, p,9.87*1025). This approach that exploits highly diverse mouse strains provides an efficient and effective translational bridge to study the etiology of human developmental disorders, such as autism and schizophrenia
The more narrow category of neurogenesis (GO:0007399) includes 11 genes (DCX, EFNB1, EP300, FCMD, FLNA, HESX1, L1CAM, LARGE, PAFAH1B1, PAX6, and ZFHX1B; p,0.0001 and Bayes Factor 16). Both the p values and the Bayes factor, indicating the fold-likelihood that a model fits the data vs. the neutral null-hypothesis, indicate a highly significant association of these Gene Ontology (GO) categories with an abnormal corpus callosum (ACC) [12]
Summary
The corpus callosum is the fibrous structure that connects both hemispheres of the cortex in all placental mammals [1,2]. In humans, this bridge is made up of more than 100 million axons of neocortical neurons routing information between the left and the right sides of the brain [3,4]. Recent studies have put forward potential candidate genetic mechanisms underlying an ACC in humans, the question remains how these genes contribute to abnormal development of this brain region relevant to proper human functioning. The aim of our study is to test a cross-species genetic mapping strategy, which compares data of gene mapping in human patients with functional data obtained by QTL mapping in recombinant inbred mouse strains in order to prioritize human disease candidate genes
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