Abstract
BackgroundQuantitative trait locus (QTL) mapping is an important tool for identifying potential candidate genes linked to complex traits. QTL mapping has been used to identify genes associated with cytoarchitecture, cell number, brain size, and brain volume. Previously, QTL mapping was utilized to examine variation of barrel field size in the somatosensory cortex in a limited number of recombinant inbred (RI) strains of mice. In order to further elucidate the underlying natural variation in mouse primary somatosensory cortex, we measured the size of the posterior medial barrel subfield (PMBSF), associated with the representation of the large mystacial vibrissae, in an expanded sample set that included 42 BXD RI strains, two parental strains (C57BL/6J and DBA/2J), and one F1 strain (B6D2F1). Cytochrome oxidase labeling was used to visualize barrels within the PMBSF.ResultsWe observed a 33% difference between the largest and smallest BXD RI strains with continuous variation in-between. Using QTL linkage analysis from WebQTL, we generated linkage maps of raw total PMBSF and brain weight adjusted total PMBSF areas. After removing the effects of brain weight, we detected a suggestive QTL (likelihood ratio statistic [LRS]: 14.20) on the proximal arm of chromosome 4. Candidate genes under the suggestive QTL peak for PMBSF area were selected based on the number of single nucleotide polymorphisms (SNPs) present and the biological relevance of each gene. Among the candidate genes are Car8 and Rab2. More importantly, mRNA expression profiles obtained using GeneNetwork indicated a strong correlation between total PMBSF area and two genes (Adcy1 and Gap43) known to be important in mouse cortex development. GAP43 has been shown to be critical during neurodevelopment of the somatosensory cortex, while knockout Adcy1 mice have disrupted barrel field patterns.ConclusionWe detected a novel suggestive QTL on chromosome 4 that is linked to PMBSF size. The present study is an important step towards identifying genes underlying the size and possible development of cortical structures.
Highlights
Quantitative trait locus (QTL) mapping is an important tool for identifying potential candidate genes linked to complex traits
Synopsis This study was an extension of our previous work [8] in which the total posterior medial barrel subfield (PMBSF)/anterior lateral barrel subfield (ALBSF) area was examined in four common inbred strains and 10 BXD recombinant inbred (RI) strains of mice
Correlation analysis with a whole brain microarray expression database revealed a number of highly correlated genes throughout the genome including adenylate cyclase 1 (Adcy1), a gene known to disrupt barrel organization of mouse somatosensory cortex [17], and growth associated protein 43 (Gap43), a gene previously reported to be involved in barrel formation during mouse development [18]
Summary
Quantitative trait locus (QTL) mapping is an important tool for identifying potential candidate genes linked to complex traits. QTL mapping was utilized to examine variation of barrel field size in the somatosensory cortex in a limited number of recombinant inbred (RI) strains of mice. BMC Neuroscience 2008, 9:3 http://www.biomedcentral.com/1471-2202/9/3 ping is an efficient means of associating positions in the genome with variation in a phenotype [1]. Such quantitative genetic approaches applied in recombinant inbred (RI) strains of mice have been used to map and characterize genes responsible for heritable variation in a number of CNS morphologic phenotypes including ventricular size [2], hippocampal structure, size, and cell number [3,4], and cerebellar size and structure [5]. Many of the RI strains have been densely genotyped, eliminating this often costly and time-consuming step
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