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Genetic analysis of posterior medial barrel subfield (PMBSF) size in somatosensory cortex (SI) in recombinant inbred strains of mice.

Jan TA, Lu L, Li CX, Williams RW, Waters RS - BMC Neurosci (2008)

Bottom Line: QTL mapping has been used to identify genes associated with cytoarchitecture, cell number, brain size, and brain volume.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.The present study is an important step towards identifying genes underlying the size and possible development of cortical structures.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. tjan@stanford.edu

ABSTRACT

Background: Quantitative 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.

Results: We 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.

Conclusion: We 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.

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Genome-wide total PMBSF raw and adjusted linkage maps and chromosome 4 interval map. (A) Genome-wide linkage map of raw PMBSF area shows two suggestive QTLs on chromosomes 4 and 17. (B) Total PMBSF area linkage map after adjustment for brain weight shows a suggestive QTL on chromosome 4. Chromosome 17 linkage is not observed here. (C) Chromosome 4 interval map of adjusted total PMBSF area. Genes spanning the interval of 5.5 to 9.0 Mb on chromosome 4 were examined. Lower gray horizontal line: suggestive LRS genome-wide threshold at p ≤ 0.63. Upper red horizontal line: significant LRS genome-wide threshold at p ≤ 0.05. Yellow histogram: frequency of peak LRS (bootstrap analysis). Orange seismograph marks indicate SNP density.
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Figure 3: Genome-wide total PMBSF raw and adjusted linkage maps and chromosome 4 interval map. (A) Genome-wide linkage map of raw PMBSF area shows two suggestive QTLs on chromosomes 4 and 17. (B) Total PMBSF area linkage map after adjustment for brain weight shows a suggestive QTL on chromosome 4. Chromosome 17 linkage is not observed here. (C) Chromosome 4 interval map of adjusted total PMBSF area. Genes spanning the interval of 5.5 to 9.0 Mb on chromosome 4 were examined. Lower gray horizontal line: suggestive LRS genome-wide threshold at p ≤ 0.63. Upper red horizontal line: significant LRS genome-wide threshold at p ≤ 0.05. Yellow histogram: frequency of peak LRS (bootstrap analysis). Orange seismograph marks indicate SNP density.

Mentions: We used our 42 BXD strains to map total PMBSF area QTL. Both raw data and adjusted values of PMBSF area were utilized for mapping in order to test whether our data modeling affected position of the identified PMBSF area QTL. By examining the simple regression QTL map of raw PMBSF area (Figure 3A), we immediately noticed two suggestive QTLs, one on the proximal arm of chromosome 4 and the other on chromosome 17. In addition, a couple of other signals (chromosomes 15 and X) were also observed to cross the suggestive threshold. When PMBSF area was adjusted for brain weight, the suggestive QTL on chromosome 4 remained largely unchanged, in terms of its significance and its location (Figure 3B). However, most of the other suggestive QTLs observed in the raw data map had diminished signals, in particular those on chromosomes 17 and X. Marker regression analysis using WebQTL revealed four loci with highly suggestive LRS values, all at 14.20 (suggestive threshold LRS = 10.68). The detected loci are: rs3674982, rs13477546, gnf04.004.855, rs13477551.


Genetic analysis of posterior medial barrel subfield (PMBSF) size in somatosensory cortex (SI) in recombinant inbred strains of mice.

Jan TA, Lu L, Li CX, Williams RW, Waters RS - BMC Neurosci (2008)

Genome-wide total PMBSF raw and adjusted linkage maps and chromosome 4 interval map. (A) Genome-wide linkage map of raw PMBSF area shows two suggestive QTLs on chromosomes 4 and 17. (B) Total PMBSF area linkage map after adjustment for brain weight shows a suggestive QTL on chromosome 4. Chromosome 17 linkage is not observed here. (C) Chromosome 4 interval map of adjusted total PMBSF area. Genes spanning the interval of 5.5 to 9.0 Mb on chromosome 4 were examined. Lower gray horizontal line: suggestive LRS genome-wide threshold at p ≤ 0.63. Upper red horizontal line: significant LRS genome-wide threshold at p ≤ 0.05. Yellow histogram: frequency of peak LRS (bootstrap analysis). Orange seismograph marks indicate SNP density.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2254631&req=5

Figure 3: Genome-wide total PMBSF raw and adjusted linkage maps and chromosome 4 interval map. (A) Genome-wide linkage map of raw PMBSF area shows two suggestive QTLs on chromosomes 4 and 17. (B) Total PMBSF area linkage map after adjustment for brain weight shows a suggestive QTL on chromosome 4. Chromosome 17 linkage is not observed here. (C) Chromosome 4 interval map of adjusted total PMBSF area. Genes spanning the interval of 5.5 to 9.0 Mb on chromosome 4 were examined. Lower gray horizontal line: suggestive LRS genome-wide threshold at p ≤ 0.63. Upper red horizontal line: significant LRS genome-wide threshold at p ≤ 0.05. Yellow histogram: frequency of peak LRS (bootstrap analysis). Orange seismograph marks indicate SNP density.
Mentions: We used our 42 BXD strains to map total PMBSF area QTL. Both raw data and adjusted values of PMBSF area were utilized for mapping in order to test whether our data modeling affected position of the identified PMBSF area QTL. By examining the simple regression QTL map of raw PMBSF area (Figure 3A), we immediately noticed two suggestive QTLs, one on the proximal arm of chromosome 4 and the other on chromosome 17. In addition, a couple of other signals (chromosomes 15 and X) were also observed to cross the suggestive threshold. When PMBSF area was adjusted for brain weight, the suggestive QTL on chromosome 4 remained largely unchanged, in terms of its significance and its location (Figure 3B). However, most of the other suggestive QTLs observed in the raw data map had diminished signals, in particular those on chromosomes 17 and X. Marker regression analysis using WebQTL revealed four loci with highly suggestive LRS values, all at 14.20 (suggestive threshold LRS = 10.68). The detected loci are: rs3674982, rs13477546, gnf04.004.855, rs13477551.

Bottom Line: QTL mapping has been used to identify genes associated with cytoarchitecture, cell number, brain size, and brain volume.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.The present study is an important step towards identifying genes underlying the size and possible development of cortical structures.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. tjan@stanford.edu

ABSTRACT

Background: Quantitative 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.

Results: We 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.

Conclusion: We 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.

Show MeSH
Related in: MedlinePlus