Mecth1^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Mecth1^DBA/2J
• Name: mechanosensation threshold 1; DBA/2J
• MGI ID: MGI:5911619
• QTL: Mecth1 Location: Chr5:4518000-19834998 bp Genetic Position: Chr5, Syntenic

Variant origin

• Strain of Specimen: DBA/2J

Variant description

• Allele Type: QTL

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:242941

Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, quantitative trait locus (QTL) mapping was performed of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Mechanosensitivity in the von Frey test is highly variable and heritable, with 69% of the variability in sensitivity of standard inbred mouse strains explained by genetic factors; but the genetic and molecular mechanisms underlying individual differences in mechanosensation have yet to be identified.

The current study employs BXD RI mice to perform genome-wide QTL mapping, genetic correlation analysis with other behavioral and neurobiological traits, expression QTL and trait-transcript correlation analysis to identify genomic loci and candidate genes underlying individual differences in von Frey mechanosensitivity.

For QTL mapping and genetic correlation analysis, adult male mice of 26 BXD RI strains were tested for mechanical thresholds in the von Frey test (N = 204; n = 69/strain).

Mechanical sensitivity was measured on the plantar surface of the hind paws of habituated mice by application of von Frey-type monofilaments with bending forces of 0.03, 0.07, 0.16, 0.41, 1.00, 2.24, 5.50 g for 12 seconds with an inter-trial interval of 10 seconds. One paw was completely tested prior to testing the other paw. The baseline thresholds for each hind paw were determined on 3 separate days. The average of values for both paws and 3 days of testing were calculated and used for QTL mapping and genetic correlation analyses.

To determine the location of genomic loci linked to variability in mechanosensation, whole-genome single locus QTL mapping using the BXD RI strain phenotypic means was performed in GeneNetwork.org (NCBI Build 37), where the data have been deposited (GeneNetwork Record ID 11296). A total of 3795 non-redundant DNA markers polymorphic between the progenitor strains and among BXD RI strains and at loci throughout the genome were considered. The threshold logarithm of the odds (LOD) score for a significant QTL was determined using an empirical P-value from 1000 permutations of the strain means with a genome-wide error rate alpha=0.05; significant LOD=3.76.

Two significant QTL were mapped:

QTL Mecth1 (mechanosensation threshold 1) mapped to Chr 5 with a LOD score of 4.0 and a 95% confidence interval between 4.468-19.63 Mb. Sixty-four genes mapped within the CI interval (MGD:GRCm38).

QTL Mecth2 (mechanosensation threshold 2) mapped to Chr 15 with a LOD score of 4.2 and a 95% confidence interval between 74.791 -79.503 Mb. One hundred and fifty-three genes mapped within the CI interval (MGD:GRCm38).

Transcript covariance analysis was used to prioritize subsequent testing of the positional candidate genes. Expression of three genes, Cacna2d1, Csnk1e and Ift27 (Rabl4) was highly correlated with von Frey withdrawal thresholds in five of eight brain areas for which data were available in the BXD RI mouse strains. Furthermore, Cacna2d1, Csnk1e and Ift27 were located in the detected QTLs on Chr 5:15.4-15.9 Mb, Chr15: 79.2-79.3 Mb and Chr 15: 78.15-78.17, respectively.

The QTL mapping of transcript abundance enables the detection of polymorphisms that act through regulation of expression or stability of RNA. Such loci should exist for transcripts that have high genetic correlation to behavioral phenotypes. Expression QTL was retrieved for each of the three transcripts in the M430 INIA brain data set in GeneNetwork.org. The peak cis QTL for each transcript is Chr 5:14.32 Mb at rs3687916 (P < 0.000055) for Cacna2d1; Chr 15: 78.74 Mb at rs3667755 (P < 0.000001) for Csnk1e and Chr 15: 77.99 Mb at rs6342608 (P < 0.000004) for Ift27.

Cacna2d1 and Csnk1e are amenable to specific pharmacological targeting and to date have no known role in punctate mechanosensation. Thus, they were considered the highest priority for candidate genes testing.

References

• Original: J:242941 Young EE, et al., Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test. Genes Brain Behav. 2016 Jul;15(6):604-15
• All: 1 reference(s)