M1fscn2^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: M1fscn2^C57BL/6J
• Name: modifier 1 of Fscn2; C57BL/6J
• MGI ID: MGI:5896346
• QTL: M1fscn2 Location: Chr5:83529661-83529661 bp Genetic Position: Chr5, Syntenic

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

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

J:227315

Inbred mouse strains serve as important models for human presbycusis or age-related hearing loss. The authors previously mapped a locus (Ahl8; allele of Fscn2, MGI:2443337) contributing to the progressive hearing loss of DBA/2J mice and later showed that a missense variant of the Fscn2 gene, unique to the DBA/2J inbred strain, was responsible for the Ahl8 effect. Although Ahl8 can explain much of the hearing loss difference between C57BL/6J and DBA/2J mice, other loci also contribute. Here, the authors present results of their linkage analyses to map QTL that modify the severity of hearing loss associated with the DBA/2J strain Fscn2^Ahl8 allele.

In this study, hearing in mice was assessed by ABR threshold analysis. Thresholds were determined for 8, 16, and 32 kHz pure-tone stimuli by increasing the sound pressure level (SPL) in 10-dB increments followed by 5-dB increases and decreases to determine the lowest level at which a distinct ABR wave pattern could be recognized.

The authors searched for modifier loci by analyzing 31 BXD recombinant inbred (RI) lines with over 750 previously typed SNP and microsatellite markers. The RI strains were fixed for the predisposing DBA/2J-derived Fscn2^Ahl8/Ahl8 genotype. The authors used the WebQTL mapping program of the GeneNetwork website (NCBI Build 37) to perform QTL mapping analysis, treating 8 and 16 kHz ABR thresholds as quantitative traits. Because of the old age of the mice when tested, the high frequency 32 kHz ABR thresholds were uniformly high in mice of all RI strains (adjusted R-square = 0.13) and therefore not useful for mapping.

The peak association for 8 kHz threshold associations was with the SNP markers rs13478357 and rs13478361 (LOD 4.6) at the 84 Mb position of Chromosome 5, with the 1.5-LOD confidence interval extending from 80 - 92 Mb. The authors designate this locus M5ahl8 (modifier on chromosome 5 of age-related hearing loss 8). For the purposes of nomenclature clarity, we have renamed this locus M1fscn2 (modifier 1 of Fscn2).

Analyses of 16 kHz thresholds gave similar results. We named this second locus M2fscn2 (modifier 2 of Fscn2).

Average 8 and 16 kHz ABR thresholds of RI lines with DBA/2J alleles at the M1fscn2 and M2fscn2 loci are statistically significantly higher than those of RI lines with C57BL/6J alleles at the same position: mean elevations of 18 dB for 8 kHz thresholds and 13 dB for 16 kHz thresholds. The Chromosome 5 map position of M1fscn2/M2fscn2 and the DBA/2J origin of its susceptibility allele correspond to Tmc1m4, a previously reported QTL that modifies outer hair cell degeneration in Tmc1^Bth mutant mice, suggesting that M1fscn2, M2fscn2, and Tmc1m4 may represent the same gene affecting maintenance of stereocilia structure and function during aging.

M1fscn2 and M2fscn2 could explain about 46% of the among-RI strain variation in auditory brainstem response (ABR) threshold means. The semidominant nature of the modifying effect of these two loci on the Fscn2^Ahl8/Ahl8 phenotype was demonstrated by analysis of a backcross involving DBA/2J and B6.D2-Chr11D/LusJ congenic mice. The authors use the notation (B6.D2-Chr11D/LusJ x DBA/2J) x B6.D2-Chr11D/LusJ to represent this backcross.

Out of a total of 180 N2 backcross mice produced, the authors chose 43 mice with the lowest thresholds and 42 mice with the highest thresholds for linkage analysis. They undertook a genome-wide screen for linkage of ABR thresholds with 120 SNP markers located throughout the genome. SNP rs3023047 (92 Mb position on Chromosome 5) showed a statistically significant linkage association with 16 kHz ABR thresholds (LOD = 3.3), but not with 8 kHz (LOD = 1.9) or 32 kHz thresholds (LOD<1.5) thresholds. SNP rs3023047 is within the M1fscn2/M2fscn2 region. Because this third locus was identified in a different mapping population than M1fscn2 and M2fscn2 (congenic backcross versus BXD RI panel, respectively), we have named it separately as M3fscn2 (modifier 3 of Fscn2).

References

• Original: J:227315 Johnson KR, et al., A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice. Mamm Genome. 2015 Aug;26(7-8):338-47
• All: 1 reference(s)