Mlh1fc3^CAST/EiJ
QTL Variant Detail

Summary

• QTL variant: Mlh1fc3^CAST/EiJ
• Name: MLH1 foci count 3; CAST/EiJ
• MGI ID: MGI:6400599
• QTL: Mlh1fc3 Location: ChrX:61343606-89843606 bp Genetic Position: ChrX, Syntenic

Variant origin

• Strain of Specimen: CAST/EiJ

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

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

J:279476

The synaptonemal complex (SC) is a proteinaceous scaffold required for synapsis and recombination between homologous chromosomes during meiosis. Although the SC has been linked to differences in genome-wide crossover rates, the genetic basis of standing variation in SC structure remains unknown. To investigate the possibility that recombination evolves through changes to the SC, the authors characterized the genetic architecture of SC divergence on two evolutionary timescales. Applying a novel digital image analysis technique to spermatocyte spreads, the authors measured total SC length in 9,532 spermatocytes from recombinant offspring of wild-derived mouse strains with differences in this fundamental meiotic trait. Using this large dataset, they identified the first known genomic regions involved in the evolution of SC length.

Mice used:

289 (CAST/EiJ x PWD/PhJ) F2 mice (5893 spermatocytes)

229 (GI/Wisc x WSB/EiJ) F2 mice (3639 spermatocytes)

PWD/PhJ spermatocytes have longer SCs than CAST/EiJ spermatocytes (PWD/PhJ mean = 174.2 micrometers, SE = 0.7 micrometers; CAST/EiJ mean = 150.4 micrometers, SE = 0.4 micrometers; t-test p < 0.05). SC length is continuously distributed among F2s from the (CAST/EiJ x PWD/PhJ) intercross, with a mean close to the mid-parent value.

GI/Wisc spermatocytes have longer SCs than WSB/EiJ spermatocytes (GI/Wisc mean = 139.6 micrometers, SE: 1.6 micrometers; WSB/EiJ mean = 131.8 micrometers, SE: 1.4 micrometers; t-test p < 0.05). Approximately half of the F2s from the (GI/Wisc x WSB/EiJ) intercross have mean SC lengths beyond the parental means.

The authors conducted genome-wide QTL scans to identify QTL driving evolution of the SC between and within subspecies (all genome coordinates relative to GRCm38/mm10).

Mice from the (CAST/EiJ x PWD/PhJ) cross were genotyped at 295 SNPs using the Sequenom iPLEX MassARRAY system. Of these, 222 SNPs with Mendelian segregation patterns were retained for the QTL analysis. Mice from the (GI/Wisc x WSB/EiJ) cross were genotyped at 77,808 markers on the Mega Mouse Universal Genotyping Array (MegaMUGA). Of these, 11,833 SNPs with Mendelian segregation patterns were retained for the QTL analysis.

All QTL analyses were performed in R (v. 3.3.3) with the R/qtl package (v. 1.408).

Five QTL were found for synaptonemal complex length:

Syncl1 (synaptonemal complex length 1) maps to Chr 3: 68.0 - 128.6 Mb with a peak LOD score of 4.12 at 103.5 Mb (38.0 cM) and contributes 6.4% of trait variance in (CAST/EiJ x PWD/PhJ) F2 mice. PWD/PhJ alleles increase mean SC length at Syncl1 in an additive manner.

Syncl2 (synaptonemal complex length 2) maps to Chr 4: 65.8 - 146.5 Mb with a peak LOD score of 5.10 at 112.3 Mb (44.0 cM) and contributes 6.7% of trait variance in (CAST/EiJ x PWD/PhJ) F2 mice. PWD/PhJ alleles increase mean SC length at Syncl2 in an additive manner.

Syncl3 (synaptonemal complex length 3) maps to Chr X: 52.9 - 90.7 Mb with a peak LOD score of 9.51 at 71.7 Mb (31.9 cM) and contributes 14.6% of trait variance in (CAST/EiJ x PWD/PhJ) F2 mice. PWD/PhJ alleles decrease SC length at Syncl3, acting in opposition to the phenotypic difference between strains.

Syncl4 (synaptonemal complex length 4) maps to Chr 5: 102.9 - 115.4 Mb with a peak LOD score of 4.97 at 106.3 Mb (44.8 cM) and contributes 6.8% of trait variance in (GI/Wisc x WSB/EiJ) F2 mice. WSB/EiJ alleles increase SC length at Syncl4, with heterozygotes displaying significantly decreased SC length compared to either parental strain.

Syncl5 (synaptonemal complex length 5) maps to Chr X: 123.0 - 153.8 Mb with a peak LOD score of 3.78 at 138.1 (54.0 cM) and contributes 4.9% of of trait variance in (GI/Wisc x WSB/EiJ) F2 mice. WSB/EiJ alleles decrease SC length at Syncl5.

Hfm1 and Rnf212 are identified as probable candidate genes for the Syncl4 locus.

MLH1 foci are immunofluorescent markers of genetic crossovers. The ratio of mean SC length to mean MLH1 count (SC/CO ratio) varies more among F2s from the (CAST/EiJ x PWD/PhJ) cross (CAST/EiJ mean: 6.5 +/- 0.03 m / focus, PWD/PhJ: 5.8 +/- 0.04, F2s: 6.4 +/- 0.52) than among F2s from the (GI/Wisc x WSB/EiJ) cross (GI/Wisc: 6.0 +/- 0.1 m / focus, WSB/EiJ: 6.1 +/- 0.12, F2s: 6.0 +/- 0.30 m / focus). This mirrors the greater divergence of both traits in the inter-subspecific cross. Treating the transformation of the two trait values as an individual trait, the authors scanned for associated QTL in both crosses.

Four QTL were identified that influence MLH1 foci count:

Mlh1fc1 (MLH1 foci count 1) maps to Chr 4: 48.5 - 77.0 Mb with a peak LOD score of 5.07 at 65.0 Mb (25.0 cM) and contributes 2.8% of trait variance in (CAST/EiJ x PWD/PhJ) F2 mice. PWD/PhJ alleles increase mean SC length at Mlh1fc1 in an additive manner.

Mlh1fc2 (MLH1 foci count 2) maps to Chr 7: 6.5 - 133.9 Mb with a peak LOD score of 4.77 at 35.8 Mb (11.0 cM) and contributes 6.7% of trait variance in (CAST/EiJ x PWD/PhJ) F2 mice.

Mlh1fc3 (MLH1 foci count 3) maps to Chr X: 62.3 - 90.8 Mb with a peak LOD score of 34.92 at 71.7 Mb (31.9 cM) and contributes 45.9% of trait variance in (CAST/EiJ x PWD/PhJ) F2 mice. PWD/PhJ alleles decrease SC length at Mlh1fc3, acting in opposition to the phenotypic difference between strains.

Mlh1fc4 (MLH1 foci count 4) maps to Chr 5: 74.3 - 132.5 Mb with a peak LOD score of 4.39 at 124.9 Mb (53.5 cM) and contributes 6.1% of trait variance in (GI/Wisc x WSB/EiJ) F2 mice. WSB/EiJ alleles decrease SC length at Mlh1fc4.

Three QTL were identified that influence the SC/CO ratio:

Sccor1 (synaptonemal complex length to mean MLH1 count ratio 1) maps to Chr 7: 13.6 - 47.7 Mb with a peak LOD score of 6.90 at 30.3 Mb (8.0 cM) and contributes 13.1% of trait variance in (CAST/EiJ x PWD/PhJ) F2 mice.

Sccor2 (synaptonemal complex length to mean MLH1 count ratio 2) maps to Chr X: 71.5 - 97.5 Mb with a peak LOD score of 18.65 at 85.4 Mb (34.0 cM) and contributes 30.0% of trait variance in (CAST/EiJ x PWD/PhJ) F2 mice.

Sccor3 (synaptonemal complex length to mean MLH1 count ratio 3) maps to Chr 5: 104.2 - 114.6 Mb with a peak LOD score of 9.19 at 113.2 Mb (47.8 cM) and contributes 12.5% of trait variance in (GI/Wisc x WSB/EiJ) F2 mice. WSB/EiJ alleles increase SC/CO ratio at Sccor3.

References

• Original: J:279476 Wang RJ, et al., A first genetic portrait of synaptonemal complex variation. PLoS Genet. 2019 Aug;15(8):e1008337
• All: 1 reference(s)