Didion John P, Morgan Andrew P, Clayshulte Amelia M-F, Mcmullan Rachel C, Yadgary Liran, Petkov Petko M, Bell Timothy A, Gatti Daniel M, Crowley James J, Hua Kunjie, Aylor David L, Bai Ling, Calaway Mark, Chesler Elissa J, French John E, Geiger Thomas R, Gooch Terry J, Garland Theodore, Harrill Alison H, Hunter Kent, McMillan Leonard, Holt Matt, Miller Darla R, O'Brien Deborah A, Paigen Kenneth, Pan Wenqi, Rowe Lucy B, Shaw Ginger D, Simecek Petr, Sullivan Patrick F, Svenson Karen L, Weinstock George M, Threadgill David W, Pomp Daniel, Churchill Gary A, Pardo-Manuel de Villena Fernando
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS Genet. 2015 Feb 13;11(2):e1004850. doi: 10.1371/journal.pgen.1004850. eCollection 2015 Feb.
Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 - 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using real-time PCR assays for the copy number, we identified a mutation (R2d2WSBdel1) that eliminates the majority of the R2d2WSB copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for R2d2WSBdel1, the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for R2d2WSBdel1, thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in R2d2WSB heterozygous females vary between Mendelian segregation and complete distortion depending on the genetic background, and that TRD is under genetic control of unlinked distorter loci. Although the R2d2WSB transmission ratio was inversely correlated with average litter size, several independent lines of evidence support the contention that female meiotic drive is the cause of the distortion. We discuss the implications and potential applications of this novel meiotic drive system.
在实验杂交和自然种群中，经常观察到与预期孟德尔遗传比率的显著偏差（传递比率畸变，TRD）。在包括协作杂交（CC）在内的多个实验杂交中，均报道了小鼠2号染色体（Chr）上的TRD。在八个CC创始近交系中，我们发现2号染色体TRD仅在9.3 Mb区域（Chr 2 76.9 - 86.2 Mb）内对WSB/EiJ等位基因杂合的雌性小鼠中出现。一个127 kb长的DNA片段（称为驱动响应者，R2d）的拷贝数增加成为致病等位基因的最强候选者。我们将R2d序列定位到候选区间内的两个位点。R2d1位于近端边界附近，在所有测试菌株中均包含R2d的单拷贝。R2d2定位到一个900 kb的区间，R2d拷贝数在经典菌株（包括小鼠参考基因组）中为零，而在野生来源菌株中则超过30个。通过实时PCR检测拷贝数，我们鉴定出一个突变（R2d2WSBdel1），该突变消除了大多数R2d2WSB拷贝，而周围的WSB/EiJ单倍型没有明显改变。在一个三代家系中，R2d2WSBdel1发生分离，该突变传递给后代，并且在R2d2WSBdel1杂合的雌性小鼠中恢复了孟德尔分离，从而提供了直接证据表明拷贝数增加是母体TRD的原因。我们发现，R2d2WSB杂合雌性小鼠的传递比率在孟德尔分离和完全畸变之间变化，这取决于遗传背景，并且TRD受不连锁的畸变位点的遗传控制。尽管R2d2WSB传递比率与平均窝仔数呈负相关，但几条独立的证据支持雌性减数分裂驱动是畸变原因的观点。我们讨论了这种新型减数分裂驱动系统的意义和潜在应用。
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