Prokop Jeremy W, Tsaih Shirng-Wern, Faber Allison B, Boehme Shannon, Underwood Adam C, Troyer Samuel, Playl Lauren, Milsted Amy, Turner Monte E, Ely Daniel, Martins Almir S, Tutaj Marek, Lazar Jozef, Dwinell Melinda R, Jacob Howard J
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806 USA ; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI 53226 USA ; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226 USA.
Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI 53226 USA.
Biol Sex Differ. 2016 Feb 3;7:10. doi: 10.1186/s13293-016-0064-z. eCollection 2016.
The male-specific region of chromosome-Y (MSY) contributes to phenotypes outside of testis development and has a high rate of evolution between mammalian species. With a lack of genomic crossover, MSY is one of the few genomic areas under similar variation and evolutionary selection in inbred and outbred animal populations, allowing for an assessment of evolutionary mechanisms to translate between the populations.
Using next-generation sequencing, MSY consomic strains, molecular characterization, and large-scale phenotyping, we present here regions of MSY that contribute to inbred strain phenotypes.
We have shown that (1) MSY of rat has nine autosomal gene transposition events with strain-specific selection; (2) sequence variants in MSY occur with a 1.98-fold higher number of variants than other chromosomes in seven sequenced rat strains; (3) Sry, the most studied MSY gene, has undergone extensive gene duplications, driving ubiquitous expression not seen in human or mouse; (4) the expression profile of Sry in the rat is driven by the insertion of the Sry2 copy into an intron of the ubiquitously expressed Kdm5d gene in antisense orientation, but due to several loss of function mutations in the Sry2 protein, nuclear localization and transcriptional control are decreased; (5) expression of Sry copies other than Sry2 in the rat overlaps with the expression profile for human SRY; (6) gene duplications and sequence variants (P76T) of Sry can be selected for phenotypes such as high blood pressure and androgen receptor signaling within inbred mating; and most importantly, (7) per chromosome size, MSY contributes to higher strain-specific phenotypic variation relative to all other chromosomes, with 53 phenotypes showing both a male to female and consomic cross significance.
The data presented supports a high probability of MSY genetic variation altering a broad range of inbred rat phenotypes.
Y染色体雄性特异区域（MSY）对睾丸发育以外的表型有影响，并且在哺乳动物物种之间具有较高的进化速率。由于缺乏基因组交叉，MSY是近交和远交动物群体中少数在相似变异和进化选择下的基因组区域之一，这使得我们能够评估在不同群体之间起作用的进化机制。
通过使用下一代测序、MSY染色体代换系、分子特征分析和大规模表型分析，我们在此展示了对近交系表型有贡献的MSY区域。
我们已经表明：（1）大鼠的MSY有9个常染色体基因转座事件，并具有品系特异性选择；（2）在7个已测序的大鼠品系中，MSY中的序列变异数量比其他染色体高1.98倍；（3）研究最多的MSY基因Sry经历了广泛的基因重复，导致其在大鼠中普遍表达，而在人类或小鼠中未见此现象；（4）大鼠中Sry的表达谱是由Sry2拷贝以反义方向插入普遍表达的Kdm5d基因的一个内含子所驱动，但由于Sry2蛋白中的几个功能丧失突变，其核定位和转录调控作用减弱；（5）大鼠中除Sry2以外的Sry拷贝的表达与人SRY的表达谱重叠；（6）Sry的基因重复和序列变异（P76T）可在近交交配中被选择用于诸如高血压和雄激素受体信号传导等表型；最重要的是，（7）相对于所有其他染色体，按染色体大小计算，MSY对品系特异性表型变异的贡献更高，有53种表型在雄性与雌性以及染色体代换杂交中均显示出显著差异。
所呈现的数据支持MSY基因变异极有可能改变广泛的近交大鼠表型。
