Regional Selection Acting on the OFD1 Gene Family

The OFD1 (oral-facial-digital, type 1) gene is implicated in several developmental disorders in humans. The X-linked OFD1 (OFD1X) is conserved in Eutheria. Knowledge about the Y-linked paralog (OFD1Y) is limited. In this study, we identified an OFD1Y on the bovine Y chromosome, which is expressed differentially from the bovine OFD1X. Phylogenetic analysis indicated that: a) the eutherian OFD1X and OFD1Y were derived from the pair of ancestral autosomes during sex chromosome evolution; b) the autosomal OFD1 pseudogenes, present in Catarrhini and Murinae, were derived from retropositions of OFD1X after the divergence of primates and rodents; and c) the presence of OFD1Y in the ampliconic region of the primate Y chromosome is an indication that the expansion of the ampliconic region may initiate from the X-degenerated sequence. In addition, we found that different regions of OFD1/OFD1X/OFD1Y are under differential selection pressures. The C-terminal half of OFD1 is under relaxed selection with an elevated Ka/Ks ratio and clustered positively selected sites, whereas the N-terminal half is under stronger constraints. This study provides some insights into why the OFD1X gene causes OFD1 (male-lethal X-linked dominant) and SGBS2 & JSRDs (X-linked recessive) syndromes in humans, and reveals the origin and evolution of the OFD1 family, which will facilitate further clinical investigation of the OFD1-related syndromes.OFD1（oral-facial-digital type 1，口面指综合征1型）基因与人类多种发育障碍密切相关。X连锁型OFD1（OFD1X）在真哺乳亚纲（Eutheria）物种中高度保守。目前学界对Y连锁旁系同源基因OFD1Y的认知仍较为有限。本研究在牛Y染色体上成功鉴定出OFD1Y基因，其表达模式与牛源OFD1X存在显著差异。系统发育分析结果显示：其一，真哺乳亚纲的OFD1X与OFD1Y起源于性染色体演化进程中的一对祖先常染色体；其二，狭鼻小目（Catarrhini）与鼠科（Murinae）中存在的常染色体OFD1假基因，是灵长类与啮齿类分化后由OFD1X经逆转座产生的；其三，灵长类Y染色体扩增子区域中存在OFD1Y基因，这提示扩增子区域的扩张可能起始于X退化序列。此外，本研究还发现OFD1、OFD1X与OFD1Y的不同区域受到差异化的选择压力：OFD1的C端半区处于松弛选择状态，其Ka/Ks比值升高且存在聚集的正选择位点，而N端半区则受到更强的选择约束。本研究阐明了OFD1X基因为何会引发人类OFD1（雄性致死X连锁显性遗传病）及SGBS2、JSRDs（X连锁隐性遗传病）综合征，并揭示了OFD1基因家族的起源与演化历程，可为后续OFD1相关综合征的临床研究提供重要参考。