Nat Commun:携带该基因突变的男性,患2型糖尿病风险高达30%

2021-07-30 “生物世界”公众号 “生物世界”公众号

白细胞中Y染色体的镶嵌缺失(LOY)是克隆镶嵌最常见的形式,由细胞周期和DNA损伤反应途径的失调引起。LOY与许多复杂疾病和性状的风险有关,然而,支持这些观察结果的生物学机制尚不清楚。

白细胞中Y染色体的镶嵌缺失(LOY)是克隆镶嵌最常见的形式,由细胞周期和DNA损伤反应途径的失调引起。LOY与许多复杂疾病和性状的风险有关,然而,支持这些观察结果的生物学机制尚不清楚。

与其他形式的克隆嵌合体一样,LOY与年龄密切相关,反映出造血干细胞分裂中有丝分裂错误和随后的克隆扩增。迄今为止,对LOY的遗传学研究主要集中于基因型阵列推断的常见遗传变异,这在很大程度上忽略了罕见的、往往是更有害的等位基因的贡献。因此,识别与LOY相关的新遗传决定因素不仅有可能促进人们对克隆造血的了解,还可能通过共同的生物学机制识别对其他复杂性状易感的位点。

近日,剑桥大学的 John Perry 教授团队在 Nature Communications 期刊发表了题为:GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health 的研究论文。

该研究发现,大约3000人中出现1个的 GIGYF1 基因突变,大大增加了 Y 染色体缺失(LOY)的易感性,这些人患2型糖尿病的风险为30%,而普通人群患2型糖尿病风险仅为5%,这表明GIGYF1 基因突变将2型糖尿病风险增加到了6倍。

量化LOY的方法目前有两种:一种是通过信号强度的平均log2-transform R ratio(mLRR-Y),一种是通过在性染色体伪常染色体区域(PAR)中使用二分测量(PAR-LOY)。这两种方法各有所长,于是研究团队融合了它们以提高信噪比,从而增强检测遗传关联的统计能力。他们将这种联合定量测量方法称为PAR-LOYq。

为了识别与LOY相关的基因,他们使用外显子组序列数据对82277名英国生物银行(UK Buibank)男性参与者的PAR-LOYq进行了基因负荷分析。通过将每个单独基因中罕见的功能丧失或中度影响变异体折叠在一起,对两个模型进行了关联试验。他们发现,CHEK2和GIGYF1的负荷试验关联具有统计学意义,其中的CHEK2具有显着意义。

接下来,研究团队进行了几项敏感性分析,以进一步探索GIGYF1-LOY关联的遗传结构。首先,研究团队使用之前的两个LOY性状观察到了一致的效应,PAR-LOY二分法的风险增加了6倍,mLRRy降低了0.038 。其次,在敏感性分析中,当排除多等位基因位点或INDEL仅限于LOFTEE定义的功能变异体的高置信度缺失时,PAR-LOYq关联结果高度一致。他们使用在STAAR实现的第二个分析管道再现了相同的关联信号,表明GIGYF1功能丧失与任何遗传衍生的主要成分无关,并且携带者在地理上分散在英国各地。

总的来说,这种外显子组测序的方法在 GIGYF1 基因中发现了罕见的功能等位基因缺失,这一罕见突变会大大增加 Y 染色体缺失(LOY)的易感性和患2型糖尿病的风险。强调了克隆嵌合与代谢健康之间潜在的直接联系。

这项发现了突出了对大量人群进行基因组测序的令人兴奋的科学潜力,能够帮助人们更好地了解常见疾病,如2型糖尿病,也为预防和治疗这些疾病提供了新的方法。

原始出处:

Zhao, Y., Stankovic, S., Koprulu, M. et al. GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health. Nat Commun 12, 4178 (2021). https://doi.org/10.1038/s41467-021-24504-y.

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