Abstract

Male infertility is a heterogeneous condition of largely unknown etiology that affects at least 7% of men worldwide. Classical genetic approaches and emerging next-generation sequencing studies support genetic variants as a frequent cause of male infertility. Meanwhile, the barriers to transmission of this disease mean that most individual genetic cases will be rare, but because of the large percentage of the genome required for spermatogenesis, the number of distinct causal mutations is potentially large. Identifying bona fide causes of male infertility thus requires advanced filtering techniques to select for high-probability candidates, including the ability to test causality in animal models. The mouse remains the gold standard for defining the genotype–phenotype connection in male fertility. Here, we present a best practice guide consisting of (a) major points to consider when interpreting next-generation sequencing data performed on infertile men, and, (b) a systematic strategy to categorize infertility types and how they relate to human male infertility. Phenotyping infertility in mice can involve investigating the function of multiple cell types across the testis and epididymis, as well as sperm function. These findings will feed into the diagnosis and treatment of male infertility as well as male health broadly.

中文翻译：

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候选雄性不育突变体的高分辨率表型分析框架：从人类到小鼠。

摘要

男性不育症是一种病因不明的异质性疾病，影响全球至少 7% 的男性。经典遗传方法和新兴的下一代测序研究支持遗传变异是男性不育的常见原因。同时，这种疾病传播的障碍意味着大多数个体遗传病例将很少见，但由于精子发生所需的基因组比例很大，不同的因果突变的数量可能很大。因此，识别男性不育的真正原因需要先进的过滤技术来选择高概率候选者，包括在动物模型中测试因果关系的能力。小鼠仍然是定义男性生育力中基因型-表型联系的金标准。这里，我们提出了一个最佳实践指南，其中包括 (a) 在解释对不育男性进行的下一代测序数据时要考虑的要点，以及 (b) 对不育类型进行分类以及它们与人类男性不育的关系的系统策略。小鼠不育症的表型分析可能涉及研究睾丸和附睾中多种细胞类型的功能，以及精子功能。这些发现将广泛用于男性不育症的诊断和治疗以及男性健康。小鼠不育症的表型分析可能涉及研究睾丸和附睾中多种细胞类型的功能，以及精子功能。这些发现将广泛用于男性不育症的诊断和治疗以及男性健康。小鼠不育症的表型分析可能涉及研究睾丸和附睾中多种细胞类型的功能，以及精子功能。这些发现将广泛用于男性不育症的诊断和治疗以及男性健康。