In search of the genetic variants of human sex ratio at birth: Was Fisher wrong about sex ratio evolution?

The human sex ratio (fraction of males) at birth is close to 0.5 at the population level, an observation commonly explained by Fisher's principle. However, past human studies yielded conflicting results regarding the existence of sex ratio-influencing mutations-a prerequisite to Fisher’s principle, raising the question of whether the nearly even population sex ratio is instead dictated by the random X/Y chromosome segregation in male meiosis. Here we show that, because a person’s offspring sex ratio (OSR) has an enormous measurement error, a gigantic sample is required to detect OSR-influencing genetic variants. Conducting a UK Biobank-based genome-wide association study that is more powerful than previous studies, we detect an OSR-associated genetic variant, which awaits verification in independent samples. Given the abysmal precision in measuring OSR, it is unsurprising that the estimated heritability of OSR is effectively zero. We further show that OSR’s estimated heritability would ..., GWAS: When conducting the GWAS in the UKB, we did not simply use the sibling sex ratio as the trait, because of the difficulty in accounting for different estimation errors of the sibling sex ratio for different families as a result of the variation in family size. For example, individual A has one brother and zero sister, while individual B has four brothers and one sister. Although A has a higher sibling sex ratio than B, B’s siblings obviously provide stronger evidence for a male-biased sibling sex ratio than A’s siblings. To properly weigh the data by the family size, we considered the birth of each sibling as an independent event. In the above example, we would associate A’s genotype with one male birth and associate B’s genotype with four male births and one female birth. In GWAS, a male birth is coded as 1 and a female birth is coded as 0. The UKB participants have a total of 873,715 full siblings, leading to an unprecedented statistical power. In our GWAS in the UKB, we i..., , # In search of the genetic variants of human sex ratio at birth: Was Fisher wrong about sex ratio evolution? [https://doi.org/10.5061/dryad.vdncjsz43](https://doi.org/10.5061/dryad.vdncjsz43) ## Description of the data and file structure GWAS summary statistics and simulation data of the paper \"In search of the genetic variants of human sex ratio at birth: Was Fisher wrong about sex ratio evolution?\" ### Files and variables #### File: Human\_sex\_ratio\_scrit.zip **Description:** Scripts for the project. For descriptions of each script files, see README.md in the zip file or [https://github.com/song88180/Human_sex_ratio](https://github.com/song88180/Human_sex_ratio) #### File: GWAS\_OSR\_cov\_logistic.tsv **Description:** GWAS summary statistics of offspring sex ratio. Cells with \"NA\" means the value is not available. ##### Variables * CHROM: chromosome number * POS: SNP position (GRCh37) * ID: rsid of the SNP * REF: reference allele * ALT: alternative allele * P: P-value * t...人群层面的出生人口性别比（男性占比）接近0.5，这一观测结果通常用费希尔原理（Fisher's principle）来解释。然而，过往针对人类的研究在“是否存在影响性别比的突变”这一问题上得出了相互矛盾的结论——而这一突变的存在正是费希尔原理成立的前提，这也引发了一个疑问：近乎均衡的人群出生性别比，是否实际上是由男性减数分裂时X/Y染色体的随机分离所决定的？ 本研究表明，由于个体的后代性别比（Offspring Sex Ratio, OSR）存在极大的测量误差，因此需要极其庞大的样本量才能检测出影响OSR的遗传变异。我们开展了一项基于英国生物样本库（UK Biobank, UKB）的全基因组关联研究（Genome-Wide Association Study, GWAS），其统计效力优于以往同类研究，并成功检测到一个与OSR相关的遗传变异，该变异有待在独立样本中进行验证。鉴于OSR的测量精度极低，OSR的估计遗传力实际为0也就不足为奇了。我们进一步证明，OSR的估计遗传力将……，GWAS： 在英国生物样本库中开展GWAS时，我们并未直接使用同胞性别比作为表型，这是因为不同家庭的家族规模存在差异，难以对不同家庭的同胞性别比的估计误差进行校正。例如，个体A有1个兄弟、0个姐妹，而个体B有4个兄弟、1个姐妹。尽管个体A的同胞性别比高于个体B，但个体B的同胞显然比个体A的同胞能提供更有力的男性偏倚同胞性别比证据。为了基于家族规模对数据进行合理加权，我们将每一次同胞出生视为独立事件。在上述例子中，我们会将个体A的基因型与1次男性出生相关联，将个体B的基因型与4次男性出生和1次女性出生相关联。在GWAS分析中，男性出生编码为1，女性出生编码为0。英国生物样本库参与者共计拥有873715名全同胞，这带来了前所未有的统计效力。在我们的英国生物样本库GWAS中，我们i…… # 《寻找人类出生性别比的遗传变异：费希尔在性别比演化研究中是否有误？》 [https://doi.org/10.5061/dryad.vdncjsz43](https://doi.org/10.5061/dryad.vdncjsz43) ## 数据与文件结构说明 本数据集对应上述论文的全基因组关联研究汇总统计数据与模拟数据。 ### 文件与变量 #### 文件：Human_sex_ratio_scrit.zip **描述**：本项目所用的脚本文件。各脚本文件的详细说明请参阅压缩包内的README.md，或访问链接[https://github.com/song88180/Human_sex_ratio](https://github.com/song88180/Human_sex_ratio)。 #### 文件：GWAS_OSR_cov_logistic.tsv **描述**：后代性别比的全基因组关联研究汇总统计数据。单元格中标记“NA”表示该值不可用。 ##### 变量说明 * CHROM：染色体编号 * POS：单核苷酸多态性（Single Nucleotide Polymorphism, SNP）的位置（GRCh37参考基因组版本） * ID：SNP的rs号（rsid） * REF：参考等位基因 * ALT：备选等位基因 * P：P值 * t……