Kun Xia | Search bioRxiv

bioRxiv2016

Han Chinese males with surnames related to the legendary Huang and Yan Emperors are enriched for the top two Neolithic super-grandfather Y chromosomes O3a2c1a and O3a1c, respectively

Recent studies found three Neolithic super-grandfather Y haplotypes among Han Chinese, consistent with the legend of Yan and Huang Emperors. Individuals of royal and noble ancestry or high social economic status (SES) are known to practice assortative mating and consanguineous marriages, which can produce offspring of both higher and lower than average fitness. However, the roles of the super-grandfather Y haplotypes and their descendant lines in history, fitness, and the male biased autism spectrum disorder (ASD) remain unknown. Here we show a link between the super-grandfathers and the legend of Yan-Huang Emperors and between their descendant haplotypes and ASD. We found that subjects carrying the O3a1c and O3a2c1a super-grandfather haplotypes were enriched with Yan and Huang related surnames, respectively, in two independent datasets of 1564 and 772 male Han subjects. We identified high and low SES descendant haplotypes of the super-grandfathers using the Han dataset of the 1000 genomes project based on two criteria: more descendant branches and fewer mutations before star-like expansions. By genotyping 505 fathers of ASD affected male children from the Autism Clinical and Genetic Resources in China with surnames either closely related to Huang (Ying group) or less related (Ji group), we found the high SES haplotypes within the O3a2c1a clade at [~]2 fold lower (odds ratio 2.05, 95% CI 1.28-3.26, P=0.0026) while the low SES haplotypes at [~]2 fold higher frequency (odds ratio 1.92, 95% CI 1.01-3.64, P = 0.046) in the fathers relative to 505 normal subjects. The fraction of low SES haplotypes was greater than that of high SES in ASD fathers of the Ying group, in contrast to Ying controls or the Ji fathers and Ji controls. Consistently, analysis of 2366 ASD affected children showed higher male to female ratio for Ying versus Ji group (6.52 +/-1.11 v 4.59 +/-0.41, P = 0.028, one tailed). These results provide evidence for the Yan-Huang legend and suggest a role for Y in ASD.

Genetics↗

bioRxiv2016

Contribution of de novo non-coding mutations to autism and identification of risk genes from whole-genome sequencing of affected families

Analysis of de novo mutations (DNMs) from sequencing data of nuclear families has identified risk genes for many complex diseases, including multiple neurodevelopmental and psychiatric disorders. Most of these efforts have focused on mutations in protein-coding sequences. Evidence from genome-wide association studies (GWAS) strongly suggests that variants important to human diseases often lie in non-coding regions. Extending DNM-based approaches to non-coding sequences is, however, challenging because the functional significance of non-coding mutations is difficult to predict. We propose a new statistical framework for analyzing DNMs from whole-genome sequencing (WGS) data. This method, TADA-Annotations (TADA-A), is a major advance of the TADA method we developed earlier for DNM analysis in coding regions. TADA-A is able to incorporate many functional annotations such as conservation and enhancer marks, learn from data which annotations are informative of pathogenic mutations and combine both coding and non-coding mutations at the gene level to detect risk genes. It also supports meta-analysis of multiple DNM studies, while adjusting for study-specific technical effects. We applied TADA-A to WGS data of [~]300 autism family trios across five studies, and discovered several new autism risk genes. The software is freely available for all research uses.

Genetics↗