Biology subjects

Fang, Z.-H.

Publications and source records attributed to Fang, Z.-H..

8 recordsLinked to original sources

bioRxiv2026

Massive-scale single-nucleus multi-omics identifies novel rare noncoding drivers of Parkinson's disease

Most genetic variants contributing to complex diseases reside in the noncoding genome. While common variants uncovered by genome-wide association studies often fail to explain much of the observed heritability of these diseases, rare variants often have higher effect sizes and cumulatively explain a larger portion of heritability. However, rare variants, particularly rare noncoding variants, have remained under-characterized largely due to the difficulties of accurately predicting variant functionality at scale, given that each individual carries an average of [~]10,000 rare variants. Here, we generated multi-omic data from >3.3 million nuclei sampled from five brain regions across a cohort of 80 individuals with Parkinsons disease (PD) and 21 neurologically normal control individuals with matched 30x whole-genome sequencing. We use this data to identify cell type-specific features of PD, map cell type-specific chromatin accessibility and expression quantitative trait loci, and train machine learning models to predict the effect of variants on gene regulation. We identify rare noncoding variants statistically associated with sporadic PD and extend our approaches to predict drivers of familial PD of unknown genetic origin. Our results underscore the significance of rare noncoding variants in complex diseases and provide a roadmap for applying similar approaches in other disease systems.

genetics↗

bioRxiv2024

GenoTools: An Open-Source Python Package for Efficient Genotype Data Quality Control and Analysis

GenoTools, a Python package, streamlines population genetics research by integrating ancestry estimation, quality control (QC), and genome-wide association studies (GWAS) capabilities into efficient pipelines. By tracking samples, variants, and quality-specific measures throughout fully customizable pipelines, users can easily manage genetics data for large and small studies. GenoTools "Ancestry" module renders highly accurate predictions, allowing for high-quality ancestry-specific studies, and enables custom ancestry model training and serialization, specified to the users genotyping or sequencing platform. As the genotype processing engine that powers several large initiatives, including the NIHs Center for Alzheimers and Related Dementias (CARD) and the Global Parkinsons Genetics Program (GP2). GenoTools was used to process and analyze the UK Biobank and major Alzheimers Disease (AD) and Parkinsons Disease (PD) datasets with over 400,000 genotypes from arrays and 5000 sequences and has led to novel discoveries in diverse populations. It has provided replicable ancestry predictions, implemented rigorous QC, and conducted genetic ancestry-specific GWAS to identify systematic errors or biases through a single command. GenoTools is a customizable tool that enables users to efficiently analyze and scale genotype data with reproducible and scalable ancestry, QC, and GWAS pipelines.

genomics↗

bioRxiv2021

A 1-bp deletion in bovine QRICH2 causes low sperm count and immotile sperm with multiple morphological abnormalities

BackgroundSemen quality and male fertility are monitored in artificial insemination bulls to ensure high insemination success rates. Only ejaculates that fulfill minimum quality requirements are processed and eventually used for artificial inseminations. We examined 70,990 ejaculates from 1343 Brown Swiss bulls to identify bulls from which all ejaculates were rejected due to low semen quality. This procedure identified a bull that produced twelve ejaculates with an aberrantly low number of sperm (0.2{+/-}0.2 x 109 sperm per ml) which were mostly immotile due to multiple morphological abnormalities. ResultsThe genome of the bull was sequenced at 12-fold coverage to investigate a suspected genetic cause. Comparing the sequence variant genotypes of the bull with those from 397 fertile bulls revealed a 1-bp deletion in the coding sequence of QRICH2 encoding glutamine rich 2 as a compelling candidate causal variant. The 1-bp deletion causes a frameshift in translation and induces a premature termination codon (ENSBTAP00000018337.1:p.Cys1644AlafsTer52). The analysis of testis transcriptomes from 76 bulls showed that the transcript with the premature termination codon is subjected to nonsense-mediated mRNA decay. The 1-bp deletion resides on a 675 kb haplotype spanning 181 SNPs from the Illumina BovineHD Bead chip. The haplotype segregates at a frequency of 5% in the Brown Swiss cattle population. This analysis also identified another bull that carried the 1-bp deletion in the homozygous state. Semen analyses from the second bull confirmed low sperm concentration and immotile sperm with multiple morphological abnormalities primarily affecting the sperm flagellum and, to a lesser extent, the sperm head. ConclusionsA recessive loss-of-function allele of bovine QRICH2 likely causes low sperm concentration and immotile sperm with multiple morphological abnormalities. Routine sperm analyses unambiguously identify homozygous bulls. A direct gene test can be implemented to monitor the frequency of the undesired allele in cattle populations.

genetics↗

bioRxiv2021

Novel functional sequences uncovered through a bovine multi-assembly graph

Linear reference genomes are typically assembled from single individuals. They are unable to reflect the genetic diversity of populations and lack millions of bases. To overcome such limitations and make non-reference sequences amenable to genetic investigations, we build a multi-assembly graph from six reference-quality assemblies from taurine cattle and their close relatives. We uncover 70,329,827 bases that are missing in the bovine linear reference genome. The missing sequences encode novel transcripts that are differentially expressed between individual animals. Reads which were previously poorly or unmapped against the bovine reference genome now align accurately to the non-reference sequences. We show that the non-reference sequences contain polymorphic sites that segregate within and between breeds of cattle. Our efforts to uncover novel functional sequences from a multi-assembly graph pave the way towards the transition to a more representative bovine reference genome.

genomics↗

bioRxiv2020

Deletion of an intronic polypyrimidine tract of porcine DNAH17 perturbs splicing and causes defective sperm flagella

Artificial insemination in pig (Sus scrofa domesticus) breeding involves the evaluation of the semen quality of breeding boars. Ejaculates that fulfill predefined quality requirements are processed, diluted and used for inseminations. Within short time, eight Swiss Large White boars producing immotile sperm that had multiple morphological abnormalities of the sperm flagella were noticed at a semen collection center. The eight boars were inbred on a common ancestor suggesting that the novel sperm flagella defect is a recessive trait. Transmission electron microscopy cross-sections revealed that the immotile sperm had disorganized flagellar axonemes. Haplotype-based association testing involving microarray-derived genotypes at 41,094 SNPs of six affected and 100 fertile boars yielded strong association (P=4.22 x 10-15) at chromosome 12. Autozygosity mapping enabled us to pinpoint the causal mutation on a 1.11 Mb haplotype located between 3,473,632 and 4,587,759 bp. The haplotype carries an intronic 13-bp deletion (Chr12:3,556,401-3,556,414 bp) that is compatible with recessive inheritance. The 13-bp deletion excises the polypyrimidine tract upstream exon 56 of DNAH17 (XM_021066525.1:c.8510-17_8510-5del) encoding dynein axonemal heavy chain 17. Transcriptome analysis of the testis of two affected boars revealed that the loss of the polypyrimidine tract causes exon skipping which results in the in-frame loss of 89 amino acids from DNAH17. Disruption of DNAH17 impairs the assembly of the flagellar axoneme and manifests in multiple morphological abnormalities of the sperm flagella. Direct gene testing may now be implemented to monitor the defective allele in the Swiss Large White population and prevent the frequent manifestation of a sterilizing sperm tail disorder in breeding boars.

genomics↗

bioRxiv2020

A 63-bp insertion in exon 2 of the porcine KIF21A gene is associated with arthrogryposis multiplex congenita

Arthrogryposis multiplex congenita (AMC) is a recessively inherited fatal disease detected almost 20 years ago in the Swiss Large White pig population. A diagnostic marker test enabled the identification of carrier animals, but the underlying causal mutation remains unknown. To identify the mutation underlying AMC, we collected whole-genome genotyping and sequencing data for 11 affected piglets and 23 healthy pigs. Haplotype-based case-control association testing using 47,829 SNPs confirmed that AMC maps to SSC5 (P = 9.4 x10-13). Subsequent autozygosity mapping revealed a common 6.06 Mb region (from 66,757,970 to 72,815,151 bp) of extended homozygosity in 11 piglets affected by AMC. We detected a 63-bp insertion in the second exon of KIF21A gene encoding Kinesin Family Member 21A using whole-genome sequences of a carrier boar, two of its affected and two heterozygous piglets. This insertion was compatible with the recessive inheritance of AMC. The 63-bp insertion likely represents a loss-of-function allele because it is predicted to introduce a premature stop codon in KIF21A gene (p.Val41_Phe42insTer) that truncates 1,614 amino acids ([~] 97%) from the protein. Lack of KIF21A protein is lethal in mice, thus providing additional evidence that a loss-of function allele of KIF21A might cause fatal AMC in pigs. We found that this deleterious allele still segregates at low frequency in the Swiss Large White pig population. The unambiguous detection of carrier animals can now facilitate the eradication of the deleterious allele from the population.

genomics↗

bioRxiv2020

Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility

Cattle are ideally suited to investigate the genetics of male reproduction, because semen quality and fertility are recorded for all ejaculates of artificial insemination bulls. We analysed 26,090 ejaculates of 794 Brown Swiss bulls to assess ejaculate volume, sperm concentration, sperm motility, sperm head and tail anomalies and insemination success. The heritability of the six semen traits was between 0 and 0.26. Genome-wide association testing on 607,511 SNPs revealed a QTL on bovine chromosome 6 that was associated with sperm motility (P = 2.5 x 10-27), head (P = 2.0 x 10-44) and tail anomalies (P = 7.2 x 10-49) and insemination success (P = 9.9 x 10-13). The QTL harbors a recessive allele that compromises semen quality and male fertility. We replicated the effect of the QTL on fertility (P = 7.1 x 10-32) in an independent cohort of 2481 Brown Swiss bulls. The analysis of whole-genome sequencing data revealed that a synonymous variant (BTA6:58373887C>T, rs474302732) in WDR19 encoding WD repeat-containing protein 19 was in linkage disequilibrium with the fertility-associated haplotype. WD repeat-containing protein 19 is a constituent of the intraflagellar transport complex that is essential for the physiological function of motile cilia and flagella. Bioinformatic and transcription analyses revealed that the BTA6:58373887 T-allele activates a cryptic exonic splice site that eliminates three evolutionarily conserved amino acids from WDR19. Western blot analysis demonstrated that the BTA6:58373887 T-allele decreases protein expression. We make the remarkable observation that, in spite of negative effects on semen quality and bull fertility, the BTA6:58373887 T-allele has a frequency of 24 % in the Brown Swiss population. Our findings are the first to uncover a variant that is associated with quantitative variation in semen quality and male fertility in cattle. Author summaryIn cattle farming, artificial insemination is the most commonly used method of breeding. To ensure high fertilization rates, ejaculate quality and insemination success are closely monitored in artificial insemination bulls. We analyse semen quality, insemination success and microarray-called genotypes at more than 600,000 genome-wide SNP markers in 794 bulls to identify a recessive allele that compromises semen quality. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence of WDR19 encoding WD repeat-containing protein 19 that activates a novel exonic splice site. Our results indicate that cryptic splicing in WDR19 is associated with reduced male reproductive performance. This is the first report of a variant that contributes to quantitative variation in bovine semen quality.

genomics↗

bioRxiv2019

Multi-trait meta-analyses reveal 25 quantitative trait loci for economically important traits in Brown Swiss cattle

BackgroundThe Brown Swiss dual-purpose cattle breed is renowned for high milk and protein yield and long productive lifetime under different production conditions. However, little is known about the genetic architecture of those traits because only few genome-wide association studies (GWAS) have been carried out in this breed. Moreover, most GWAS had been performed for single traits, thus preventing insights into potentially existing pleiotropic effects of trait-associated loci. ResultsTo compile a comprehensive catalogue of large-effect QTL segregating in Brown Swiss cattle, we carried out association tests between partially imputed genotypes at 598,016 SNPs and daughter-derived phenotypes for more than 50 economically important traits, including milk production, growth and carcass quality, body conformation, reproduction and calving traits in 4,578 artificial insemination bulls from two cohorts of Brown Swiss cattle (Austrian-German and Swiss populations). Across-cohort multi-trait meta-analyses of the results from the single-trait GWAS revealed 25 quantitative trait loci (QTL; P < 8.36 x 10-8) for economically relevant traits on 17 Bos taurus autosomes (BTA). Evidence of pleiotropy was detected at five QTL located on BTA5, 6, 17, 21 and 25. Of these, two QTL at BTA6:90,486,780 and BTA25:1,455,150 affect a diverse range of economically important traits, including traits related to body conformation, calving, longevity and milking speed. Furthermore, the QTL at BTA6:90,486,780 seems to be a target of ongoing selection as evidenced by an integrated haplotype score of 2.49 and significant changes in allele frequency over the past 25 years, whereas either no or only weak evidence of selection was detected at all other QTL. ConclusionsOur findings provide a comprehensive overview of QTL segregating in Brown Swiss cattle. Detected QTL explain between 2 and 10% of the variation in the daughter-derived phenotypes and thus may be considered as the most important QTL segregating in the Brown Swiss cattle breed. Multi-trait association testing boosts the power to detect pleiotropic QTL and assesses the full spectrum of phenotypes that are affected by trait-associated variants.

genomics↗