Biology subjects

Wang, G.-D.

Publications and source records attributed to Wang, G.-D..

8 recordsLinked to original sources

bioRxiv2024

Determinants of de novo mutations in extended pedigrees of 43 dog breeds

Intensive breeding of dogs has had dramatic effects on genetic variants underlying phenotypes. To investigate whether this also affected mutation rates, we deep-sequenced pedigrees from 43 different dog breeds representing 404 trios. We find that the mutation rate is remarkably stable across breeds and is predominantly influenced by variation in parental ages. The effect of paternal age per year on mutation rates is approximately 1.5 times greater in dogs than humans, suggesting that the elevated yearly mutation rate in dogs is only partially attributed to earlier reproduction. While there is no significant effect of breeds on the overall mutation rate, larger breeds accumulate proportionally more mutations earlier in development than small breeds. Interestingly, we find a 2.6 times greater mutation rate in CG Islands (CGIs) compared to the remaining genome in dogs, unlike humans, where there is no difference. Our estimated rate of mutation by recombination in dogs is more than 10 times larger than estimates in humans. We ascribe these to the fact that canids have lost PRDM9-directed recombination and draw away recombination from CGIs. In conclusion, our study sheds light on stability of mutation processes and disparities in mutation accumulation rates reflecting the influence of differences in growth patterns among breeds, and the impact of PRDM9 gene loss on the de novo mutations of canids.

evolutionary biology↗

bioRxiv2022

Single-nuclei transcriptomics of dog hippocampus reveals the distinct cellular mechanism of domestication

The process of dog domestication leads to dramatic differences in behavioral traits compared to grey wolves. A class of putative positively selected genes is related to learning and memory, for instance, long-term potentiation and long-term depression. In this study, we constructed a single-nuclei transcriptomic atlas of the dog hippocampus to illustrate its cell types, cell lineage, and molecular features. Using the transcriptomes of 105,057 single-nuclei from the hippocampus of a Beagle dog, we identified 26 cell clusters and a putative trajectory of oligodendrocyte development. Comparative analysis revealed a significant convergence between dog differentially expressed genes (DEGs) and putative positively selected genes (PSGs). 40 putative PSGs were DEGs in the glutamatergic neurons, especially in the cluster 14, which is related to the regulation of nervous system development. In summary, this study provided a blueprint to understand the cellular mechanism of dog domestication.

evolutionary biology↗

bioRxiv2021

Dog10K_Boxer_Tasha_1.0: A long-read assembly of the dog reference genome

The domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named "Tasha" initially published in 2005. Derived from a Sanger whole genome shotgun sequencing approach coupled with limited clone-based sequencing, the initial assembly and subsequent updates have served as the predominant resource for canine genetics for 15 years. While the initial assembly produced a good quality draft, as with all assemblies produced at the time it contained gaps, assembly errors and missing sequences, particularly in GC-rich regions, which are found at many promoters and in the first exons of protein coding genes. Here we present Dog10K_Boxer_Tasha_1.0, an improved chromosome-level highly contiguous genome assembly of Tasha created with long-read technologies, that increases sequence contiguity >100-fold, closes >23,000 gaps of the Canfam3.1 reference assembly and improves gene annotation by identifying >1200 new protein-coding transcripts. The assembly and annotation are available at NCBI under the accession GCF_000002285.5.

genomics↗

bioRxiv2021

Best practices for analyzing imputed genotypes from low-pass sequencing in dogs

Although DNA array-based approaches for genome wide association studies (GWAS) permit the collection of thousands of low-cost genotypes, it is often at the expense of resolution and completeness, as SNP chip technologies are ultimately limited by SNPs chosen during array development. An alternative low-cost approach is low-pass whole genome sequencing (WGS) followed by imputation. Rather than relying on high levels of genotype confidence at a set of select loci, low-pass WGS and imputation relies on the combined information from millions of randomly sampled low confidence genotypes. To investigate low-pass WGS and imputation in the dog, we assessed accuracy and performance by downsampling 97 high-coverage (>15x) WGS datasets from 51 different breeds to approximately 1x coverage, simulating low-pass WGS. Using a reference panel of 676 dogs from 91 breeds, genotypes were imputed from the downsampled data and compared to a truth set of genotypes generated from high coverage WGS. Using our truth set, we optimized a variant quality filtering strategy that retained approximately 80% of 14M imputed sites and lowered the imputation error rate from 3.0% to 1.5%. Seven million sites remained with a MAF > 5% and an average imputation quality score of 0.95. Finally, we simulated the impact of imputation errors on outcomes for case-control GWAS, where small effect sizes were most impacted and medium to large effect sizes were minorly impacted. These analyses provide best practice guidelines for study design and data post-processing of low-pass WGS imputed genotypes in dogs.

genomics↗

bioRxiv2021

Homo-harringtonine (HHT) - A highly effective drug against coronaviruses and the potential for large-scale clinical applications

In the search for treatment schemes of COVID-19, we start by examining the general weakness of coronaviruses and then identify approved drugs attacking that weakness. The approach, if successful, should identify drugs with a specific mechanism that is at least as effective as the best drugs proposed and are ready for clinical trials. All coronaviruses translate their non-structural proteins ([~]16) in concatenation, resulting in a very large super-protein. Homo-harringtonine (HHT), which has been approved for the treatment of leukemia, blocks protein elongation very effectively. Hence, HHT can repress the replication of many coronaviruses at the nano-molar concentration. In two mouse models, HHT clears SARS-CoV-2 in 3 days, especially by nasal dripping of 40 ug per day. We also use dogs to confirm the safety of HHT delivered by nebulization. The nebulization scheme could be ready for large-scale applications at the onset of the next epidemics. For the current COVID-19, a clinical trial has been approved by the Ditan hospital of Beijing but could not be implemented for want of patients. The protocol is available to qualified medical facilities.

microbiology↗

bioRxiv2019

Genomic approaches reveal an endemic sub-population of gray wolves in Southern China

Despite being one of the most widely distributed terrestrial mammals, the history of gray wolves (Canis lupus) in China is not well understood as their habitats have been destroyed with growing economic development. Using six specimens from wolf skins in Chinese Natural History museums, we sequenced their genome using a modified ancient DNA procedure. Using whole genome sequence analysis, we showed that gray wolves from Southern China (SC) derive from a single lineage, distinct from gray wolves from the Tibetan Plateau (Canis lupus chanco) and Northern China, suggesting that SC gray wolves may form a distinct sub-population. Of SC gray wolves, one wolf from Zhejiang carries a genetic component from a canid that must have diverged earlier from other wolves than jackals did, perhaps through gene flow from a population related to or further diverged from wolves than the dhole, a species distributed in Southern China and Southeast Asia. This may indicate that interspecific gene flow likely played an important role in shaping the speciation patterns and population structure in the genus Canis. Our study is the first to survey museum genomes of gray wolves from Southern China, revealing the presence of an endemic population with ancient interspecific gene flow from a population related to the dhole, and highlighting how sequencing the paleogenome from museum specimens can help us to study extinct species.

evolutionary biology↗

bioRxiv2018

Genomic analysis of dingoes identifies genomic regions under reversible selection during domestication and feralization

Dingoes (Canis dingo) are wild canids living in Australia. They have lived isolated from both the wild and the domestic ancestor and are a unique model for studying feralization, the process in which a domestic species escapes human control, adapts to the wild, and diverges from the domestic ancestor into a genetically distinct population. Here, we sequenced the genomes of 10 dingoes and 2 New Guinea Singing Dogs, to study the origins and feralization process of the dingo. Phylogenetic and demographic analyses show that dingoes originate from domestic dogs in southern East Asia, which migrated via Island Southeast Asia to reach Australia 4300-5000 years ago, and subsequently diverged into a genetically distinct population. Selection analysis identified 99 positively selected genes enriched in starch and fat metabolism pathways, indicating a diet change during feralization of dingoes. Interestingly, we found that 14 genes have shifted allele frequencies compared to dogs but not compared to wolves. This suggests that the selection affecting these genes during domestication of the wolf was reversed in the feralization process. One of these genes, ARHGEF7, may promote the formation of neural spine and synapses in hippocampal neurons. Functional assays showed that an A to G mutation in ARHGEF7, located in a transcription factor-binding site, decreases the endogenous expression. This suggests that ARHGEF7 may have been under selection for behavioral adaptations related to the transitions in environment both from wild to domestic and from domestic back to wild. Our results indicate that adaptation to domestication and feralization primarily affected different genomic regions, but that some genes, related to neurodevelopment, metabolism and reproduction, may have been reversibly affected in the two processes.

genomics↗

bioRxiv2018

Canine transmissible venereal tumor genome reveals ancient introgression from coyotes to arctic sled dogs

Dear Editor,\n\nAncient genome-sequencing studies have extensively refined our understanding of the genetic histories and adaptive evolution of humans1, as well as the domestic process of livestock and crops2. Recent studies about ancient and modern canids all indicate that canids have intricate histories, and lots of canine populations disappeared during evolution3-6. Thus, ancient genomes from canine fossils are in high demand to clarify canine evolution and the processes leading to dog domestication. Canine transmissible venereal tumor (CTVT), the oldest known somatic cell line, is a living fossil, originating from cancer cells transmitted from a host to other canids during the mating process7. Clonal origin analyses hints that the original dog infected with CTVT (CTVT founder) came from an ancient sled dog or wolf population ...

evolutionary biology↗