Peking University
Center for Bioinformatics
Transporters are essential in homeostatic exchange of endogenous and exogenous substances at the systematic, organic, cellular, and subcellular levels. Gene mutations of transporters are often related to pharmacogenetics traits. Recent... more
Transporters are essential in homeostatic exchange of endogenous and exogenous substances at the systematic, organic, cellular, and subcellular levels. Gene mutations of transporters are often related to pharmacogenetics traits. Recent developments in high throughput technologies on genomics, transcriptomics and proteomics allow in depth studies of transporter genes in normal cellular processes and diverse disease conditions. The flood of high throughput data have resulted in urgent need for an updated knowledgebase with curated, organized, and annotated human transporters in an easily accessible way. Using a pipeline with the combination of automated keywords query, sequence similarity search and manual curation on transporters, we collected 1,555 human non-redundant transporter genes to develop the Human Transporter Database (HTD) (http://htd.cbi.pku.edu.cn). Based on the extensive annotations, global properties of the transporter genes were illustrated, such as expression patterns and polymorphisms in relationships with their ligands. We noted that the human transporters were enriched in many fundamental biological processes such as oxidative phosphorylation and cardiac muscle contraction, and significantly associated with Mendelian and complex diseases such as epilepsy and sudden infant death syndrome. Overall, HTD provides a well-organized interface to facilitate research communities to search detailed molecular and genetic information of transporters for development of personalized medicine.
- by Adam Yongxin Ye and +2
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Cas9/CRISPR has been reported to efficiently induce targeted gene disruption and homologous recombination in both prokaryotic and eukaryotic cells. Thus, we developed a Guide RNA Sequence Design Platform for the Cas9/CRISPR silencing... more
Cas9/CRISPR has been reported to efficiently induce targeted gene disruption and homologous recombination in both prokaryotic and eukaryotic cells. Thus, we developed a Guide RNA Sequence Design Platform for the Cas9/CRISPR silencing systemfor model organisms. The platform is easy to use for gRNA design with input query sequences. It finds potential targets by PAM and ranks them according to factors including uniqueness, SNP, RNA secondary structure, and AT content. The platform allows users to upload and share their experimental results. In addition,most guide RNA sequences from published papers have been put into our database.
- by Adam Yongxin Ye and +1
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- CRISPR-Cas9 system
Postzygotic single-nucleotide mutations (pSNMs) have been studied in cancer and a few other overgrowth human disorders at whole-genome scale and found to play critical roles. However, in clinically unremarkable individuals, pSNMs have... more
Postzygotic single-nucleotide mutations (pSNMs) have been studied in cancer and a few other overgrowth human disorders at whole-genome scale and found to play critical roles. However, in clinically unremarkable individuals, pSNMs have never been identified at whole-genome scale largely due to technical difficulties and lack of matched control tissue samples, and thus the genome-wide characteristics of pSNMs remain unknown. We developed a new Bayesian-based mosaic genotyper and a series of effective error filters, using which we were able to identify 17 SNM sites from ~80× whole-genome sequencing of peripheral blood DNAs from three clinically unremarkable adults. The pSNMs were thoroughly validated using pyrosequencing, Sanger sequencing of individual cloned fragments, and multiplex ligation-dependent probe amplification. The mutant allele fraction ranged from 5%-31%. We found that C→T and C→A were the predominant types of postzygotic mutations, similar to the somatic mutation profile in tumor tissues. Simulation data showed that the overall mutation rate was an order of magnitude lower than that in cancer. We detected varied allele fractions of the pSNMs among multiple samples obtained from the same individuals, including blood, saliva, hair follicle, buccal mucosa, urine, and semen samples, indicating that pSNMs could affect multiple sources of somatic cells as well as germ cells. Two of the adults have children who were diagnosed with Dravet syndrome. We identified two non-synonymous pSNMs in SCN1A, a causal gene for Dravet syndrome, from these two unrelated adults and found that the mutant alleles were transmitted to their children, highlighting the clinical importance of detecting pSNMs in genetic counseling.
- by Adam Yongxin Ye and +1
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- Somatic Mosaicism
Background: Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and interaction, and restrictive and repetitive patterns of behavior, interests or activities. This study aimed to analyze trends... more
Background: Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and interaction, and restrictive and repetitive patterns of behavior, interests or activities. This study aimed to analyze trends in ASD diagnosis and intervention in 20 years of data from the Beijing Stars and Rain Education Institute for Autism (SR), the first autism intervention center in mainland China, and from a recent survey of members of the Heart Alliance, an industry association of autism intervention centers in China.
Methods: We analyzed the registration data at the SR from 1993 to 2012 for a total of 2,222 children who had a parent-reported diagnosis of ASD and 612 of ‘autistic tendencies’. Most of the children who were the primary focus of our analyses were age six and under. We also analyzed results of a survey we conducted in 2013 of 100 member centers of the Heart Alliance. Generalized Estimating Equations, multiple linear regression and the Mann-Whitney test were used for data analysis. Statistically significant findings are reported here.
Results: The number of hospitals where SR children received their diagnosis increased from several in the early 1990s to 276 at present. The proportion of ‘autistic tendencies’ diagnosis increased 2.04-fold from 1998 to 2012 and was higher for children diagnosed at a younger age. The mean age at first diagnosis of ASD or ‘autistic tendencies’ decreased by 0.27 years every decade. A higher level of parental education was statistically significantly associated with an earlier diagnosis of the child. The mean parental age at childbirth increased by about 1.48 years per decade, and the mean maternal age was 1.40 and 2.10 years higher than that in the national population censuses of 2000 and 2010, respectively. At the time of the survey 3,957 children with ASD were being trained at the 100 autism intervention centers. Ninety-seven of these centers opened after the year 2000. Economically underdeveloped regions are still underserved.
Conclusions: This study revealed encouraging trends and remaining challenges in ASD diagnosis and intervention among children at the SR over the past 20 years and the 100 autism intervention centers in China at present.
Methods: We analyzed the registration data at the SR from 1993 to 2012 for a total of 2,222 children who had a parent-reported diagnosis of ASD and 612 of ‘autistic tendencies’. Most of the children who were the primary focus of our analyses were age six and under. We also analyzed results of a survey we conducted in 2013 of 100 member centers of the Heart Alliance. Generalized Estimating Equations, multiple linear regression and the Mann-Whitney test were used for data analysis. Statistically significant findings are reported here.
Results: The number of hospitals where SR children received their diagnosis increased from several in the early 1990s to 276 at present. The proportion of ‘autistic tendencies’ diagnosis increased 2.04-fold from 1998 to 2012 and was higher for children diagnosed at a younger age. The mean age at first diagnosis of ASD or ‘autistic tendencies’ decreased by 0.27 years every decade. A higher level of parental education was statistically significantly associated with an earlier diagnosis of the child. The mean parental age at childbirth increased by about 1.48 years per decade, and the mean maternal age was 1.40 and 2.10 years higher than that in the national population censuses of 2000 and 2010, respectively. At the time of the survey 3,957 children with ASD were being trained at the 100 autism intervention centers. Ninety-seven of these centers opened after the year 2000. Economically underdeveloped regions are still underserved.
Conclusions: This study revealed encouraging trends and remaining challenges in ASD diagnosis and intervention among children at the SR over the past 20 years and the 100 autism intervention centers in China at present.
The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to... more
The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered “de novo” by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low-level mosaicism in parents of families with seemingly “de novo” mutations will allow for better informed genetic counseling.