MTM: a multi-task learning framework to predict individualized tissue gene expression profiles.

MOTIVATION: Transcriptional profiles of diverse tissues provide significant insights in both fundamental and translational researches, while transcriptome information is not always available for tissues that require invasive biopsies. Alternatively, predicting tissue expression profiles from more accessible "surrogate" samples, especially blood transcriptome, has become a promising strategy when invasive procedures are not practical. However, existing approaches ignore tissue-shared intrinsic relevance, inevitably limiting predictive performance. RESULTS: We propose a unified deep learning-based multi-task learning framework, multi-tissue transcriptome mapping (MTM), enabling the prediction of individualized expression profiles from any available tissue of an individual. By jointly leveraging individualized cross-tissue information from reference samples through multi-task learning, MTM achieves superior sample-level and gene-level performance on unseen individuals. With the high prediction accuracy and the ability to preserve individualized biological variations, MTM could facilitate both fundamental and clinical biomedical research. AVAILABILITY AND IMPLEMENTATION: MTM's code and documentation are available upon publication on GitHub (https://github.com/yangence/MTM).

Genetic analysis of type 2 tri-allelic pattern at TPOX locus in the Chinese Han population.

Tri-allelic patterns can occasionally be observed during the profiling of short tandem repeats (STRs) in routine forensic practice. In previous studies, the Type 2 tri-allelic pattern at TPOX has been widely studied in African and Brazilian populations. In this study, we investigated the incidence, rearrangement, and inheritance of the Type 2 tri-allelic pattern at the TPOX locus in a Chinese Han population. The frequency of the Type 2 pattern at TPOX was approximately 0.0189%, and the major extra allele was allele 11 in the Chinese Han population. Two major allelic combinations, 8/11 and 11/12, were observed, which are different from the configuration of that in both African and Brazilian populations. Tight linkage between alleles 11 and 12 was observed in the majority of the Type 2 pattern at TPOX in the Chinese Han population, while the location of the extra copy on chromosome 2 was validated, which shows an identical ancestral origin. The excess allelic combination 8/11 implies a homogeneous origin and tight linkage relationship. However, the rearrangement in the Type 2 pattern with the 8/11 allelic combination remained unknown. Altogether, these results show the configuration of the Type 2 tri-allelic pattern at the TPOX locus in the Chinese Han population, which will assist in the understanding of the Type 2 tri-allelic pattern at the TPOX locus in the global population.

Development and validation of a custom panel including 183 Y-SNPs for Chinese Y-chromosomal haplogroups dissection using a MALDI-TOF MS system.

Y-chromosome SNP haplogroups exhibit geographic structuring in many populations around the world. Therefore, Y-chromosome haplogroups have been widely used to infer paternal biogeographical ancestry and high-resolution paternal lineage classification. In the present study, we designed a customized panel containing 183 Y-SNPs based on previous studies and evaluated the genotyping performance and repeatability, concordance, sensitivity, and ability of analysing case-type samples using a MALDI-TOF MS platform. The average call rate for duplicate typing of any one SNP in the panel was 97.0%. In the concordance and accuracy study, the results of haplogroup designation obtained from MALDI-TOF MS platform were fully consistent with those obtained from the next-generation sequencing (NGS) platform. The optimal amount of template DNA in the PCR seemed to be 10 ng. However, if less DNA (≥156.25 pg) was available, it was still possible to obtain meaningful haplogroup information. For the application part, this panel could be applied for the detection of blood, semen, and buccal swabs samples. Particularly, blood stain on FTA card samples could be dissected by direct PCR amplification on the MALDI-TOF MS platform. Besides, 371 unrelated male individuals from four Chinese ethnic groups (Han, Hui, Mongolian, and Kazak) were detected using this panel. Total 78 terminal haplogroups were found and the haplogroup diversity was 0.933576. The results demonstrate that this panel could be an accurate, fast, and cost-effective method for database construction where the amount of sample material is less of a concern and when the cost of the assay is taken into consideration.

[Genetic Polymorphisms of 26 Y-STR Loci in Fujian She Nationality and Its Forensic Application].

OBJECTIVE: To study the forensic application of Goldeneye DNA ID 26Y Kit in the She nationality. METHODS: Through capillary electrophoresis, the genotype of 26 Y-STR loci were analyzed in 53 unrelated male individuals from Fujian She nationality. The population genetics parameters such as allele frequency and haplotype diversity were calculated. The comparisons among the She nationality and the other nationalities were analyzed. RESULTS: A total of 126 alleles were observed on the 26 Y-STR loci of 53 unrelated male individuals. The allele frequencies and GD value ranged from 0.010 1 to 0.886 8 and 0.211 2 to 0.846 2, respectively. The GD value was greater than 0.5 in the 19 loci. A total of 47 haplotypes were observed. Based on R(ST), multidimensional scaling plot indicated that the genetic relationship among Fujian She nationality and Minnan Han nationality was closest, followed by Southern China Han nationality and Northern China nationality. CONCLUSION: Goldeneye™ DNA ID 26Y Kit including 26 Y-STR loci has good polymorphism in the She nationality. As an additional system, it has forensic application value in some special cases.

Progress of DNA-based Methods for Species Identification.

Species identification of biological samples is widely used in such fields as forensic science and food industry. A variety of accurate and reliable methods have been developed in recent years. The current review shows common target genes and screening criteria suitable for species identification, and described various DNA-based molecular biology methods about species identification. Additionally, it discusses the future development of species identification combined with real-time PCR and sequencing technologies.

Efficient electrocardiogram generation based on cardiac electric vector simulation model.

This study introduces a novel Cardiac Electric Vector Simulation Model (CEVSM) to address the computational inefficiencies and low fidelity of traditional electrophysiological models in generating electrocardiograms (ECGs). Our approach leverages CEVSM to efficiently produce reliable ECG samples, facilitating data augmentation essential for the computer-aided diagnosis of myocardial infarction (MI). Significantly, experimental results show that our model dramatically reduces computation time compared to conventional models, with the self-adapting regression transformation matrix method (SRTM) providing clear advantages. SRTM not only achieves high fidelity in ECG simulations but also ensures exceptional consistency with the gold standard method, greatly enhancing MI localization accuracy by data augmentation. These advancements highlight the potential of our model to generate dependable ECG training samples, making it highly suitable for data augmentation and significantly advancing the development and validation of intelligent MI diagnostic systems. Furthermore, this study demonstrates the feasibility of applying life system simulations in the training of medical big models.

Developmental validation of a 381 Y-chromosome SNP panel for haplogroup analysis in the Chinese populations.

Y-chromosome single nucleotide polymorphism (Y-SNP) shows great variation in geographical distribution and population heterogeneity and can be used to map population genetics around the world. Massive parallel sequencing (MPS) methodology enables high-resolution Y-SNP haplogrouping for a certain male and is widely used in forensic genetics and evolutionary studies. In this present study, we used MPS to develop a customized 381 Y-SNP panel (SifaMPS 381 Y-SNP panel) to investigate the basic structure and subbranches of the haplogroup tree of the Chinese populations. The SifaMPS 381 Y-SNP panel covers all the Y-SNPs from our previously designed 183 Y-SNP panel and additional SNPs under the predominant haplogroups in the Chinese populations based on certain criteria. We also evaluated the sequencing matrix, concordance, sensitivity, repeatability of this panel and the ability to analyze mixed and case-type samples based on the Illumina MiSeq System. The results demonstrated that the novel MPS Y-SNP panel possessed good sequencing performance and generated accurate Y-SNP genotyping results. Although the recommended DNA input was greater than 1.25 ng, we observed that a lower DNA amount could still be used to analyze haplogroups correctly. In addition, this panel could handle mixed samples and common case-type samples and had higher resolution among Chinese Han males than previously reported. In conclusion, the SifaMPS 381 Y-SNP panel showed an overall good performance and offers a better choice for Y-SNP haplogrouping of the Chinese population, thereby facilitating paternal lineage classification, familial searching and other forensic applications.

Forensic characteristics and population construction of two major minorities from southwest China revealed by a novel 37 Y-STR loci system.

Y-chromosome short tandem repeats (Y-STRs) have become important supplementary evidence in forensic science. Nowadays, the Y-chromosome STR haplotype reference database (YHRD) contains abundant Y-STR haplotype data from all over the world, while haplotype data of Guizhou Miao and Tujia are scarce. Hence, genetic polymorphisms of 37 Y-STRs were investigated in 446 unrelated males (206 Miao males and 246 Tujia males) residing in Guizhou Province. A total of 206 and 242 unique haplotypes with the highest diversity value of 0.9665 and 0.9470 were obtained. The heatmap, multidimensional scaling (MDS), the unweighted pair-group method with arithmetic means (UPGMA) tree and principal component analysis (PCA) based on the genetic distance (Rst) value within our studied populations and other 26 populations indicated that population structures follow the boundary of the continent. Guizhou Miao and Guizhou Tujia populations have intimate relationships with East Asian populations, especially the geographically close, similar history and the same language family populations.

MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT.

Prostate cancer (PCa) is the second leading cause of cancer death in American men. Androgen receptor (AR) signaling is essential for PCa cell growth/survival and remains a key therapeutic target for lethal castration-resistant PCa (CRPC). GATA2 is a pioneer transcription factor crucial for inducing AR expression/activation. We recently reported that MAPK4, an atypical MAPK, promotes tumor progression via noncanonical activation of AKT. Here, we demonstrated that MAPK4 activated AR by enhancing GATA2 transcriptional expression and stabilizing GATA2 protein through repression of GATA2 ubiquitination/degradation. MAPK4 expression correlated with AR activation in human CRPC. Concerted activation of both GATA2/AR and AKT by MAPK4 promoted PCa cell proliferation, anchorage-independent growth, xenograft growth, and castration resistance. Conversely, knockdown of MAPK4 decreased activation of both AR and AKT and inhibited PCa cell and xenograft growth, including castration-resistant growth. Both GATA2/AR and AKT activation were necessary for MAPK4 tumor-promoting activity. Interestingly, combined overexpression of GATA2 plus a constitutively activated AKT was sufficient to drive PCa growth and castration resistance, shedding light on an alternative, MAPK4-independent tumor-promoting pathway in human PCa. We concluded that MAPK4 promotes PCa growth and castration resistance by cooperating parallel pathways of activating GATA2/AR and AKT and that MAPK4 is a novel therapeutic target in PCa, especially CRPC.

Development and validation of a novel 29-plex Y-STR typing system for forensic application.

Short tandem repeat within the male-specific part of the human Y chromosome (Y-STR) is an effective forensic tool in mixture identification, patrilineal relationship evaluation, and familial searches. Despite their usefulness, current Y-STR-based genotyping systems often lack the discriminatory power to resolve genetic relationships between distant relatives or within patrilocal populations. In this study, we developed a novel Y-STR 29-plex typing system, which combined the 17 Y-STR loci used in the AmpFLSTR® Yfiler® PCR Amplification Kit (Yfiler), eight Y-STR loci with a low-medium mutation rate, and four rapidly mutating Y-STR loci. The system was generated to achieve greater discriminatory power between male subjects and improved ability to infer haplogroup classifications. The system was extensively tested on data from 752 individuals for its sensitivity, male specificity, species specificity, mixture resolution, reproducibility, concordance, stutter and size accuracy, precision, and population genetics, following the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines. The results demonstrated that the Y-STR 29-plex typing system was time-efficient, reproducible, accurate, sensitive, and robust to familial searching and paternal biogeographic ancestry inference.

Genetic polymorphism of both 29 Y-STRs and 213 Y-SNPs in Han populations from Shandong Province, China.

Genetic markers on the Y chromosome, including short tandem repeats (Y-STRs) and single nucleotide polymorphisms (Y-SNPs), are used widely in forensic genetics. Both Y-STR-based haplotypes and Y-SNP-based haplogroups provide information on a population's genetic structure, which is useful for the identification of individuals. However, there are few studies on these two types of genetic markers in the various Chinese populations. In this study, 284 Han individuals from four prefecture-level cities in Shandong Province (Binzhou, Dezhou, Heze, and Weihai) were genotyped by 29 Y-STRs (from our previous study) and 213 Y-SNPs (self-designed for the Haplogroup O2 Y-SNP panel). Haplogroup O was the most predominant among the four cities. The highest haplogroup diversity (0.9745) was observed in the Heze population, with a discrimination capacity (DC) value of 0.5625. The haplotype diversity and DC values of the Binzhou and Heze populations were 1.0000. Furthermore, genetic differences were observed between the coastal and inland cities; the results of their statistical analysis are presented herein.

Development and validation of a multiplex insertion/deletion marker panel, SifaInDel 45plex system.

In addition to commonly used short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs), insertion and deletion polymorphisms (InDels) have considerable potential in the field of forensic genetics because they combine desirable characteristics of both STRs and SNPs. In the present study, the SifaInDel 45plex system was designed to amplify 45 InDel markers, including 27 autosomal InDels (A-InDels), 16 X chromosome InDels (X-InDels) and two Y chromosome InDels (Y-InDels), simultaneously in a single PCR procedure and then detect products by capillary electrophoresis (CE). We also optimized the PCR conditions for the novel panel and performed several validation studies including repeatability/reproducibility, concordance, accuracy, sensitivity, stability, species specificity and population genetics. The results confirmed that full profiles could be obtained from ≥62.5 pg of input DNA and from a series of challenging samples encountered in routine casework. The SifaInDel 45plex panel could tolerate different concentrations of inhibitors, such as ≤50 µM hematin, ≤20 ng/µL nigrosine and ≤8000 ng/µL urea. In a population investigation, for the 27 A-InDels, the combined power of discrimination (CPD) exceeded 0.999999, and the combined power of exclusion in duos (CPED) and trios (CPET) was 0.955118 and 0.997754, respectively. For the 16 X-InDels, the combined PDMale and PDFemale was computed as 0.999845 and 0.999998, respectively, and the combined mean exclusion chance in father/daughter or mother/son duos (MECDuo) and mean exclusion chance in standard trios involving daughters (MECTrio) was 0.976220 and 0.998163, respectively. In addition, the two Y-InDels could play a role in correctly determining gender. Overall, the established SifaInDel 45plex panel is a well-performing, reliable and robust multiplex system that stands out for combining a considerable number of A-indels, X-indels and Y-indels based on a CE platform. The population study results also demonstrated that the SifaInDel 45plex panel could be a valid complementary approach for human identification and complex kinship analysis.

Validation studies of the ParaDNA® Intelligence System with artificial evidence items.

Short tandem repeat (STR) profiling is one of the mostly used systems for forensic applications. In certain circumstances, STR profiling is time-consuming and costly, which potentially leads to delays in criminal investigations. LGC (Laboratory of the Government Chemist, UK) Forensics has developed a robust STR profiling platform called the ParaDNA® Intelligence Test System which can provide early tactical intelligence and aid investigators in making informed decisions on sample prioritization for detection. Here, we validated the ParaDNA intelligence test for its application in forensic cases using a range of mock evidence items following guidelines set by the Scientific Working Group on DNA Analysis Methods (SWGDAM). Specifically, we tested the sensitivity and accuracy of the ParaDNA intelligence test, as well as the success rates for detecting mock samples and for use in case scenarios. Our findings demonstrate that the ParaDNA intelligence test generates useful DNA profiles, especially for samples such as blood, saliva, and semen that contain ample DNA, indicating the benefits of including ParaDNA as a prior step in forensic STR profiling pipelines.

Thanatomicrobiome composition profiling as a tool for forensic investigation.

Thanatomicrobiome, or the postmortem microbiome, has been recognized as a useful microbial marker of the time and location of host death. In this mini-review, we compare the experimental methods commonly applied to thanatomicrobiome studies to the state-of-the-art methodologies in the microbiome field. Then, we review present findings in thanatomicrobiome studies, focusing on the diversity of the thanatomicrobiome composition and prediction models that have been proposed. Finally, we discuss potential improvements and future directions of the field.

Investigation of 12 X-STR loci in Mongolian and Eastern Han populations of China with comparison to other populations.

Due to the unique inheritance pattern, X-chromosomal short tandem repeats (X-STRs) have several advantages in complex kinship cases, such as deficiency cases or grandparent-grandchild and half-sisters testing. In our study, 541 unrelated individuals gathered from Mongolian and Eastern Chinese Han populations were successfully genotyped using the Investigator Argus X-12 kit. We calculated allele/haplotype frequencies and other forensic parameters of the two populations and further explored their genetic distance with already published Chinese populations and six global populations. Our results showed that the 12 X-STR markers were highly informative in the two populations when compared with nine other Chinese populations: significant differences were found at several loci. Geographically neighboring populations or different ethnic groups within the same area appeared to have closer evolutionary relationships. We also analyzed population genetic structure by performing clustering with the STRUCTURE program and Principal Coordinate Analysis (PCoA), and we found that the Chinese and other populations enrolled in this study could be distinguished. Furthermore, Mongolian males were distinguishable from the other studied males by a moderate genetic distance. Our study also expanded the X-STR database, which could facilitate the appropriate application of the 12 X-STR markers in the forensic field in China.

Sequence investigation of 34 forensic autosomal STRs with massively parallel sequencing.

STRs vary not only in the length of the repeat units and the number of repeats but also in the region with which they conform to an incremental repeat pattern. Massively parallel sequencing (MPS) offers new possibilities in the analysis of STRs since they can simultaneously sequence multiple targets in a single reaction and capture potential internal sequence variations. Here, we sequenced 34 STRs applied in the forensic community of China with a custom-designed panel. MPS performance were evaluated from sequencing reads analysis, concordance study and sensitivity testing. High coverage sequencing data were obtained to determine the constitute ratios and heterozygous balance. No actual inconsistent genotypes were observed between capillary electrophoresis (CE) and MPS, demonstrating the reliability of the panel and the MPS technology. With the sequencing data from the 200 investigated individuals, 346 and 418 alleles were obtained via CE and MPS technologies at the 34 STRs, indicating MPS technology provides higher discrimination than CE detection. The whole study demonstrated that STR genotyping with the custom panel and MPS technology has the potential not only to reveal length and sequence variations but also to satisfy the demands of high throughput and high multiplexing with acceptable sensitivity.

Population genetics of 30 insertion/deletion polymorphisms in Han Chinese population from Zhejiang Province.

Insertion/deletion (InDels) markers can serve as a useful supporting tool to short tandem repeat (STR) typing systems for human identification. The Qiagen DIPplex Investigator kit, which contains 30 biallelic autosomal InDels and amelogenin, has been developed for forensic use. To estimate the genetic diversity of the 30 markers in Han Chinese individuals living in Zhejiang and to further evaluate their applicability in forensic science, 246 unrelated Han Chinese from Zhejiang were genotyped at these loci. No significant departures from Hardy-Weinberg equilibrium were observed at these loci in these participants. The combined power of discrimination was over 0.99999999 and the combined probability of exclusion was over 0.9901. Results demonstrated that the 30 InDel markers could be used as a supporting tool for the human identification of specific Han Chinese individuals from Zhejiang. The genetic differences and phylogenetic relationships among Han Chinese from Zhejiang, Han Chinese from five other areas, nine minority ethnic groups, as well as two other East Asian populations were also investigated. Two InDel markers, HLD39 and HLD40, showed significant allele-frequency differences between Han Chinese from Zhejiang and ethnic minorities. Further analysis can be used to evaluate their role in forensic science.

Massively parallel sequencing of 231 autosomal SNPs with a custom panel: a SNP typing assay developed for human identification with Ion Torrent PGM.

The custom-designed single nucleotide polymorphism (SNP) panel amplified 231 autosomal SNPs in one PCR reaction and subsequently sequenced with massively parallel sequencing (MPS) technology and Ion Torrent personal genome machine (PGM). SNPs were chosen from SNPforID, IISNP, HapMap, dbSNP, and related published literatures. Full concordance was obtained between available MPS calling and Sanger sequencing with 9947A and 9948 controls. Ten SNPs (rs4606077, rs334355, rs430046, rs2920816, rs4530059, rs1478829, rs1498553, rs7141285, rs12714757 and rs2189011) with low coverage or heterozygote imbalance should be optimized or excluded from the panel. Sequence data had sufficiently high coverage and gave reliable SNP calling for the remaining 221 loci with the custom MPS-SNP panel. A default DNA input amount of 10 ng per reaction was recommended by Ampliseq technology but sensitivity testing revealed positive results from as little as 1 ng input DNA. Mixture testing with this panel is possible through analysis of the F MAR (frequency of major allele reads) values at most loci with enough high coverage depth and low level of sequencing noise. These results indicate the potential advantage of the custom MPS-SNP assays and Ion Torrent PGM platform for forensic study.

Developmental validation of a custom panel including 273 SNPs for forensic application using Ion Torrent PGM.

Utilizing massively parallel sequencing (MPS) technology for SNP testing in forensic genetics is becoming attractive because of the shortcomings of STR markers, such as their high mutation rates and disadvantages associated with the current PCR-CE method as well as its limitations regarding multiplex capabilities. MPS offers the potential to genotype hundreds to thousands of SNPs from multiple samples in a single experimental run. In this study, we designed a customized SNP panel that includes 273 forensically relevant identity SNPs chosen from SNPforID, IISNP, and the HapMap database as well as previously related studies and evaluated the levels of genotyping precision, sequence coverage, sensitivity and SNP performance using the Ion Torrent PGM. In a concordant study of the custom MPS-SNP panel, only four MPS callings were missing due to coverage reads that were too low (<20), whereas the others were fully concordant with Sanger's sequencing results across the two control samples, that is, 9947A and 9948. The analyses indicated a balanced coverage among the included loci, with the exception of the 16 SNPs that were used to detect an inconsistent allele balance and/or lower coverage reads among 50 tested individuals from the Chinese HAN population and the above controls. With the exception of the 16 poorly performing SNPs, the sequence coverage obtained was extensive for the bulk of the SNPs, and only three Y-SNPs (rs16980601, rs11096432, rs3900) showed a mean coverage below 1000. Analyses of the dilution series of control DNA 9948 yielded reproducible results down to 1ng of DNA input. In addition, we provide an analysis tool for automated data quality control and genotyping checks, and we conclude that the SNP targets are polymorphic and independent in the Chinese HAN population. In summary, the evaluation of the sensitivity, accuracy and genotyping performance provides strong support for the application of MPS technology in forensic SNP analysis, and the assay offers a straightforward sample-to-genotype workflow that could be beneficial in forensic casework with respect to both individual identification and complex kinship issues.

Characterization of microRNA expression profiles in blood and saliva using the Ion Personal Genome Machine(®) System (Ion PGM™ System).

MicroRNA (miRNA) expression profiling is gaining interest in the forensic community because the intrinsically short fragment and tissue-specific expression pattern enable miRNAs as a useful biomarker for body fluid identification. Measuring the quantity of miRNAs in forensically relevant body fluids is an important step to screen specific miRNAs for body fluid identification. The recent introduction of massively parallel sequencing (MPS) has the potential for screening miRNA biomarkers at the genome-wide level, which allows both the detection of expression pattern and miRNA sequences. In this study, we employed the Ion Personal Genome Machine(®) System (Ion PGM™ System, Thermo Fisher) to characterize the distribution and expression of 2588 human mature miRNAs (miRBase v21) in 5 blood samples and 5 saliva samples. An average of 1,885,000 and 1,356,000 sequence reads were generated in blood and saliva respectively. Based on miRDong, a Perl-based tool developed for semi-automated miRNA distribution designations, and manually ascertained, 6 and 19 miRNAs were identified respectively as potentially blood and saliva-specific biomarkers. Herein, this study describes a complete and reliable miRNA workflow solution based on Ion PGM™ System, starting from efficient RNA extraction, followed by small RNA library construction and sequencing. With this workflow solution and miRDong analysis it will be possible to measure miRNA expression pattern at the genome-wide level in other forensically relevant body fluids.