Genomic evidence for inbreeding depression and purging of deleterious genetic variation in Indian tigers.

Increasing habitat fragmentation leads to wild populations becoming small, isolated, and threatened by inbreeding depression. However, small populations may be able to purge recessive deleterious alleles as they become expressed in homozygotes, thus reducing inbreeding depression and increasing population viability. We used whole-genome sequences from 57 tigers to estimate individual inbreeding and mutation load in a small-isolated and two large-connected populations in India. As expected, the small-isolated population had substantially higher average genomic inbreeding (FROH = 0.57) than the large-connected (FROH = 0.35 and FROH = 0.46) populations. The small-isolated population had the lowest loss-of-function mutation load, likely due to purging of highly deleterious recessive mutations. The large populations had lower missense mutation loads than the small-isolated population, but were not identical, possibly due to different demographic histories. While the number of the loss-of-function alleles in the small-isolated population was lower, these alleles were at higher frequencies and homozygosity than in the large populations. Together, our data and analyses provide evidence of 1) high mutation load, 2) purging, and 3) the highest predicted inbreeding depression, despite purging, in the small-isolated population. Frequency distributions of damaging and neutral alleles uncover genomic evidence that purifying selection has removed part of the mutation load across Indian tiger populations. These results provide genomic evidence for purifying selection in both small and large populations, but also suggest that the remaining deleterious alleles may have inbreeding-associated fitness costs. We suggest that genetic rescue from sources selected based on genome-wide differentiation could offset any possible impacts of inbreeding depression.

LMNet: Lightweight multi-scale convolutional neural network architecture for COVID-19 detection in IoMT environment.

The COVID-19 disease, initially known as SARS-CoV-2, was first reported in early December 2019 and has caused immense damage to humans globally. The most widely used clinical screening method for COVID-19 is Reverse Transcription Polymerase Chain Reaction (RT-PCR). RT-PCR uses respiratory samples for testing, because of which, this manual technique becomes complicated, laborious and time-consuming. Even though it has a low sensitivity, it carries a considerable risk for the testing medical staff. Hence, there is a need for an automated diagnosis system that can provide quick and efficient diagnosis results. This research proposed a multi-scale lightweight CNN (LMNet) architecture for COVID-19 detection. The proposed model is computationally less expensive than previously available models and requires less memory space. The performance of the proposed LMNet model ensemble with DenseNet169 and MobileNetV2 is higher than the other state-of-the-art models. The ensemble model can be integrated at the backend of the smart devices; hence it is useful for the Internet of Medical Things (IoMT) environment.

hg19KIndel: ethnicity normalized human reference genome.

BACKGROUND: The most widely used human genome reference assembly hg19 harbors minor alleles at 2.18 million positions as revealed by 1000 Genome Phase 3 dataset. Although this is less than 2% of the 89 million variants reported, it has been shown that the minor alleles can result in 30% false positives in individual genomes, thus misleading and burdening downstream interpretation. More alarming is the fact that, significant percentage of variants that are homozygous recessive for these minor alleles, with potential disease implications, are masked from reporting. RESULTS: We have demonstrated that the false positives (FP) and false negatives (FN) can be corrected for by simply replacing nucleotides at the minor allele positions in hg19 with corresponding major allele. Here, we have effectively replaced 2.18 million minor alleles Single Nucleotide Polymorphism (SNPs), Insertion and Deletions (INDELs), Multiple Nucleotide Polymorphism (MNPs) in hg19 with the corresponding major alleles to create an ethnically normalized reference genome called hg19KIndel. In doing so, hg19KIndel has both corrected for sequencing errors acknowledged to be present in hg19 and has improved read alignment near the minor alleles in hg19. CONCLUSION: We have created and made available a new version human reference genome called hg19KIndel. It has been shown that variant calling using hg19KIndel, significantly reduces false positives calls, which in-turn reduces the burden from downstream analysis and validation. It also improved false negative variants call, which means that the variants which were getting missed due to the presence of minor alleles in hg19, will now be called using hg19KIndel. Using hg19KIndel, one even gets a better mapping percentage when compared to currently available human reference genome. hg19KIndel reference genome and its auxiliary datasets are available at https://doi.org/10.5281/zenodo.2638113.

Genetic variation in recalcitrant repetitive regions of the Drosophila melanogaster genome.

Many essential functions of organisms are encoded in highly repetitive genomic regions, including histones involved in DNA packaging, centromeres that are core components of chromosome segregation, ribosomal RNA comprising the protein translation machinery, telomeres that ensure chromosome integrity, piRNA clusters encoding host defenses against selfish elements, and virtually the entire Y chromosome. These regions, formed by highly similar tandem arrays, pose significant challenges for experimental and informatic study, impeding sequence-level descriptions essential for understanding genetic variation. Here, we report the assembly and variation analysis of such repetitive regions in Drosophila melanogaster, offering significant improvements to the existing community reference assembly. Our work successfully recovers previously elusive segments, including complete reconstructions of the histone locus and the pericentric heterochromatin of the X chromosome, spanning the Stellate locus to the distal flank of the rDNA cluster. To infer structural changes in these regions where alignments are often not practicable, we introduce landmark anchors based on unique variants that are putatively orthologous. These regions display considerable structural variation between different D. melanogaster strains, exhibiting differences in copy number and organization of homologous repeat units between haplotypes. In the histone cluster, although we observe minimal genetic exchange indicative of crossing over, the variation patterns suggest mechanisms such as unequal sister chromatid exchange. We also examine the prevalence and scale of concerted evolution in the histone and Stellate clusters and discuss the mechanisms underlying these observed patterns.

Tomato Flu in the Time of COVID-19: Another Challenge for the Indian Health System.

Just as the country has recently dealt with the increase in COVID-19 and monkey pox cases, another dark cloud of "Tomato flu/ Tomato fever" loomed the skies of the nation. As of 24 august, 2022, 100 kids mainly below the age of 5 have been reported showing symptoms of the flu. Another state of Odisha, suspected similar infectious etiology in 36 cases out of which 26 Children were below the age of 10. This endemic viral illness has triggered an alert to the neighboring states of Tamil Nadu and Karnataka, along with the entire nation at large. The wrath of this disease is not just restricted to India but crossing borders. Tang, et al reported a case of a 13-month-old female child and her 5-year old brother based in United kingdom with similar etiology. Through this report, we aim to alert the frontline pediatricians, who are most likely to come across and manage such daunting cases with these non-specific clinical features in their routine clinical practice across the globe. Early and extreme preventive and surveillance measures must be undertaken to prevent substantial loss in public and private sector.

Species-specific chromatin landscape determines how transposable elements shape genome evolution.

Transposable elements (TEs) are selfish genetic parasites that increase their copy number at the expense of host fitness. The 'success', or genome-wide abundance, of TEs differs widely between species. Deciphering the causes for this large variety in TE abundance has remained a central question in evolutionary genomics. We previously proposed that species-specific TE abundance could be driven by the inadvertent consequences of host-direct epigenetic silencing of TEs-the spreading of repressive epigenetic marks from silenced TEs into adjacent sequences. Here, we compared this TE-mediated local enrichment of repressive marks, or 'the epigenetic effect of TEs', in six species in the Drosophila melanogaster subgroup to dissect step-by-step the role of such effect in determining genomic TE abundance. We found that TE-mediated local enrichment of repressive marks is prevalent and substantially varies across and even within species. While this TE-mediated effect alters the epigenetic states of adjacent genes, we surprisingly discovered that the transcription of neighboring genes could reciprocally impact this spreading. Importantly, our multi-species analysis provides the power and appropriate phylogenetic resolution to connect species-specific host chromatin regulation, TE-mediated epigenetic effects, the strength of natural selection against TEs, and genomic TE abundance unique to individual species. Our findings point toward the importance of host chromatin landscapes in shaping genome evolution through the epigenetic effects of a selfish genetic parasite.

All the instructions required for life are encoded in the set of DNA present in a cell. It therefore seems natural to think that every bit of this genetic information should serve the organism. And yet most species carry parasitic 'transposable' sequences, or transposons, whose only purpose is to multiply and insert themselves at other positions in the genome. It is possible for cells to suppress these selfish elements. Chemical marks can be deposited onto the DNA to temporarily 'silence' transposons and prevent them from being able to move and replicate. However, this sometimes comes at a cost: the repressive chemical modifications can spread to nearby genes that are essential for the organism and perturb their function. Strangely, the prevalence of transposons varies widely across the tree of life. These sequences form the majority of the genome of certain species ­ in fact, they represent about half of the human genetic information. But their abundance is much lower in other organisms, forming a measly 6% of the genome of puffer fish for instance. Even amongst fruit fly species, the prevalence of transposable elements can range between 2% and 25%. What explains such differences? Huang et al. set out to examine this question through the lens of transposon silencing, systematically comparing how this process impacts nearby regions in six species of fruit flies. This revealed variations in the strength of the side effects associated with transposon silencing, resulting in different levels of perturbation on neighbouring genes. A stronger impact was associated with the species having fewer transposons in its genome, suggesting that an evolutionary pressure is at work to keep the abundance of transposons at a low level in these species. Further analyses showed that the genes which determine how silencing marks are distributed may also be responsible for the variations in the impact of transposon silencing. They could therefore be the ones driving differences in the abundance of transposons between species. Overall, this work sheds light on the complex mechanisms shaping the evolution of genomes, and it may help to better understand how transposons are linked to processes such as aging and cancer.

Near-chromosomal de novo assembly of Bengal tiger genome reveals genetic hallmarks of apex predation.

The tiger, a poster child for conservation, remains an endangered apex predator. Continued survival and recovery will require a comprehensive understanding of genetic diversity and the use of such information for population management. A high-quality tiger genome assembly will be an important tool for conservation genetics, especially for the Indian tiger, the most abundant subspecies in the wild. Here, we present high-quality near-chromosomal genome assemblies of a female and a male wild Indian tiger (Panthera tigris tigris). Our assemblies had a scaffold N50 of >140 Mb, with 19 scaffolds corresponding to the 19 numbered chromosomes, containing 95% of the genome. Our assemblies also enabled detection of longer stretches of runs of homozygosity compared to previous assemblies, which will help improve estimates of genomic inbreeding. Comprehensive genome annotation identified 26,068 protein-coding genes, including several gene families involved in key morphological features such as the teeth, claws, vision, olfaction, taste, and body stripes. We also identified 301 microRNAs, 365 small nucleolar RNAs, 632 transfer RNAs, and other noncoding RNA elements, several of which are predicted to regulate key biological pathways that likely contribute to the tiger's apex predatory traits. We identify signatures of positive selection in the tiger genome that are consistent with the Panthera lineage. Our high-quality genome will enable use of noninvasive samples for comprehensive assessment of genetic diversity, thus supporting effective conservation and management of wild tiger populations.

Tumor relevant protein functional interactions identified using bipartite graph analyses.

An increased surge of -omics data for the diseases such as cancer allows for deriving insights into the affiliated protein interactions. We used bipartite network principles to build protein functional associations of the differentially regulated genes in 18 cancer types. This approach allowed us to combine expression data to functional associations in many cancers simultaneously. Further, graph centrality measures suggested the importance of upregulated genes such as BIRC5, UBE2C, BUB1B, KIF20A and PTH1R in cancer. Pathway analysis of the high centrality network nodes suggested the importance of the upregulation of cell cycle and replication associated proteins in cancer. Some of the downregulated high centrality proteins include actins, myosins and ATPase subunits. Among the transcription factors, mini-chromosome maintenance proteins (MCMs) and E2F family proteins appeared prominently in regulating many differentially regulated genes. The projected unipartite networks of the up and downregulated genes were comprised of 37,411 and 41,756 interactions, respectively. The conclusions obtained by collating these interactions revealed pan-cancer as well as subtype specific protein complexes and clusters. Therefore, we demonstrate that incorporating expression data from multiple cancers into bipartite graphs validates existing cancer associated mechanisms as well as directs to novel interactions and pathways.

CerebroVis: Designing an Abstract yet Spatially Contextualized Cerebral Artery Network Visualization.

Blood circulation in the human brain is supplied through a network of cerebral arteries. If a clinician suspects a patient has a stroke or other cerebrovascular condition, they order imaging tests. Neuroradiologists visually search the resulting scans for abnormalities. Their visual search tasks correspond to the abstract network analysis tasks of browsing and path following. To assist neuroradiologists in identifying cerebral artery abnormalities, we designed CerebroVis, a novel abstract-yet spatially contextualized-cerebral artery network visualization. In this design study, we contribute a novel framing and definition of the cerebral artery system in terms of network theory and characterize neuroradiologist domain goals as abstract visualization and network analysis tasks. Through an iterative, user-centered design process we developed an abstract network layout technique which incorporates cerebral artery spatial context. The abstract visualization enables increased domain task performance over 3D geometry representations, while including spatial context helps preserve the user's mental map of the underlying geometry. We provide open source implementations of our network layout technique and prototype cerebral artery visualization tool. We demonstrate the robustness of our technique by successfully laying out 61 open source brain scans. We evaluate the effectiveness of our layout through a mixed methods study with three neuroradiologists. In a formative controlled experiment our study participants used CerebroVis and a conventional 3D visualization to examine real cerebral artery imaging data to identify a simulated intracranial artery stenosis. Participants were more accurate at identifying stenoses using CerebroVis (absolute risk difference 13%). A free copy of this paper, the evaluation stimuli and data, and source code are available at osf.io/e5sxt.