African Genome Research Articles

Abstract C093: Epigenetic insights and gene expression in African pan genome contig sequences

Abstract An often-overlooked component in our cancer genomics workflows is the reference genome. While most genomics analytical tools and findings are based on reference builds GRCh37 and GRCh38, these references are largely Eurocentric, and their representativeness among diverse populations has not been studied comprehensively. A previously published study conducted deep whole genome sequencing of over 900 individuals of African ancestry, where they revealed ∼296 million unique base pairs, assembled into 125,715 African Pan Genome (APG) contig sequences that are not represented in the reference genome. To further characterize these APG contig sequences, we sought to determine the epigenetic and expression potential of these sequences. We have previously reported preliminary efforts to characterize the unexplored epigenetic potential across the 125,715 APG contig sequences, where we have utilized Emboss CpG plot for CpG island prediction. Across all contig sequences, we identified 8,353 potential CpG islands across 6,352 contig sequences, where contigs had 1 to 9 predicted CpG islands. Taken together ∼5% of all APG contigs contained at least 1 predicted CpG island. To determine the expression potential of these contigs, we mapped RNAseq reads from an African ancestry-enriched triple negative breast cancer cohort to APG contigs that previously failed to map to the reference genome. Approximately 9% of APG contigs had transcriptomic reads mapping, and 1106 APG contigs had both reads mapping and predicted CpG islands. Given our RNAseq mapping from our African ancestry enriched cohort, we have begun to explore differential expression measures among contigs by African ancestry population groups, highlighting the potential for differential regulation at these understudied loci. Since the publication of the APG contig sequences, the recent telomere-to-telomere (T2T) reference has filled the gaps of GRCh37 and GRCh38, however, is even less diverse. With T2T containing novel sequences that were not present at the time the APG contigs were assembled, we performed BLASTn queries of APG contigs to the T2T genome, where preliminary analysis shows ∼17% fail to map to T2T. For those with BLASTn mapping results, we are currently assessing the coverage and identity of the mapping results to evaluate the alignment. In conclusion, these APG contig sequences harbor potential epigenetic regulatory function and expressed sequences not represented in our standard reference genomes. While some APG contig sequences are represented in the newer T2T genome, preliminary investigations show that these APG contig sequences map to the T2T genome in regions novel from GRCh37 and GRCh38. As we continue to explore these APG contig sequences, we may find ancestry-specific regulatory mechanisms not yet described. Citation Format: Rachel Martini, Kyriaki Founta, Sebastian Maurice, Jason White, Lisa Newman, Onyinye Balogun, Nyasha Chambwe, Melissa Davis. Epigenetic insights and gene expression in African pan genome contig sequences [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C093.

Population genomics of Plasmodium ovale species in sub-Saharan Africa.

Plasmodium ovale curtisi (Poc) and Plasmodium ovale wallikeri (Pow) are relapsing malaria parasites endemic to Africa and Asia that were previously thought to represent a single species. Amid increasing detection of ovale malaria in sub-Saharan Africa, we performed a population genomic study of both species across the continent. We conducted whole-genome sequencing of 25 isolates from Central and East Africa and analyzed them alongside 20 previously published African genomes. Isolates were predominantly monoclonal (43/45), with their genetic similarity aligning with geography. Pow showed lower average nucleotide diversity (1.8×10-4) across the genome compared to Poc (3.0×10-4) (p < 0.0001). Signatures of selective sweeps involving the dihydrofolate reductase gene were found in both species, as were signs of balancing selection at the merozoite surface protein 1 gene. Differences in the nucleotide diversity of Poc and Pow may reflect unique demographic history, even as similar selective forces facilitate their resilience to malaria control interventions.

A Standardized Pipeline for Assembly and Annotation of African Swine Fever Virus Genome.

Obtaining a complete good-quality sequence and annotation for the long double-stranded DNA genome of the African swine fever virus (ASFV) from next-generation sequencing (NGS) technology has proven difficult, despite the increasing availability of reference genome sequences and the increasing affordability of NGS. A gap analysis conducted by the global African swine fever research alliance (GARA) partners identified that a standardized, automatic pipeline for NGS analysis was urgently needed, particularly for new outbreak strains. Whilst there are several diagnostic and research labs worldwide that collect isolates of the ASFV from outbreaks, many do not have the capability to analyze, annotate, and format NGS data from outbreaks for submission to NCBI, and some publicly available ASFV genomes have missing or incorrect annotations. We developed an automated, standardized pipeline for the analysis of NGS reads that directly provides users with assemblies and annotations formatted for their submission to NCBI. This pipeline is freely available on GitHub and has been tested through the GARA partners by examining two previously sequenced ASFV genomes; this study also aimed to assess the accuracy and limitations of two strategies present within the pipeline: reference-based (Illumina reads) and de novo assembly (Illumina and Nanopore reads) strategies.

Pharmacogenetics of Calcineurin inhibitors in kidney transplant recipients: the African gap. A narrative review.

Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.

Modelling the demographic history of human North African genomes points to a recent soft split divergence between populations

BackgroundNorth African human populations present a complex demographic scenario due to the presence of an autochthonous genetic component and population substructure, plus extensive gene flow from the Middle East, Europe, and sub-Saharan Africa.ResultsWe conducted a comprehensive analysis of 364 genomes to construct detailed demographic models for the North African region, encompassing its two primary ethnic groups, the Arab and Amazigh populations. This was achieved through an Approximate Bayesian Computation with Deep Learning (ABC-DL) framework and a novel algorithm called Genetic Programming for Population Genetics (GP4PG). This innovative approach enabled us to effectively model intricate demographic scenarios, utilizing a subset of 16 whole genomes at > 30X coverage. The demographic model suggested by GP4PG exhibited a closer alignment with the observed data compared to the ABC-DL model. Both point to a back-to-Africa origin of North African individuals and a close relationship with Eurasian populations. Results support different origins for Amazigh and Arab populations, with Amazigh populations originating back in Epipaleolithic times, while GP4PG supports Arabization as the main source of Middle Eastern ancestry. The GP4PG model includes population substructure in surrounding populations (sub-Saharan Africa and Middle East) with continuous decaying gene flow after population split. Contrary to ABC-DL, the best GP4PG model does not require pulses of admixture from surrounding populations into North Africa pointing to soft splits as drivers of divergence in North Africa.ConclusionsWe have built a demographic model on North Africa that points to a back-to-Africa expansion and a differential origin between Arab and Amazigh populations.

An assessment of the genomic structural variation landscape in Sub-Saharan African populations.

Structural variants are responsible for a large part of genomic variation between individuals and play a role in both common and rare diseases. Databases cataloguing structural variants notably do not represent the full spectrum of global diversity, particularly missing information from most African populations. To address this representation gap, we analysed 1,091 high-coverage African genomes, 545 of which are public data sets, and 546 which have been analysed for structural variants for the first time. Variants were called using five different tools and datasets merged and jointly called using SURVIVOR. We identified 67,795 structural variants throughout the genome, with 10,421 genes having at least one variant. Using a conservative overlap in merged data, 6,414 of the structural variants (9.5%) are novel compared to the Database of Genomic Variants. This study contributes to knowledge of the landscape of structural variant diversity in Africa and presents a reliable dataset for potential applications in population genetics and health-related research.

Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry.

Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses. A novel AD-risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF=0.002, p=3.68×10-9). Two additional novel common and nine rare loci were identified with suggestive associations (P<9×10-7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. These analyses identified novel AD-associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta-analysis identified a novel genome-wide significant AD-risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome-wide significance at p<9×10-7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry-informed genetic screening tools and therapeutic interventions.

Anthropogenic events and responses to environmental stress are shaping the genomes of Ethiopian indigenous goats

Anthropological and biophysical processes have shaped livestock genomes over Millenia and can explain their current geographic distribution and genetic divergence. We analyzed 57 Ethiopian indigenous domestic goat genomes alongside 67 equivalents of east, west, and north-west African, European, South Asian, Middle East, and wild Bezoar goats. Cluster, ADMIXTURE (K = 4) and phylogenetic analysis revealed four genetic groups comprising African, European, South Asian, and wild Bezoar goats. The Middle Eastern goats had an admixed genome of these four genetic groups. At K = 5, the West African Dwarf and Moroccan goats were separated from East African goats demonstrating a likely historical legacy of goat arrival and dispersal into Africa via the coastal Mediterranean Sea and the Horn of Africa. FST, XP-EHH, and Hp analysis revealed signatures of selection in Ethiopian goats overlaying genes for thermo-sensitivity, oxidative stress response, high-altitude hypoxic adaptation, reproductive fitness, pathogen defence, immunity, pigmentation, DNA repair, modulation of renal function and integrated fluid and electrolyte homeostasis. Notable examples include TRPV1 (a nociception gene); PTPMT1 (a critical hypoxia survival gene); RETREG (a regulator of reticulophagy during starvation), and WNK4 (a molecular switch for osmoregulation). These results suggest that human-mediated translocations and adaptation to contrasting environments are shaping indigenous African goat genomes.

Kataegis associated mutational processes linked to adverse prostate cancer presentation in African men.

Kataegis, the focal hypermutation of single base substitutions (SBS) in tumour genomes, has received little attention with respect to prostate cancer (PCa) associated molecular and clinical features. Most notably, data is lacking with regards to this tumour evolutionary phenomenon and PCa racial disparities, with African men disproportionately impacted. Here through comparison between African (n = 109) and non-African (n = 79) whole genome sequenced treatment naïve primary tumours, using a single analytical workflow we assessed for shared and unique features of kataegis. Linking kataegis to aggressive presentation, structural variant burden and copy number loss, we attributed APOBEC3 activity through higher rates of SBS2 to high-risk African tumours. While kataegis positive African patients presented with elevated prostate specific antigen levels, their tumours showed evolutionary unique trajectories marked by increased subclonal and structural variant-independent kataegis. The potential to exacerbate tumour heterogeneity emphases the significance of continued exploration of biological behaviours and environmental exposures for African patients.

Establishment of a Suitable Diagnostic Workflow to Ensure Sensitive Detection of African Swine Fever Virus Genome in Porcine Semen.

The rapid spread of African swine fever virus (ASFV), causing severe and often lethal disease in domestic pigs and Eurasian wild boar, continues to be a threat to pig populations and dependent industries. Despite scientific achievements that have deepened our understanding of ASFV pathogenesis, alternative transmission routes for ASFV remain to be elucidated. We previously demonstrated the efficient transmission of ASFV from infected boars to naïve recipient gilts via artificial insemination, thereby highlighting the importance of surveillance of boar semen prior to its shipment. Since the accurate and reliable detection of even low amounts of ASFV in boar semen is key to disease prevention and control, we established a suitable diagnostic workflow to efficiently detect the ASFV genome in boar semen. Here, we assessed the sensitivity of various routine nucleic acid extraction kits as well as qPCR protocols in detecting the ASFV genome in the blood and semen of infected boars. The feasibility of the respective kits and methods for future use in boar studs was also considered. Variability in sensitivity mostly concerned samples with low to very low amounts of the ASFV genome. Ultimately, we defined a well-suited workflow for precisely detecting the ASFV genome in boar semen as early as 2 days post ASFV infection.

Structural polymorphism and diversity of human segmental duplications.

Segmental duplications (SDs) contribute significantly to human disease, evolution, and diversity yet have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies where the majority of SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms, we identify 173.2 Mbp of duplicated sequence (47.4 Mbp not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable with rare events mapping near their progenitor sequences. African genomes harbor significantly more intrachromosomal SDs and are more likely to have recently duplicated gene families with higher copy number when compared to non-African samples. A comparison to a resource of 563 million full-length Iso-Seq reads identifies 201 novel, potentially protein-coding genes corresponding to these copy number polymorphic SDs.

Understanding the genomic heterogeneity of North African Imazighen: from broad to microgeographical perspectives.

The strategic location of North Africa has led to cultural and demographic shifts, shaping its genetic structure. Historical migrations brought different genetic components that are evident in present-day North African genomes, along with autochthonous components. The Imazighen (plural of Amazigh) are believed to be the descendants of autochthonous North Africans and speak various Amazigh languages, which belong to the Afro-Asiatic language family. However, the arrival of different human groups, especially during the Arab conquest, caused cultural and linguistic changes in local populations, increasing their heterogeneity. We aim to characterize the genetic structure of the region, using the largest Amazigh dataset to date and other reference samples. Our findings indicate microgeographical genetic heterogeneity among Amazigh populations, modeled by various admixture waves and different effective population sizes. A first admixture wave is detected group-wide around the twelfth century, whereas a second wave appears in some Amazigh groups around the nineteenth century. These events involved populations with higher genetic ancestry from south of the Sahara compared to the current North Africans. A plausible explanation would be the historical trans-Saharan slave trade, which lasted from the Roman times to the nineteenth century. Furthermore, our investigation shows that assortative mating in North Africa has been rare.

Abstract LB336: The African Cancer Atlas: Leveraging African data to diversify precision oncology

Abstract Africa has some of the highest age adjusted cancer mortality rates globally and cancer incidence in Africa is expected to double by 2040. Despite this disproportionate burden of disease, African cancer patients are woefully understudied along the cancer continuum. People of African descent are significantly underrepresented in cancer research, accounting for less than 3% of globally available genomic data and are often the least well served by advances in precision medicine.To address this gap, we have initiated the African Cancer Atlas project. This is an Africa-centred approach to overcoming cancer inequities - providing much needed biological and clinical data, but also seeking to identify and address the social determinants of inequities both within the continent and between high and low-middle income countries (LMIC). We have established an oncology partner network across 9 geographically dispersed African countries (Senegal, Côte d’Ivoire, Ghana, Nigeria, Kenya, Uganda, Zimbabwe, South Africa, and Tunisia). We have developed LMIC-specific standardised protocols and best practices for sample collection and processing across multiple sites and continue to build a well-annotated bank of tissue, plasma, bone marrow and PBMC from individuals with breast, prostate, gastrointestinal cancers, liver, urinogenital and pediatric cancers that will be unrivalled in its diversity. So far, 1800 cancer samples have been collected and banked. We have also built a unique cloud-based clinical data management platform to facilitate the collection of longitudinal clinical metadata into a unified clinico-demographic database. We have initiated extensive genomic and molecular profiling of African-specific cancers using whole exome/genome sequencing (WES/WGS) of paired germline and tumour samples as well as RNA- sequencing of tumors. We have so far completed the first 200 WES, representing the first cancer samples sequenced entirely on the African continent. Ongoing work is investigating how population-specific genetic variation contributes to cancer risk, identifying driver mutations, somatic copy number alterations (SCNAs) and mutational signatures that can point to disease-relevant environmental exposures or impaired core biological pathways. Comparative analysis with existing cancer genomics cohorts will determine the prevalence of known hotspot mutations, cancer drivers and or common SCNAs in African cancer genomes. By comparing with available data for African Americans and other diasporan Africans, we will provide better understanding of cancer aetiology related to African ancestry applicable to the broader African diasporic communities in other regions of the world. We are also collecting data to assess socio-economic and health system factors affecting access to cancer care and survival across all study sites. Socio-demographic data collection is integrated with tissue/biodata collection creating digital longitudinal hospital-based cohorts. We will develop systems that integrate genomics, molecular demographics and clinical data with machine learning and a publicly accessible portal for data access and analytics will be available for the broader scientific community. Ultimately, this project will contribute towards better understanding of cancer among people of African descent and make precision oncology more effective for diverse populations. Citation Format: Yaw Bediako, Joyce Ngoi, Ruth Kiome, Seth Agyemang, Stephen Darkoh, Audrey Lemacon, Aida Manu, Frank Onyambu, Kanny Diallo, Lily Paemka, David Hutchful, Emmanuella Amoako, Abdoulaye Diallo. The African Cancer Atlas: Leveraging African data to diversify precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB336.

Abstract 2948: Unveiling hidden genomic diversity: Exploring epigenetic potential and gene expression in African Pan Genome contig sequences

Abstract An important consideration when studying cancer in diverse populations is the representativeness of the reference genome. Cancer genomics findings are largely based upon alignments to GRCh37 and GRCh38 references, and with the recent release of the telomere-to-telomere (T2T) and the Human Pangenome Reference Consortium references, analyses of sequences distinct from previous references in the cancer context provide exciting opportunities to identify novel targets that may be linked to cancer outcomes. Because GRCh38 and T2T are overwhelmingly Eurocentric, the question remains if these references have applicability outside the ancestral populations that comprise them. Prior to T2T and pangenome, whole genome sequencing of 910 individuals of African descent revealed 296.5 million distinct base pairs, which were assembled into 125,715 African Pan Genome (APG) contigs. These unique sequences represent African ancestry novel genomic sequences whose function was unclear. Here we present provisional efforts to determine the function of APG contigs, and whether they are represented in newer references. To determine the epigenetic potential of the 125,715 APG contigs, we used Emboss Cpgplot to predict CpG islands. We identified 8,353 potential CpG islands, where 6,352 contigs had at least 1 predicted CpG island, and 1 contig had 9. There was weak correlation between contig length, GC content and number of predicted CpG islands suggesting that these sequences represented potentially functional regions. Using unmapped transcriptomic reads from our published African ancestry triple negative breast cancer cohort, we sought to determine the expression potential of these contigs. Unmapped reads mapped to ~9% of the contigs, where ~1100 APG contigs had both predicted CpG islands and alignment of the unmapped transcriptomic reads. This strongly suggests that these APG contigs contain African ancestry-specific regulatory regions and functional gene coding sequences. Preliminary BLASTn queries of contigs with regulatory potential revealed that these sequences may be present in T2T. Mapping to T2T and visualization of expression and CpG islands showed that our predictions matched novel T2T sequences. We anticipated some contigs would map to T2T given one- or two-end placement in GRCh38 and wanted to determine if any of the ~1100 contigs mapped to T2T. Initial analysis of this contig subset shows ~15% fail to map to T2T, indicating that T2T may still fail to capture diversity across ancestry groups. These sequences represent previously unstudied expression and epigenetic potential not captured in the reference genome, and we are working to evaluate all 125,715 sequences. Capturing the diversity across the genome remains extremely important to contextualize these findings and build resources to continue moving precision medicine approaches forward across diverse ancestry groups. Citation Format: Rachel Martini, Kyriaki Founta, Sebastian Maurice, Jason White, Onyinye Balogun, Nyasha Chambwe, Melissa Davis. Unveiling hidden genomic diversity: Exploring epigenetic potential and gene expression in African Pan Genome contig sequences [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2948.

Near-complete genome sequences of multiple genotype 1 African swine fever virus isolates from 2016 to 2018 in Cameroon.

African swine fever virus has been endemic in Cameroon since 1982. Here, we announce the sequences of Cameroon/2016/C1, Cameroon/2016/C5, Cameroon/2017/C-A2, Cameroon/2018/C02, and Cameroon/2018/CF3, five genotype 1 African swine fever virus genomes collected from domestic pigs between 2016 and 2018.

Generation of High-Quality African Swine Fever Virus Complete Genome from Field Samples by Next-Generation Sequencing.

African swine fever (ASF) is a lethal contagious viral disease of domestic pigs and wild boars caused by the African swine fever virus (ASFV). The pandemic spread of ASF has caused severe effects on the global pig industry. Whole-genome sequencing provides crucial information for virus strain characterization, epidemiology analysis and vaccine development. Here, we evaluated the performance of next-generation sequencing (NGS) in generating ASFV genome sequences from clinical samples. Thirty-four ASFV-positive field samples including spleen, lymph node, lung, liver and blood with a range of Ct values from 14.73 to 25.95 were sequenced. For different tissue samples collected from the same sick pigs, the proportion of ASFV reads obtained from the spleen samples was 3.69-9.86 times higher than other tissues. For the high-viral-load spleen samples (Ct < 20), a minimum of a 99.8% breadth of ≥10× coverage was revealed for all the samples. For the spleen samples with Ct ≥ 20, 6/12 samples had a minimum of a 99.8% breadth of ≥10× coverage. A high average depth of sequencing coverage was also achieved from the blood samples. According to our results, high-quality ASFV whole-genome sequences could be obtained from the spleen or blood samples with Ct < 20. The high-quality ASFV genome sequence generated in this study was further used for the high-resolution phylogenetic analysis of the ASFV genomes in the early stage of the ASF epidemic in China. Our study demonstrates that NGS may act as a useful tool for efficient ASFV genome characterization, providing valuable information for disease control.

The Addis Ababa Lions: Whole-Genome Sequencing of a Rare and Precious Population.

Lions are widely known as charismatic predators that once roamed across the globe, but their populations have been greatly affected by environmental factors and human activities over the last 150 yr. Of particular interest is the Addis Ababa lion population, which has been maintained in captivity at around 20 individuals for over 75 yr, while many wild African lion populations have become extinct. In order to understand the molecular features of this unique population, we conducted a whole-genome sequencing study on 15 Addis Ababa lions and detected 4.5 million distinct genomic variants compared with the reference African lion genome. Using functional annotation, we identified several genes with mutations that potentially impact various traits such as mane color, body size, reproduction, gastrointestinal functions, cardiovascular processes, and sensory perception. These findings offer valuable insights into the genetics of this threatened lion population.

Systematic analysis of the codon usage patterns of African swine fever virus genome coding sequences reveals its host adaptation phenotype.

African swine fever (ASF) is a severe haemorrhagic disease caused by the African swine fever virus (ASFV), transmitted by ticks, resulting in high mortality among domestic pigs and wild boars. The global spread of ASFV poses significant economic threats to the swine industry. This study employs diverse analytical methods to explore ASFV's evolution and host adaptation, focusing on codon usage patterns and associated factors. Utilizing phylogenetic analysis methods including neighbour-joining and maximum-likelihood, 64 ASFV strains were categorized into four clades. Codon usage bias (CUB) is modest in ASFV coding sequences. This research identifies multiple factors - such as nucleotide composition, mutational pressures, natural selection and geographical diversity - contributing to the formation of CUB in ASFV. Analysis of relative synonymous codon usage reveals CUB variations within clades and among ASFVs and their hosts. Both Codon Adaptation Index and Similarity Index analyses confirm that ASFV strains are highly adapted to soft ticks (Ornithodoros moubata) but less so to domestic pigs, which could be a result of the long-term co-evolution of ASFV with ticks. This study sheds light on the factors influencing ASFV's codon usage and fitness dynamics, enriching our understanding of its evolution, adaptation and host interactions.

Identification of L11L and L7L as virulence-related genes in the African swine fever virus genome.

African swine fever (ASF) is an infectious disease that causes considerable economic losses in pig farming. The agent of this disease, African swine fever virus (ASFV), is a double-stranded DNA virus with a capsid membrane and a genome that is 170-194 kb in length encoding over 150 proteins. In recent years, several live attenuated strains of ASFV have been studied as vaccine candidates, including the SY18ΔL7-11. This strain features deletion of L7L, L8L, L9R, L10L and L11L genes and was found to exhibit significantly reduced pathogenicity in pigs, suggesting that these five genes play key roles in virulence. Here, we constructed and evaluated the virulence of ASFV mutations with SY18ΔL7, SY18ΔL8, SY18ΔL9, SY18ΔL10, and SY18ΔL11L. Our findings did not reveal any significant differences in replication efficiency between the single-gene deletion strains and the parental strains. Pigs inoculated with SY18ΔL8L, SY18ΔL9R and SY18ΔL10L exhibited clinical signs similar to those inoculated with the parental strains. Survival rate of pigs inoculated with 103.0TCID50 of SY18ΔL7L was 25%, while all pigs inoculated with 103.0TCID50 of SY18ΔL11L survived, and 50% inoculated with 106.0TCID50 SY18ΔL11L survived. The results indicate that L8L, L9R and L10L do not affect ASFV SY18 virulence, while the L7L and L11L are associated with virulence.

Familial FTD in India

AbstractBackgroundThe burden of dementia in India is estimated to increase by 197% by 2050, and Frontotemporal dementia (FTD) is among the leading causes of young‐onset dementia. With recent advances in molecular pathology, genetic mechanisms and emerging therapies in FTD, it is important to understand familial FTD patterns in the heterogeneous sociocultural context of India. High genetic diversity is characteristic of India, and its population bears genetic imprints of European, Asian and even African genomes. The objective of this presentation is to provide an account of FTD in India, with a focus on familial FTD and genetic mechanisms recently being identified.MethodThe prevalence of FTD in clinical dementia cohorts across different geographic regions in India, frequency of familial FTD, clinical presentations in the context of sociolinguistic and ethnic diversity, and genetic mechanisms are reported.ResultThe reported prevalence of FTD in clinical and research groups across India varies from 7% to 26%. The proportion of familial FTD ranges from 9.5% in Kolkata in the east, 15% in Trivandrum in the south, 24.6% from Hyderabad and more recently, as high as 40% in a recent study from Bangalore. Few genetic mutations were reported in early studies. In a recent large effort from Bangalore, India, 200 patients with FTD syndromes underwent three generation pedigree analysis, clinical and neuropsychological evaluation and MRI according to ADNI protocol. Nearly half underwent genetic analysis by next generation sequencing and RT‐PCR was done to analyse C9orf 11 in a subset. Novel gene mutations including SQSTM1, GRN, MAPT, PSEN2, TBK1 and C9orf were detected. Of these mutations, 11 were pathogenic in 11 and 26 were variants of unknown significance (VUS). Apart from abnormal protein accumulation due to MAPT and GRN, we also identified CSF1R, TREM2 and TYROBP, that are recognised as primary microgliopathies. A few examples of VUS include PRNP, LRRK2, GBA and PANK2 mutations.ConclusionResearch from familial FTD cohorts in India is contributing to growing evidence of a wider spectrum of genetic mechanisms for FTD. Our findings provide compelling evidence to increase harmonised global efforts to reduce risk and develop novel treatment strategies for FTD.