Predisposition to anterior cruciate ligament (ACL) rupture is multi-factorial, with variation in the genome considered a key intrinsic risk factor. Most implicated loci have been identified from ...candidate gene-based approach using case-control association settings. Here, we leverage a hypothesis-free whole genome sequencing in two two unrelated families (Family A and B) each with twins with a history of recurrent ACL ruptures acquired playing rugby as their primary sport, aimed to elucidate biologically relevant function-altering variants and genetic modifiers in ACL rupture. Family A monozygotic twin males (Twin 1 and Twin 2) both sustained two unilateral non-contact ACL ruptures of the right limb while playing club level touch rugby. Their male sibling sustained a bilateral non-contact ACL rupture while playing rugby union was also recruited. The father had sustained a unilateral non-contact ACL rupture on the right limb while playing professional amateur level football and mother who had participated in dancing for over 10 years at a social level, with no previous ligament or tendon injuries were both recruited. Family B monozygotic twin males (Twin 3 and Twin 4) were recruited with Twin 3 who had sustained a unilateral non-contact ACL rupture of the right limb and Twin 4 sustained three non-contact ACL ruptures (two in right limb and one in left limb), both while playing provincial level rugby union. Their female sibling participated in karate and swimming activities; and mother in hockey (4 years) horse riding (15 years) and swimming, had both reported no previous history of ligament or tendon injury. Variants with potential deleterious, loss-of-function and pathogenic effects were prioritised. Identity by descent, molecular dynamic simulation and functional partner analyses were conducted. We identified, in all nine affected individuals, including twin sets, non-synonymous SNPs in three genes: COL12A1 and CATSPER2, and KCNJ12 that are commonly enriched for deleterious, loss-of-function mutations, and their dysfunctions are known to be involved in the development of chronic pain, and represent key therapeutic targets. Notably, using Identity By Decent (IBD) analyses a long shared identical sequence interval which included the LINC01250 gene, around the telomeric region of chromosome 2p25.3, was common between affected twins in both families, and an affected brother'. Overall gene sets were enriched in pathways relevant to ACL pathophysiology, including complement/coagulation cascades (p = 3.0e-7), purine metabolism (p = 6.0e-7) and mismatch repair (p = 6.9e-5) pathways. Highlighted, is that this study fills an important gap in knowledge by using a WGS approach, focusing on potential deleterious variants in two unrelated families with a historical record of ACL rupture; and providing new insights into the pathophysiology of ACL, by identifying gene sets that contribute to variability in ACL risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background: Estimating single nucleotide polymorphism (SNP)-heritability (h2g) of severe malaria resistance and its distribution across the genome might shed new light in to the underlying ...biology. Method: We investigated h2g of severe malaria resistance from a genome-wide association study (GWAS) dataset (sample size = 11 657). We estimated the h2g and partitioned in to chromosomes, allele frequencies and annotations using the genetic relationship-matrix restricted maximum likelihood approach. We further examined non-cell type-specific and cell type-specific enrichments from GWAS-summary statistics. Results: The h2g of severe malaria resistance was estimated at 0.21 (se = 0.05, P = 2.7 × 10−5), 0.20 (se = 0.05, P = 7.5 × 10−5) and 0.17 (se = 0.05, P = 7.2 × 10−4) in Gambian, Kenyan and Malawi populations, respectively. A comparable range of h2g 0.21 (se = 0.02, P < 1 × 10−5) was estimated from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h2g in genic SNPs while summary statistics analysis suggests evidences of enrichment in multiple categories. Supporting the polygenic inheritance, the h2g of severe malaria resistance is distributed across the chromosomes and allelic frequency spectrum. However, the h2g is disproportionately concentrated on three chromosomes (chr 5, 11 and 20), suggesting cost-effectiveness of targeting these chromosomes in future malaria genomic sequencing studies. Conclusion: We report for the first time that the heritability of malaria resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Further studies with larger sample sizes are needed to better understand the underpinning genetics of severe malaria resistance.
Over the past decades, advanced high-throughput technologies have continuously contributed to genome-wide association studies (GWASs). GWAS meta-analysis has been increasingly adopted, has ...cross-ancestry replicability, and has power to illuminate the genetic architecture of complex traits, informing about the reliability of estimation effects and their variability across human ancestries. However, detecting genetic variants that have low disease risk still poses a challenge. Designing a meta-analysis approach that combines the effect of various SNPs within genes or genes within pathways from multiple independent population GWASs may be helpful in identifying associations with small effect sizes and increasing the association power. Here, we proposed ancMETA, a Bayesian graph-based framework, to perform the gene/pathway-specific meta-analysis by combining the effect size of multiple SNPs within genes, and genes within subnetwork/pathways across multiple independent population GWASs to deconvolute the interactions between genes underlying the pathogenesis of complex diseases across human populations. We assessed the proposed framework on simulated datasets, and the results show that the proposed model holds promise for increasing statistical power for meta-analysis of genetic variants underlying the pathogenesis of complex diseases. To illustrate the proposed meta-analysis framework, we leverage seven different European bipolar disorder (BD) cohorts, and we identify variants in the angiotensinogen (
) gene to be significantly associated with BD across all 7 studies. We detect a commonly significant BD-specific subnetwork with the
gene as the main hub of a subnetwork, associated with neurotrophin signaling (p = 4
) and myometrial relaxation and contraction (p = 3
) pathways. ancMETA provides a new contribution to post-GWAS methodologies and holds promise for comprehensively examining interactions between genes underlying the pathogenesis of genetic diseases and also underlying ethnic differences.
Abstract
Despite the meteoric rise in genome-wide association studies for metabolic diseases (MetD) over the last few years, our understanding of the pathogenesis of these diseases is still far from ...complete. Recent developments have established that MetD arises from complex interactions between host genetics, the gut microbiome and the environment. However, our knowledge of the genetic and microbiome components involved and the underlying molecular mechanisms remains limited. Here, we review and summarize recent studies investigating the genetic and microbiome basis of MetD. Then, given the critical importance of study-individual’s ancestry in these studies, we leverage 4932 whole-genome sequence samples from 18 worldwide ethnic groups to examine genetic diversity in currently reported variants associated with MetD. The analyses show marked differences in gene-specific proportion of pathogenic single-nucleotide polymorphisms (SNPs) and gene-specific SNPs MAFs across ethnic groups, highlighting the importance of population- and ethnic-specific investigations in pinpointing the causative factors for MetD. We conclude with a discussion of research areas where further investigation on interactions between host genetics, microbiome and the environment is needed.
Tuberculosis (TB) is one of the major public health problems in Ethiopia. Data on genetic diversity and resistance profile of circulating TB strains is critical for informing the national TB control ...program.
A cross-sectional study was conducted on 213 smear positive pulmonary TB patients between 2015 and 2016. Sputum samples were cultured on LJ media following the Petroff's method. Region of difference-9 (RD9)-deletion typing and spoligo-typing were performed for molecular analysis of M. tuberculosis at species and strain levels, respectively. Drug sensitivity and mutation patterns of the isolates were assessed by the conventional indirect proportion method and molecular line probe assays (LPAs), respectively. Data were analyzed using statistical package for social sciences (SPSS) software version 20.
Spoligo-typing of 150 M. tuberculosis isolates led to 57 different patterns of which 25 were new strains. The majority (71.6%) of the isolates were grouped in to 17 clusters consisting 2 to 24 isolates. The majority of the strains belonged to Euro-American lineage and the predominant spoligotypes were SIT 37 and SIT 149. MDR-TB was detected in 5.2% and 20.3% of new and retreatment cases, respectively. Two MDR-TB isolates exhibited additional resistance to one of the second line anti-TB drugs. Common gene mutations including S531L, S315T1 and M306V were detected in RIF, INH and EMB resistant strains, respectively.
The identification of several new strains, higher proportion of MDR-TB and higher clustering rate in this study, warrants the need for re-enforcement of the national TB control program. The detection of common gene mutations in the majority drug resistant strains might suggest the feasibility of LPAs for rapid screening of drug resistant M. tuberculosis strains in Ethiopia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Drug-like compounds are most of the time denied approval and use owing to the unexpected clinical side effects and cross-reactivity observed during clinical trials. These unexpected outcomes ...resulting in significant increase in attrition rate centralizes on the selected drug targets. These targets may be disease candidate proteins or genes, biological pathways, disease-associated microRNAs, disease-related biomarkers, abnormal molecular phenotypes, crucial nodes of biological network or molecular functions. This is generally linked to several factors, including incomplete knowledge on the drug targets and unpredicted pharmacokinetic expressions upon target interaction or off-target effects. A method used to identify targets, especially for polygenic diseases, is essential and constitutes a major bottleneck in drug development with the fundamental stage being the identification and validation of drug targets of interest for further downstream processes. Thus, various computational methods have been developed to complement experimental approaches in drug discovery. Here, we present an overview of various computational methods and tools applied in predicting or validating drug targets and drug-like molecules. We provide an overview on their advantages and compare these methods to identify effective methods which likely lead to optimal results. We also explore major sources of drug failure considering the challenges and opportunities involved. This review might guide researchers on selecting the most efficient approach or technique during the computational drug discovery process.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
As we observe the $70$th anniversary of the publication by Robertson that formalized the notion of ‘heritability’, geneticists remain puzzled by the problem of missing/hidden heritability, ...where heritability estimates from genome-wide association studies (GWASs) fall short of that from twin-based studies. Many possible explanations have been offered for this discrepancy, including existence of genetic variants poorly captured by existing arrays, dominance, epistasis and unaccounted-for environmental factors; albeit these remain controversial. We believe a substantial part of this problem could be solved or better understood by incorporating the host’s microbiota information in the GWAS model for heritability estimation and may also increase human traits prediction for clinical utility. This is because, despite empirical observations such as (i) the intimate role of the microbiome in many complex human phenotypes, (ii) the overlap between genetic variants associated with both microbiome attributes and complex diseases and (iii) the existence of heritable bacterial taxa, current GWAS models for heritability estimate do not take into account the contributory role of the microbiome. Furthermore, heritability estimate from twin-based studies does not discern microbiome component of the observed total phenotypic variance. Here, we summarize the concept of heritability in GWAS and microbiome-wide association studies, focusing on its estimation, from a statistical genetics perspective. We then discuss a possible statistical method to incorporate the microbiome in the estimation of heritability in host GWAS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report a study of genome-wide, dense SNP (∼ 900K) and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African ...populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This finding illustrates the need to account for stratification in genome-wide association studies, and that admixture mapping would likely be a successful approach in these populations. We developed a strategy to detect the signature of selection prior to and following putative admixture events. Several genomic regions show an unusual excess of Niger-Kordofanian, and unusual deficiency of both San and Eurasian ancestry, which were considered the footprints of selection after population admixture. Several SNPs with strong allele frequency differences were observed predominantly between the admixed indigenous southern African populations, and their ancestral Eurasian populations. Interestingly, many candidate genes, which were identified within the genomic regions showing signals for selection, were associated with southern African-specific high-risk, mostly communicable diseases, such as malaria, influenza, tuberculosis, and human immunodeficiency virus/AIDs. This observation suggests a potentially important role that these genes might have played in adapting to the environment. Additionally, our analyses of haplotype structure, linkage disequilibrium, recombination, copy number variation and genome-wide admixture highlight, and support the unique position of San relative to both African and non-African populations. This study contributes to a better understanding of population ancestry and selection in south-eastern African populations; and the data and results obtained will support research into the genetic contributions to infectious as well as non-communicable diseases in the region.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Southern African Human Genome Programme is a national initiative that aspires to unlock the unique genetic character of southern African populations for a better understanding of human genetic ...diversity. In this pilot study the Southern African Human Genome Programme characterizes the genomes of 24 individuals (8 Coloured and 16 black southeastern Bantu-speakers) using deep whole-genome sequencing. A total of ~16 million unique variants are identified. Despite the shallow time depth since divergence between the two main southeastern Bantu-speaking groups (Nguni and Sotho-Tswana), principal component analysis and structure analysis reveal significant (p < 10
) differentiation, and F
analysis identifies regions with high divergence. The Coloured individuals show evidence of varying proportions of admixture with Khoesan, Bantu-speakers, Europeans, and populations from the Indian sub-continent. Whole-genome sequencing data reveal extensive genomic diversity, increasing our understanding of the complex and region-specific history of African populations and highlighting its potential impact on biomedical research and genetic susceptibility to disease.
The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity ...among African individuals has been surveyed
. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.
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