scholarly journals Using Regions of Homozygosity to Evaluate the Use of Dogs as Preclinical Models in Human Drug Development

2020 ◽  
Author(s):  
Sandra Paulina Smieszek ◽  
Mihael Polymeropoulos
Keyword(s):  
Drug Development ◽  
Human Populations ◽  
Preclinical Models ◽  
Preclinical Research ◽  
Clinical Safety ◽  
1000 Genomes ◽  
Genome Wide ◽  
A Genome ◽  
Cytochrome P450 Family ◽  
Regions Of Homozygosity

Abstract BACKGROUND Animals are used as preclinical models for human diseases in drug development. Dogs, especially, are used in preclinical research to support the clinical safety evaluations during drug development. Comparisons of patterns of regions of homozygosity (ROH) and phenotypes between dog and human are not well known. We conducted a genome-wide homozygosity analysis (GWHA) in the human and the dog genomes.RESULTS We calculated ROH patterns across distinct human cohorts including the Amish, the 1000 genomes, Wellderly, Vanda 1 k genomes, and Alzheimer’s cohort. The Amish provided a large cohort of extended kinships allowing for in depth family oriented analyses. The remaining human cohorts served as statistical references. We then calculated ROH across different dog breeds with emphasis on the beagle - the preferred breed used in drug development. Out of five studied human cohorts we reported the highest mean ROH in the Amish population. We calculated the extent of the genome covered by ROH (FROH) (human 3.2 Gb, dog 2.5 Gb). Overall FROH differed significantly between the Amish and the 1000 genomes, and between the human and the beagle genomes. The mean FROH per 1 Mb was ~ 16 kb for Amish, ~ 0.6 kb for Vanda 1 k, and ~ 128 kb for beagles. This result demonstrated the highest degree of inbreeding in beagles, far above that of the Amish, one of the most inbred human populations. ROH can contribute to inbreeding depression if they contain deleterious variants that are fully or partially recessive.CONCLUSIONS The differences in ROH characteristics between human and dog genomes question the applicability of dog models in preclinical research, especially when the goal is to gauge the subtle effects on the organism’s physiology produced by candidate therapeutic agents. Importantly, there are huge differences in a subset of ADME genes, specifically cytochrome P450 family (CYPs), constituting major enzymes involved in drug metabolism. We should use caution when generalizing from dog to human, even if human and beagle are relatively close species phylogenetically

scholarly journals Using regions of homozygosity to evaluate the use of dogs as preclinical models in human drug development

2020 ◽  
Author(s):  
SP. Smieszek ◽  
MP. Polymeropoulos
Keyword(s):  
Drug Development ◽  
Human Populations ◽  
Preclinical Models ◽  
Preclinical Research ◽  
Clinical Safety ◽  
1000 Genomes ◽  
Genome Wide ◽  
A Genome ◽  
Cytochrome P450 Family ◽  
Regions Of Homozygosity

AbstractAnimals are used as preclinical models for human diseases in drug development. Dogs, especially, are used in preclinical research to support the clinical safety evaluations during drug development. Comparisons of patterns of regions of homozygosity (ROH) and phenotypes between dog and human are not well known. We conducted a genome-wide homozygosity analysis (GWHA) in the human and the dog genomes.We calculated ROH patterns across distinct human cohorts including the Amish, the 1000 genomes, Wellderly, Vanda 1k genomes, and Alzheimer’s cohort. The Amish provided a large cohort of extended kinships allowing for in depth family oriented analyses. The remaining human cohorts served as statistical references. We then calculated ROH across different dog breeds with emphasis on the beagle - the preferred breed used in drug development.Out of five studied human cohorts we reported the highest mean ROH in the Amish population. We calculated the extent of the genome covered by ROH (FROH) (human 3.2Gb, dog 2.5Gb). Overall FROH differed significantly between the Amish and the 1000 genomes, and between the human and the beagle genomes. The mean FROH per 1Mb was ∼16kb for Amish, ∼0.6kb for Vanda 1k, and ∼128kb for beagles. This result demonstrated the highest degree of inbreeding in beagles, far above that of the Amish, one of the most inbred human populations.ROH can contribute to inbreeding depression if they contain deleterious variants that are fully or partially recessive. The differences in ROH characteristics between human and dog genomes question the applicability of dog models in preclinical research, especially when the goal is to gauge the subtle effects on the organism’s physiology produced by candidate therapeutic agents. Importantly, there are huge differences in a subset of ADME genes, specifically cytochrome P450 family (CYPs), constituting major enzymes involved in drug metabolism. We should hesitate to generalize from dog to human, even if human and beagle are relatively close species phylogenetically

A Genome-Wide Approach To Drug Development For Fibrosis

2012 ◽  
Author(s):  
Jeff Braziunas ◽  
Matthew W. Parker ◽  
Mark Peterson ◽  
Karen Smith ◽  
Jon Michael Underwood ◽  
...  
Keyword(s):  
Drug Development ◽  
Genome Wide ◽  
A Genome

scholarly journals Presence and Transmission of Mitochondrial Heteroplasmic Mutations in Human Populations of European and African Ancestry

2020 ◽  
Author(s):  
Chunyu Liu ◽  
Jessica L. Fetterman ◽  
Yong Qian ◽  
Xianbang Sun ◽  
Kaiyu Yan ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
African Ancestry ◽  
Functional Characterization ◽  
Nuclear Genome ◽  
Human Populations ◽  
Sibling Pairs ◽  
Coding Regions ◽  
Genome Wide ◽  
A Genome

ABSTRACTWe investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in different types of maternal pairs (n=6,745 pairs) of European (EA, n=4,718 pairs) and African (AA, n=2,027 pairs) Americans with whole genome sequences (WGSs). The average concordance rate of heteroplasmies was highest between mother-offspring pairs, followed by sibling-sibling pairs and more distantly related maternal pairs in both EA and AA participants. The allele fractions of concordant heteroplasmies exhibited high correlation (R2=0.8) between paired individuals. Compared to concordant heteroplasmies, discordant ones were more likely to locate in coding regions, be nonsynonymous or nonsynonymous-deleterious (p<0.001). The average number of heteroplasmies per individual (i.e. heteroplasmic burden) was at a similar level until older age (70-80 years old) and increased significantly thereafter (p<0.01). The burden of deleterious heteroplasmies (combined annotation-dependent depletion score≥15), however, was significantly correlated with advancing age (20-44, 45-64, ≥65 years, p-trend=0.01). A genome-wide association analysis of the heteroplasmic burden identified many significant (P<5e-8) common variants (minor allele frequency>0.05) at 11p11.12. Many of the top SNPs act as strong long-range cis regulators of protein tyrosine phosphatase receptor type J. This study provides further evidence that mtDNA heteroplasmies may be inherited or somatic. Somatic heteroplasmic variants increase with advancing age and are more likely to have an adverse impact on mitochondrial function. Further studies are warranted for functional characterization of the deleterious heteroplasmies occurring with advancing age and the association of the 11p11.12 region of the nuclear genome with mtDNA heteroplasmy.

scholarly journals Following the Trail of One Million Genomes: Footprints of SARS-CoV-2 Adaptation to Humans

2021 ◽  
Author(s):  
Saymon Akther ◽  
Edgaras Bezrucenkovas ◽  
Li Li ◽  
Brian Sulkow ◽  
Lia Di ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Immune Escape ◽  
Local Level ◽  
Genome Structure ◽  
Base Substitution ◽  
Human Populations ◽  
Clonal Interference ◽  
Adaptive Mutations ◽  
Genome Wide ◽  
A Genome

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has accumulated genomic mutations at an approximately linear rate since it first infected human populations in late 2019. Controversies remain regarding the identity, proportion, and effects of adaptive mutations as SARS-CoV-2 evolves from a bat- to a human-adapted virus. The potential for vaccine-escape mutations poses additional challenges in pandemic control. Despite being of great interest to therapeutic and vaccine development, human-adaptive mutations in SARS-CoV-2 are masked by a genome-wide linkage disequilibrium under which neutral and even deleterious mutations can reach fixation by chance or through hitchhiking. Furthermore, genome-wide linkage equilibrium imposes clonal interference by which multiple adaptive mutations compete against one another. Informed by insights from microbial experimental evolution, we analyzed close to one million SARS-CoV-2 genomes sequenced during the first year of the COVID-19 pandemic and identified putative human-adaptive mutations according to the rates of synonymous and missense mutations, temporal linkage, and mutation recurrence. Furthermore, we developed a forward-evolution simulator with the realistic SARS-CoV-2 genome structure and base substitution probabilities able to predict viral genome diversity under neutral, background selection, and adaptive evolutionary models. We conclude that adaptive mutations have emerged early, rapidly, and constantly to dominate SARS-CoV-2 populations despite clonal interference and purifying selection. Our analysis underscores a need for genomic surveillance of mutation trajectories at the local level for early detection of adaptive and immune-escape variants. Putative human-adaptive mutations are over-represented in viral proteins interfering host immunity and binding host-cell receptors and thus may serve as priority targets for designing therapeutics and vaccines against human-adapted forms of SARS-CoV-2.

scholarly journals A method for genome-wide genealogy estimation for thousands of samples

2019 ◽  
Author(s):  
Leo Speidel ◽  
Marie Forest ◽  
Sinan Shi ◽  
Simon R. Myers
Keyword(s):  
Blood Pressure ◽  
Human Populations ◽  
1000 Genomes Project ◽  
Hair Colour ◽  
Strong Positive Selection ◽  
Data Errors ◽  
1000 Genomes ◽  
Genome Wide ◽  
Branch Lengths ◽  
Population Sizes

AbstractKnowledge of genome-wide genealogies for thousands of individuals would simplify most evolutionary analyses for humans and other species, but has remained computationally infeasible. We developed a method, Relate, scaling to > 10,000 sequences while simultaneously estimating branch lengths, mutational ages, and variable historical population sizes, as well as allowing for data errors. Application to 1000 Genomes Project haplotypes produces joint genealogical histories for 26 human populations. Highly diverged lineages are present in all groups, but most frequent in Africa. Outside Africa, these mainly reflect ancient introgression from groups related to Neanderthals and Denisovans, while African signals instead reflect unknown events, unique to that continent. Our approach allows more powerful inferences of natural selection than previously possible. We identify multiple novel regions under strong positive selection, and multi-allelic traits including hair colour, BMI, and blood pressure, showing strong evidence of directional selection, varying among human groups.

scholarly journals Whole genome screen reveals a novel relationship between Wolbachia levels and Drosophila host translation

2018 ◽  
Author(s):  
Yolande Grobler ◽  
Chi Y. Yun ◽  
David J. Kahler ◽  
Casey M. Bergman ◽  
Hangnoh Lee ◽  
...  
Keyword(s):  
Gene Networks ◽  
Virus Transmission ◽  
Antiviral Effect ◽  
Human Populations ◽  
West Nile ◽  
Genome Wide ◽  
A Genome ◽  
Vector Borne

AbstractWolbachia is an intracellular bacterium that infects a remarkable range of insect hosts. Insects such as mosquitos act as vectors for many devastating human viruses such as Dengue, West Nile, and Zika. Remarkably, Wolbachia infection provides insect hosts with resistance to many arboviruses thereby rendering the insects ineffective as vectors. To utilize Wolbachia effectively as a tool against vector-borne viruses a better understanding of the host-Wolbachia relationship is needed. To investigate Wolbachia-insect interactions we used the Wolbachia/Drosophila model that provides a genetically tractable system for studying host-pathogen interactions. We coupled genome-wide RNAi screening with a novel high-throughput fluorescence in situ hybridization (FISH) assay to detect changes in Wolbachia levels in a Wolbachia-infected Drosophila cell line JW18. 1117 genes altered Wolbachia levels when knocked down by RNAi of which 329 genes increased and 788 genes decreased the level of Wolbachia. Validation of hits included in depth secondary screening using in vitro RNAi, Drosophila mutants, and Wolbachia-detection by DNA qPCR. A diverse set of host gene networks was identified to regulate Wolbachia levels and unexpectedly revealed that perturbations of host translation components such as the ribosome and translation initiation factors results in increased Wolbachia levels both in vitro using RNAi and in vivo using mutants and a chemical-based translation inhibition assay. This work provides evidence for Wolbachia-host translation interaction and strengthens our general understanding of the Wolbachia-host intracellular relationship.Author summaryInsects such as mosquitos act as vectors to spread devastating human diseases such as Dengue, West Nile, and Zika. It is critical to develop control strategies to prevent the transmission of these diseases to human populations. A novel strategy takes advantage of an endosymbiotic bacterium Wolbachia pipientis. The presence of this bacterium in insect vectors prevents successful transmission of RNA viruses. The degree to which viruses are blocked by Wolbachia is dependent on the levels of the bacteria present in the host such that higher Wolbachia levels induce a stronger antiviral effect. In order to use Wolbachia as a tool against vector-borne virus transmission a better understanding of host influences on Wolbachia levels is needed. Here we performed a genome-wide RNAi screen in a model host system Drosophila melanogaster infected with Wolbachia to identify host systems that affect Wolbachia levels. We found that host translation can influence Wolbachia levels in the host.

Alternative Isoform Detection Using Exon Arrays

2009 ◽  
pp. 262-277
Author(s):  
Jacek Majewski
Keyword(s):  
Human Populations ◽  
Genomic Locus ◽  
Exon Arrays ◽  
Eukaryotic Genes ◽  
Genome Wide ◽  
A Genome ◽  
Potential Problems ◽  
Recent Developments ◽  
Wide Scale ◽  
Alternative Isoforms

Eukaryotic genes have the ability to produce several distinct products from a single genomic locus. Recent developments in microarray technology allow monitoring of such isoform variation at a genome-wide scale. In our research, we have used Affymetrix Exon Arrays to detect variation in alternative splicing, initiation of transcription, and polyadenylation among humans. We demonstrated that such variation is common in human populations and has an underlying genetic component. Here, we use our study to illustrate the use of Exon Arrays to detect alternative isoforms, to outline the analysis involved, and to point out potential problems that may be encountered by researchers using this technology.

scholarly journals Genome-wide association study identifies ERBB4 on 2q34 as a novel locus associated with sperm motility in Japanese men

2018 ◽  
Vol 55 (6) ◽  
pp. 415-421 ◽  
Author(s):  
Youichi Sato ◽  
Atsushi Tajima ◽  
Takehiro Sato ◽  
Shiari Nozawa ◽  
Miki Yoshiike ◽  
...  
Keyword(s):  
Association Study ◽  
Sperm Motility ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Human Populations ◽  
Motile Sperm ◽  
Japanese Men ◽  
Genome Wide ◽  
A Genome

BackgroundThe decrease in sperm motility has a potent influence on fertilisation. Sperm motility, represented as the percentage of motile sperm in ejaculated sperms, is influenced by lifestyle habits or environmental factors and by inherited factors. However, genetic factors contributing to individual differences in sperm motility remain unclear. To identify genetic factors that influence human sperm motility, we performed a genome-wide association study (GWAS) of sperm motility.MethodsA two-stage GWAS was conducted using 811 Japanese men in a discovery stage, followed by a replication study using an additional 779 Japanese men.ResultsIn the two-staged GWAS, a single nucleotide polymorphism rs3791686 in the intron of gene for erb-b2 receptor tyrosine kinase 4 (ERBB4) on chromosome 2q34 was identified as a novel locus for sperm motility, as evident from the discovery and replication results using meta-analysis (β=−4.01, combined P=5.40×10−9).ConclusionsTogether with the previous evidence that Sertoli cell-specific Erbb4-knockout mice display an impaired ability to produce motile sperm, this finding provides the first genetic evidence for further investigation of the genome-wide significant association at the ERBB4 locus in larger studies across diverse human populations.

scholarly journals New insights into malaria susceptibility from the genomes of 17,000 individuals from Africa, Asia, and Oceania

2019 ◽  
Author(s):  
Keyword(s):  
Host Resistance ◽  
Genome Wide Association Study ◽  
Future Research ◽  
Human Populations ◽  
Chromosome 6 ◽  
Genetic Determinants ◽  
Transcription Start ◽  
Genome Wide ◽  
A Genome ◽  
Malaria Susceptibility

AbstractWe conducted a genome-wide association study of host resistance to severe Plasmodium falciparum malaria in over 17,000 individuals from 11 malaria-endemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association in ATP2B4. Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria (h2 ~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these diverse human populations.

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