scholarly journals Local ancestry analysis reveals genomic convergence in extremophile fishes

2019 ◽  
Vol 374 (1777) ◽  
pp. 20180240 ◽  
Author(s):  
Anthony P. Brown ◽  
Kerry L. McGowan ◽  
Enrique J. Schwarzkopf ◽  
Ryan Greenway ◽  
Lenin Arias Rodriguez ◽  
...  
Keyword(s):  
Candidate Genes ◽  
De Novo ◽  
Large Population ◽  
Significant Proportion ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations ◽  
Genetic Constraints ◽  
Standing Variation ◽  
Whole Genome Resequencing ◽  
Genomic Convergence

The molecular basis of convergent phenotypes is often unknown. However, convergence at a genomic level is predicted when there are large population sizes, gene flow among diverging lineages or strong genetic constraints. We used whole-genome resequencing to investigate genomic convergence in fishes ( Poecilia spp.) that have repeatedly colonized hydrogen sulfide (H 2 S)-rich environments in Mexico. We identified genomic similarities in both single nucleotide polymorphisms (SNPs) and structural variants (SVs) among independently derived sulfide spring populations, with approximately 1.2% of the genome being shared among sulfidic ecotypes. We compared these convergent genomic regions to candidate genes for H 2 S adaptation identified from transcriptomic analyses and found that a significant proportion of these candidate genes (8%) were also in regions where sulfidic individuals had similar SNPs, while only 1.7% were in regions where sulfidic individuals had similar SVs. Those candidate genes included genes involved in sulfide detoxification, the electron transport chain (the main toxicity target of H 2 S) and other processes putatively important for adaptation to sulfidic environments. Regional genomic similarity across independent populations exposed to the same source of selection is consistent with selection on standing variation or introgression of adaptive alleles across divergent lineages. However, combined with previous analyses, our data also support that adaptive changes in mitochondrially encoded subunits arose independently via selection on de novo mutations. Pressing questions remain on what conditions ultimately facilitate the independent rise of adaptive alleles at the same loci in separate populations, and thus, the degree to which evolution is repeatable or predictable. This article is part of the theme issue ‘Convergent evolution in the genomics era: new insights and directions'.

scholarly journals Characterization of metabolic responses, genetic variations, and microsatellite instability in ammonia-stressed CHO cells grown in fed-batch cultures

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dylan G. Chitwood ◽  
Qinghua Wang ◽  
Kathryn Elliott ◽  
Aiyana Bullock ◽  
Dwon Jordana ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Microsatellite Loci ◽  
Cho Cells ◽  
Genome Stability ◽  
De Novo ◽  
Genome Instability ◽  
Chinese Hamster ◽  
Functional Genes ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations

Abstract Background As bioprocess intensification has increased over the last 30 years, yields from mammalian cell processes have increased from 10’s of milligrams to over 10’s of grams per liter. Most of these gains in productivity can be attributed to increasing cell densities within bioreactors. As such, strategies have been developed to minimize accumulation of metabolic wastes, such as lactate and ammonia. Unfortunately, neither cell growth nor biopharmaceutical production can occur without some waste metabolite accumulation. Inevitably, metabolic waste accumulation leads to decline and termination of the culture. While it is understood that the accumulation of these unwanted compounds imparts a suboptimal culture environment, little is known about the genotoxic properties of these compounds that may lead to global genome instability. In this study, we examined the effects of high and moderate extracellular ammonia on the physiology and genomic integrity of Chinese hamster ovary (CHO) cells. Results Through whole genome sequencing, we discovered 2394 variant sites within functional genes comprised of both single nucleotide polymorphisms and insertion/deletion mutations as a result of ammonia stress with high or moderate impact on functional genes. Furthermore, several of these de novo mutations were found in genes whose functions are to maintain genome stability, such as Tp53, Tnfsf11, Brca1, as well as Nfkb1. Furthermore, we characterized microsatellite content of the cultures using the CriGri-PICR Chinese hamster genome assembly and discovered an abundance of microsatellite loci that are not replicated faithfully in the ammonia-stressed cultures. Unfaithful replication of these loci is a signature of microsatellite instability. With rigorous filtering, we found 124 candidate microsatellite loci that may be suitable for further investigation to determine whether these loci may be reliable biomarkers to predict genome instability in CHO cultures. Conclusion This study advances our knowledge with regards to the effects of ammonia accumulation on CHO cell culture performance by identifying ammonia-sensitive genes linked to genome stability and lays the foundation for the development of a new diagnostic tool for assessing genome stability.

scholarly journals A Systematic Review on Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

2020 ◽  
Author(s):  
Sana Amanat ◽  
Teresa Requena ◽  
Jose Antonio Lopez-Escamez
Keyword(s):  
Systematic Review ◽  
Candidate Genes ◽  
Rare Variants ◽  
De Novo ◽  
Complex Diseases ◽  
De Novo Mutations ◽  
Genetic Studies ◽  
Complex Disorders ◽  
Extreme Phenotype ◽  
Age Related

Exome sequencing has been commonly used in rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) to search for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to heritability in complex clinical traits. We have conducted a systematic review to find evidence supporting the use of EP strategies to search for rare variants in genetic studies of complex diseases, to highlight the contribution of rare variation to the genetic structure of multiallelic conditions. After performing the quality assessment of the retrieved records, we selected 19 genetic studies considering EP to demonstrate genetic association. All the studies successfully identified several rare variants, de novo mutations and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach in patients with an early onset of the disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.

scholarly journals Haplotyping by linked-read sequencing (HLRS) of the genetic disease carriers for preimplantation genetic testing without a proband or relatives

2020 ◽  
Author(s):  
Qing Li ◽  
Yan Mao ◽  
Shaoying Li ◽  
Hongzi Du ◽  
Wenzhi He ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Genetic Disease ◽  
De Novo ◽  
Monogenic Disease ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations ◽  
Preimplantation Genetic Testing ◽  
Linkage Analyses ◽  
Alpha Thalassemia ◽  
Polar Bodies

Abstract Background: In order to mitigate the risk of allele dropout (ADO) and ensure the accuracy of preimplantation genetic testing for monogenic disease (PGT-M), it is necessary to construct parental haplotypes.. Typically, haplotype resolution is obtained by genotyping multiple polymorphic markers in both parents and a proband or a relative. Sometimes, single sperm typing, or tests on the polar bodies may also be useful. Nevertheless, this process is time-consuming. At present, there was no simple linkage analysis strategy for patients without affected relatives.Method: To solve this problem, we established a haplotyping by linked-read sequencing (HLRS) method without the requirement for additional relatives. First, the haplotype of the genetic disease carriers in the family was constructed by linked-read sequencing, and then the informative single nucleotide polymorphisms (SNPs) in upstream and downstream mutation region were selected to construct the embryo haplotype and to determine whether the embryo was carrying the mutation. Two families were selected to validate this method; one with alpha thalassemia and the other with NDP gene disorder.Results: The haplotyping by linked-read sequencing (HLRS) method was successfully applied to construct parental haplotypes without recruiting additional family members; the method was also validated for PGT-M. The mutation carriers in these families were sequenced by linked-read sequencing, and their haplotypes were successfully phased. Adjacent SNPs of the mutation gene were identified. The informative SNPs were chosen for linkage analyses to identify the carrier embryos. For the alpha thalassemia family, a normal blastocyst was transferred to the uterus and the accuracy of PGT-M was confirmed by amniocentesis at 16 weeks of gestation. Conclusions: Our results suggest that HLRS can be applied for PGT-M of monogenic disorders or de novo mutations where the mutations haplotype cannot be determined due to absence of affected relatives. Keywords: Preimplantation Genetic Testing for monogenic disease, Linked-read sequencing, Linkage analyses, Haplotype

scholarly journals One Health Genomic Study of Human and Animal Klebsiella pneumoniae Isolated at Diagnostic Laboratories on a Small Caribbean Island

Antibiotics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 42
Author(s):  
Patrick Butaye ◽  
Marc Stegger ◽  
Arshnee Moodley ◽  
Peter Damborg ◽  
Andrea Williams ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
One Health ◽  
De Novo ◽  
Large Population ◽  
Vervet Monkeys ◽  
Nucleotide Polymorphisms ◽  
Caribbean Island ◽  
Indirect Contact ◽  
Genomic Study ◽  
Antimicrobial Resistance Gene

Klebsiella pneumoniae causes a variety of infections in both humans and animals. In this study, we characterised the genomes of human and animal isolates from two diagnostic laboratories on St. Kitts, a small Caribbean island inhabited by a large population of vervet monkeys. In view of the increased chances of direct or indirect contact with humans and other animal species, we used the One Health approach to assess transmission of K. pneumoniae across host species by sequencing 82 presumptive K. pneumoniae clinical isolates from humans (n = 51), vervets (n = 21), horses (n = 5), dogs (n = 4) and a cat (n = 1). Whole genome sequencing (WGS) was carried out using Illumina technology. De novo assembly was performed in CLC Genomics Workbench v.11.0. Single nucleotide polymorphisms were detected using NASP followed by phylogenetic analysis using IQ-TREE. Virulence and antimicrobial resistance gene contents were analysed using the Kleborate and CGE pipelines. WGS-based analysis showed that 72 isolates were K. pneumoniae sensu stricto and five K. quasipneumoniae and five K. variicola. K. pneumoniae isolates belonged to 35 sequence types (ST), three of which were occasionally shared between humans and animals: ST23, ST37 and ST307. The ST23 strains from vervets formed a separate cluster amongst publicly available sequenced ST23 strains, indicating the presence of a specific vervet sublineage. Animal strains harbored fewer resistance genes and displayed distinct virulence traits that appeared to be host-specific in vervet isolates. Our results show that K. pneumoniae infections on this Caribbean island are usually caused by host-specific lineages.

scholarly journals Comparative Analysis of Impatiens Leaf Transcriptomes Reveal Candidate Genes for Resistance to Downy Mildew Caused by Plasmopara obducens

2018 ◽  
Vol 19 (7) ◽  
pp. 2057 ◽  
Author(s):  
Krishna Bhattarai ◽  
Weining Wang ◽  
Zhe Cao ◽  
Zhanao Deng
Keyword(s):  
Disease Resistance ◽  
Candidate Genes ◽  
Downy Mildew ◽  
Resistance Genes ◽  
De Novo ◽  
Average Length ◽  
Disease Resistance Genes ◽  
Nucleotide Polymorphisms ◽  
Clusters Of Orthologous Groups ◽  
New Guinea Impatiens

Impatiens downy mildew (IDM) is a devastating disease to garden impatiens. A good understanding of IDM resistance in New Guinea impatiens is essential for improving garden impatiens resistance to this disease. The present study was conducted to sequence, assemble, annotate and compare the leaf transcriptomes of two impatiens cultivars differing in resistance to IDM, reveal sequence polymorphisms and identify candidate genes for IDM resistance. RNA-Seq was performed on cultivars Super Elfin® XP Pink (SEP) and SunPatiens® Compact Royal Magenta (SPR). De novo assembly of obtained sequence reads resulted in 121,497 unigenes with an average length of 1156 nucleotides and N50 length of 1778 nucleotides. Searching the non-redundant protein and non-redundant nucleotide, Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes and Clusters of Orthologous Groups and Gene Ontology databases, resulted in annotation of 57.7% to 73.6% of the unigenes. Fifteen unigenes were highly similar to disease resistance genes and more abundant in the IDM-resistant cultivar than in the susceptible cultivar. A total of 22,484 simple sequence repeats (SSRs) and 245,936 and 120,073 single nucleotide polymorphisms (SNPs) were identified from SPR and SEP respectively. The assembled transcripts and unigenes, identified disease resistance genes and SSRs and SNPs sites will be a valuable resource for improving impatiens and its IDM resistance.

scholarly journals Weakly deleterious natural genetic variation amplifies probability of resistance in multiplexed gene drive systems

2021 ◽  
Author(s):  
Bhavin S Khatri ◽  
Austin Burt
Keyword(s):  
De Novo ◽  
Large Population ◽  
Stochastic Simulations ◽  
Gene Drive ◽  
End Joining ◽  
Single Nucleotide ◽  
Major Barrier ◽  
Standing Variation ◽  
Large Populations ◽  
Drive Systems

Evolution of resistance is a major barrier to successful deployment of gene drive systems to suppress natural populations. Multiplexed guide RNAs that require resistance mutations in all target cut sites is a promising strategy to overcome resistance. Using novel stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) non-homologous end-joining mutations, 2) single nucleotide mutants arising de novo or, 3) single nucleotide polymorphisms pre-existing as standing variation. If the fraction of functional end-joining mutants is rare, we show that standing variation dominates, via a qualitatively new phenomenon where weakly deleterious variants significantly amplify the probability of multi-site resistance. This means resistance can be probable even with many target sites in not very large populations. This result has broad application to resistance arising in multi-site evolutionary scenarios including the evolution of vaccine escape mutations in large populations.

scholarly journals A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA

2021 ◽  
Author(s):  
Monica Sanchez-Contreras ◽  
Mariya T Sweetwyne ◽  
Brendan F Kohrn ◽  
Kristine A Tsantilas ◽  
Michael J Hipp ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Somatic Mutations ◽  
De Novo ◽  
Primary Source ◽  
Regulatory Elements ◽  
Genome Replication ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations ◽  
Genome Composition ◽  
Mtdna Mutations

Abstract Mutations in mitochondrial DNA (mtDNA) cause maternally inherited diseases, while somatic mutations are linked to common diseases of aging. Although mtDNA mutations impact health, the processes that give rise to them are under considerable debate. To investigate the mechanism by which de novo mutations arise, we analyzed the distribution of naturally occurring somatic mutations across the mouse and human mtDNA obtained by Duplex Sequencing. We observe distinct mutational gradients in G→A and T→C transitions delimited by the light-strand origin and the mitochondrial Control Region (mCR). The gradient increases unequally across the mtDNA with age and is lost in the absence of DNA polymerase γ proofreading activity. In addition, high-resolution analysis of the mCR shows that important regulatory elements exhibit considerable variability in mutation frequency, consistent with them being mutational ‘hot-spots’ or ‘cold-spots’. Collectively, these patterns support genome replication via a deamination prone asymmetric strand-displacement mechanism as the fundamental driver of mutagenesis in mammalian DNA. Moreover, the distribution of mtDNA single nucleotide polymorphisms in humans and the distribution of bases in the mtDNA across vertebrate species mirror this gradient, indicating that replication-linked mutations are likely the primary source of inherited polymorphisms that, over evolutionary timescales, influences genome composition during speciation.

scholarly journals Catch me if you can: Adaptation from standing genetic variation to a moving phenotypic optimum

2015 ◽  
Author(s):  
Sebastian Matuszewski ◽  
Joachim Hermisson ◽  
Michael Kopp
Keyword(s):  
Genetic Variation ◽  
De Novo ◽  
Darwinian Evolution ◽  
De Novo Mutations ◽  
Population Means ◽  
Standing Variation ◽  
Analytical Approximations ◽  
Formal Framework ◽  
Phenotype Space ◽  
Effect Size Distribution

Adaptation lies at the heart of Darwinian evolution. Accordingly, numerous studies have tried to provide a formal framework for the description of the adaptive process. Out of these, two complementary modelling approaches have emerged: While so-called adaptive-walk models consider adaptation from the successive fixation of de-novo mutations only, quantitative genetic models assume that adaptation proceeds exclusively from pre-existing standing genetic variation. The latter approach, however, has focused on short-term evolution of population means and variances rather than on the statistical properties of adaptive substitutions. Our aim is to combine these two approaches by describing the ecological and genetic factors that determine the genetic basis of adaptation from standing genetic variation in terms of the effect-size distribution of individual alleles. Specifically, we consider the evolution of a quantitative trait to a gradually changing environment. By means of analytical approximations, we derive the distribution of adaptive substitutions from standing genetic variation, that is, the distribution of the phenotypic effects of those alleles from the standing variation that become fixed during adaptation. Our results are checked against individual-based simulations. We find that, compared to adaptation from de-novo mutations, (i) adaptation from standing variation proceeds by the fixation of more alleles of small effect; (ii) populations that adapt from standing genetic variation can traverse larger distances in phenotype space and, thus, have a higher potential for adaptation if the rate of environmental change is fast rather than slow.

scholarly journals Adaptive Changes in Hemoglobin Function in High-Altitude Tibetan Canids Were Derived via Gene Conversion and Introgression

2019 ◽  
Vol 36 (10) ◽  
pp. 2227-2237 ◽  
Author(s):  
Anthony V Signore ◽  
Ying-Zhong Yang ◽  
Quan-Yu Yang ◽  
Ga Qin ◽  
Hideaki Moriyama ◽  
...  
Keyword(s):  
High Altitude ◽  
Gene Conversion ◽  
De Novo ◽  
Globin Gene ◽  
Introgressive Hybridization ◽  
Lateral Transfer ◽  
Hypoxia Tolerance ◽  
De Novo Mutations ◽  
Standing Variation ◽  
Different Sources

Abstract A key question in evolutionary biology concerns the relative importance of different sources of adaptive genetic variation, such as de novo mutations, standing variation, and introgressive hybridization. A corollary question concerns how allelic variants derived from these different sources may influence the molecular basis of phenotypic adaptation. Here, we use a protein-engineering approach to examine the phenotypic effect of putatively adaptive hemoglobin (Hb) mutations in the high-altitude Tibetan wolf that were selectively introgressed into the Tibetan mastiff, a high-altitude dog breed that is renowned for its hypoxia tolerance. Experiments revealed that the introgressed coding variants confer an increased Hb–O2 affinity in conjunction with an enhanced Bohr effect. We also document that affinity-enhancing mutations in the β-globin gene of Tibetan wolf were originally derived via interparalog gene conversion from a tandemly linked β-globin pseudogene. Thus, affinity-enhancing mutations were introduced into the β-globin gene of Tibetan wolf via one form of intragenomic lateral transfer (ectopic gene conversion) and were subsequently introduced into the Tibetan mastiff genome via a second form of lateral transfer (introgression). Site-directed mutagenesis experiments revealed that the increased Hb–O2 affinity requires a specific two-site combination of amino acid replacements, suggesting that the molecular underpinnings of Hb adaptation in Tibetan mastiff (involving mutations that arose in a nonexpressed gene and which originally fixed in Tibetan wolf) may be qualitatively distinct from functionally similar changes in protein function that could have evolved via sequential fixation of de novo mutations during the breed’s relatively short duration of residency at high altitude.

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