scholarly journals Soft sweeps predominate recent positive selection in bonobos (Pan paniscus) and chimpanzees (Pan troglodytes)

2020 ◽  
Author(s):  
Colin M Brand ◽  
Frances J White ◽  
Nelson Ting ◽  
Timothy H Webster
Keyword(s):  
Positive Selection ◽  
De Novo ◽  
Pan Paniscus ◽  
Novel Mutation ◽  
Simulated Data ◽  
Supervised Machine Learning ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Recent Positive Selection ◽  
Neural Network Classifiers

Two modes of positive selection have been recognized: 1) hard sweeps that result in the rapid fixation of a beneficial allele typically from a de novo mutation and 2) soft sweeps that are characterized by intermediate frequencies of at least two haplotypes that stem from standing genetic variation or recurrent de novo mutations. While many populations exhibit both hard and soft sweeps throughout the genome, there is increasing evidence that soft sweeps, rather than hard sweeps, are the predominant mode of adaptation in many species, including humans. Here, we use a supervised machine learning approach to assess the extent of hard and soft sweeps in the closest living relatives of humans: bonobos and chimpanzees (genus Pan). We trained convolutional neural network classifiers using simulated data and applied these classifiers to population genomic data for 71 individuals representing all five extant Pan lineages, of which we successfully analyzed 60 individuals from four lineages. We found that recent adaptation in Pan is largely the result of soft sweeps, ranging from 73.1 to 97.7% of all identified sweeps. While few hard sweeps were shared among lineages, we found that between 19 and 267 soft sweep windows were shared by at least two lineages. We also identify novel candidate genes subject to recent positive selection. This study emphasizes the importance of shifts in the physical and social environment, rather than novel mutation, in shaping recent adaptations in bonobos and chimpanzees.

scholarly journals De Novo Mutation and Rapid Protein (Co-)evolution during Meiotic Adaptation in Arabidopsis arenosa

2021 ◽  
Author(s):  
Magdalena Bohutínská ◽  
Vinzenz Handrick ◽  
Levi Yant ◽  
Roswitha Schmickl ◽  
Filip Kolář ◽  
...  
Keyword(s):  
Amino Acid ◽  
Positive Selection ◽  
De Novo ◽  
Empirical Studies ◽  
De Novo Mutation ◽  
Rapid Adaptation ◽  
De Novo Mutations ◽  
Standing Variation ◽  
Arabidopsis Arenosa ◽  
Meiosis Genes

Abstract A sudden shift in environment or cellular context necessitates rapid adaptation. A dramatic example is genome duplication, which leads to polyploidy. In such situations, the waiting time for new mutations might be prohibitive; theoretical and empirical studies suggest that rapid adaptation will largely rely on standing variation already present in source populations. Here, we investigate the evolution of meiosis proteins in Arabidopsis arenosa, some of which were previously implicated in adaptation to polyploidy, and in a diploid, habitat. A striking and unexplained feature of prior results was the large number of amino acid changes in multiple interacting proteins, especially in the relatively young tetraploid. Here, we investigate whether selection on meiosis genes is found in other lineages, how the polyploid may have accumulated so many differences, and whether derived variants were selected from standing variation. We use a range-wide sample of 145 resequenced genomes of diploid and tetraploid A. arenosa, with new genome assemblies. We confirmed signals of positive selection in the polyploid and diploid lineages they were previously reported in and find additional meiosis genes with evidence of selection. We show that the polyploid lineage stands out both qualitatively and quantitatively. Compared with diploids, meiosis proteins in the polyploid have more amino acid changes and a higher proportion affecting more strongly conserved sites. We find evidence that in tetraploids, positive selection may have commonly acted on de novo mutations. Several tests provide hints that coevolution, and in some cases, multinucleotide mutations, might contribute to rapid accumulation of changes in meiotic proteins.

scholarly journals SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2380-2387 ◽  
Author(s):  
Alisdair McNeill ◽  
Emanuela Iovino ◽  
Luke Mansard ◽  
Christel Vache ◽  
David Baux ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Developmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Sensorineural Deafness ◽  
Sensorineural Hearing ◽  
De Novo Mutation ◽  
Xenopus Laevis Oocytes ◽  
De Novo Mutations

Abstract The SLC12 gene family consists of SLC12A1–SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16–18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16–18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.

scholarly journals Genomic analysis of a spinal muscular atrophy (SMA) discordant family identifies a novel mutation in TLL2, an activator of growth differentiation factor 8 (myostatin): a case report

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jianping Jiang ◽  
Jinwei Huang ◽  
Jianlei Gu ◽  
Xiaoshu Cai ◽  
Hongyu Zhao ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
De Novo ◽  
Muscular Atrophy ◽  
Novel Mutation ◽  
Genomic Analysis ◽  
Neuromuscular Disorder ◽  
De Novo Mutation ◽  
Compound Heterozygous ◽  
Mice Model ◽  
Compound Heterozygous Mutations

Abstract Background Spinal muscular atrophy (SMA) is a rare neuromuscular disorder threating hundreds of thousands of lives worldwide. And the severity of SMA differs among different clinical types, which has been demonstrated to be modified by factors like SMN2, SERF1, NAIP, GTF2H2 and PLS3. However, the severities of many SMA cases, especially the cases within a family, often failed to be explained by these modifiers. Therefore, other modifiers are still waiting to be explored. Case presentation In this study, we presented a rare case of SMA discordant family with a mild SMA male patient and a severe SMA female patient. The two SMA cases fulfilled the diagnostic criteria defined by the International SMA Consortium. With whole exome sequencing, we confirmed the heterozygous deletion of exon7 at SMN1 on the parents’ genomes and the homozygous deletions on the two patients’ genomes. The MLPA results confirmed the deletions and indicated that all the family members carry two copies of SMN2, SERF1, NAIP and GTF2H2. Further genomic analysis identified compound heterozygous mutations at TLL2 on the male patient’s genome, and compound heterozygous mutations at VPS13A and the de novo mutation at AGAP5 on female patient’s genome. TLL2 is an activator of myostatin, which negatively regulates the growth of skeletal muscle tissue. Mutation in TLL2 has been proved to increase muscular function in mice model. VPS13A encodes proteins that control the cycling of proteins through the trans-Golgi network to endosomes, lysosomes and the plasma membrane. And AGAP5 was reported to have GTPase activator activity. Conclusions We reported a case of SMA discordant family and identified mutations at TLL2, VPS13A and AGAP5 on the patients’ genomes. The mutations at TLL2 were predicted to be pathogenic and are likely to alleviate the severity of the male SMA patient. Our finding broadens the spectrum of genetic modifiers of SMA and will contribute to accurate counseling of SMA affected patients and families.

Empirical investigation of mutation rate for herbicide resistance

Weed Science ◽  
2019 ◽  
Vol 67 (4) ◽  
pp. 361-368 ◽  
Author(s):  
Federico A. Casale ◽  
Darci A. Giacomini ◽  
Patrick J. Tranel
Keyword(s):  
Mutation Rate ◽  
Herbicide Resistance ◽  
De Novo ◽  
Selection Process ◽  
Theoretical Calculations ◽  
Acetolactate Synthase ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Sources Of Resistance ◽  
Resistant Mutants

AbstractIn a predictable natural selection process, herbicides select for adaptive alleles that allow weed populations to survive. These resistance alleles may be available immediately from the standing genetic variation within the population or may arise from immigration via pollen or seeds from other populations. Moreover, because all populations are constantly generating new mutant genotypes by de novo mutations, resistant mutants may arise spontaneously in any herbicide-sensitive weed population. Recognizing that the relative contribution of each of these three sources of resistance alleles influences what strategies should be applied to counteract herbicide-resistance evolution, we aimed to add experimental information to the resistance evolutionary framework. Specifically, the objectives of this experiment were to determine the de novo mutation rate conferring herbicide resistance in a natural plant population and to test the hypothesis that the mutation rate increases when plants are stressed by sublethal herbicide exposure. We used grain amaranth (Amaranthus hypochondriacus L.) and resistance to acetolactate synthase (ALS)-inhibiting herbicides as a model system to discover spontaneous herbicide-resistant mutants. After screening 70.8 million plants, however, we detected no spontaneous resistant genotypes, indicating the probability of finding a spontaneous ALS-resistant mutant in a given sensitive population is lower than 1.4 × 10−8. This empirically determined upper limit is lower than expected from theoretical calculations based on previous studies. We found no evidence that herbicide stress increased the mutation rate, but were not able to robustly test this hypothesis. The results found in this study indicate that de novo mutations conferring herbicide resistance might occur at lower frequencies than previously expected.

Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing

2016 ◽  
Vol 96 (2) ◽  
pp. 179-185 ◽  
Author(s):  
K.D. Khandelwal ◽  
N. Ishorst ◽  
H. Zhou ◽  
K.U. Ludwig ◽  
H. Venselaar ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Rare Variants ◽  
De Novo ◽  
Massively Parallel Sequencing ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Orofacial Clefting ◽  
Unaffected Parent ◽  
Molecular Inversion Probes ◽  
Multiplex Sequencing

Common variants in interferon regulatory factor 6 ( IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.

scholarly journals Selection bias in mutation accumulation

2021 ◽  
Author(s):  
Lindi M Wahl ◽  
Deepa Agashe
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
De Novo ◽  
Mutation Accumulation ◽  
Microbial Populations ◽  
Single Individual ◽  
Deleterious Mutations ◽  
De Novo Mutations ◽  
Fitness Effects ◽  
Wide Range

Mutation accumulation (MA) experiments, in which de novo mutations are sampled and subsequently characterized, are an essential tool in understanding the processes underlying evolution. In microbial populations, MA protocols typically involve a period of population growth between severe bottlenecks, such that a single individual can form a visible colony. While it has long been appreciated that the action of positive selection during this growth phase cannot be eliminated, it is typically assumed to be negligible. Here, we quantify the effect of both positive and negative selection in MA studies, demonstrating that selective effects can substantially bias the distribution of fitness effects (DFE) and mutation rates estimated from typical MA protocols in microbes. We then present a simple correction for this bias which applies to both beneficial and deleterious mutations, and can be used to correct the observed DFE in multiple environments. Finally, we use simulated MA experiments to illustrate the extent to which the MA-inferred DFE differs from the underlying true DFE, and demonstrate that the proposed correction accurately reconstructs the true DFE over a wide range of scenarios. These results highlight that positive selection during microbial MA experiments is in fact not negligible, but can be corrected to gain a more accurate understanding of fundamental evolutionary parameters.

scholarly journals Novel de novo heterozygous mutation on SYNGAP1 from the Indian population

2020 ◽  
Author(s):  
Vijaya Verma ◽  
Amit Mandora ◽  
Abhijeet Botre ◽  
James Premdoss Clement
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Novel Mutation ◽  
Autism Spectrum ◽  
Current Treatment ◽  
Developmental Trajectory ◽  
Global Developmental Delay ◽  
Heterozygous Mutation ◽  
Specific Gene ◽  
De Novo Mutations

Abstract Background : Exome sequencing is a prominent tool to identify novel and deleterious mutations which could be nonsense, frameshift, and canonical splice-site mutations in a specific gene. De novo mutations in SYNGAP1 , which codes for synaptic RAS-GTPase activating the protein, causes Intellectual disability (ID) and Autism Spectrum Disorder (ASD). SYNGAP1 related ASD/ID is one of the rare diseases that is detrimental to the normal neuronal developmental and disrupts the global development of a child. Results: We report a case of a child of 2-year old with global developmental delay, microcephaly subtle dysmorphism, absence seizures, disrupted sleep, delay in learning a language, and eating problems. Upon further validation, the child has a few traits of ASD. Here, based on focused exome sequencing, we report a de novo heterozygous mutation in SYNGAP1 exon 11 with c. 1861 C>T (p.arg612ter). Currently, the child is on atorvastatin and has shown considerable improvement in global behaviour and cognitive development. The long-term follow up of the child’s development would contribute to the already existing knowledge of the developmental trajectory in individuals with SYNGAP1 heterozygous mutation. Conclusion: In this report, we discuss the finding of a novel mutation in one of the genes, SYNGAP1 , implicated in ASD/ID. In addition, we discuss the current treatment prescribed to the patient and the progress of global developmental of the child.

scholarly journals Identification of a Novel Mutation and a De Novo Mutation in DKC1 in Two Chinese Pedigrees with Dyskeratosis Congenita

2004 ◽  
Vol 123 (3) ◽  
pp. 470-473 ◽  
Author(s):  
Ying-guo Ding ◽  
Tie-shan Zhu ◽  
Wei Jiang ◽  
Yong Yang ◽  
Ding-fang Bu ◽  
...  
Keyword(s):  
De Novo ◽  
Novel Mutation ◽  
Dyskeratosis Congenita ◽  
De Novo Mutation

scholarly journals Identification of a Novel Mutation Predisposing to Familial AML and MDS Syndrome By a NGS Approach

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4387-4387
Author(s):  
Simona Bernardi ◽  
Camilla Zanaglio ◽  
Elif Dereli Eke ◽  
Federica Cattina ◽  
Mirko Farina ◽  
...  
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Novel Mutation ◽  
In Silico Analysis ◽  
Buccal Swab ◽  
De Novo Mutations ◽  
New Mutation ◽  
Causative Gene ◽  
Hematopoietic Stem ◽  
Clinical Awareness

Abstract Introduction In AML and MDS cases, the genetic lesions inherited or acquired by the hematopoietic stem cells are considered as starting events. Familial AML and MDS, recently recognized in the revised WHO classification (2016) provide a useful model for investigation of predisposing genetic mutations. Genetic analysis of several pure familial leukemia pedigrees led to the discovery of well defined syndromes associated with inherited de novo mutations on germline DNA. Growing clinical awareness as well as a widespread use of NGS have led to an enlarged description of familial MDS/AML cases, and the number of mutations involved, suggesting they are more frequent than those previously recognized. Despite the recent discovery of well-established causative gene mutations (RUNX1, GATA2, ETV6, TERT, TERC, SRP72, ANKRD26, DDX41, CEBPA), many cases remain unexplained (about 80%), suggesting that other inherited mutations could predispose to MDS/AML. It is expected that new sequencing approaches will help to the identification of more cases, more genes as well as novel syndromes. In 2017, we started a multicentric prospective study (Clinical trial.gov NCT03058588) aiming to look for predisposing mutations in patients and relatives affected by Familial AML and MDS syndromes (FAMS) by NGS and to screen for old and new mutations potentially associated with the disease. Methods At present, 12 AML/MDS patients have been enrolled. Leukemic (bone marrow) and germline (buccal swab) DNA were analyzed by NGS gene panel approach based on a 28 genes associated to myeloid leukemogenesis, including the 9 above mentioned genes associated to FAMS. NGS libraries were performed by a Nimblegen (Roche) custom panel based on gene capture strategy and the sequencing was performed by MiSeq (Illumina). Results Ten patients did not reveal any germline mutations and the candidates are undergoing to whole exome sequencing. One presented a germline mutation on RUNX1, and the analysis of the affected relatives is on going. One revealed a new mutation. She was a 70 years old woman affected by RARS and her pedigree was characterized by 9 relatives affected by hematologic and solid neoplasia and trombocytopenia (fig 1). The NGS analysis revealed the mutation c.*514C>T in 3'UTR of ETV6 with VAF of 50% on tumor DNA. The variant has never been described before, while ETV6 has been already associated with FAMS. Sanger sequencing confirmed the mutation on the germline DNA in heterozygosis. The screening of 2 affected relatives still alive confirmed the presence of the variant in heterozygosis. In silico analysis performed on PolymiRST Database revealed that c.*514C>T in 3'UTR of ETV6 results in a gain of miRNA binding site: hsa-miR- 4717-3p and hsa-miR- 942-3p. Discussion The variant c.*514C>T in 3'UTR of ETV6 seems to repress ETV6 due to RNA interference. The new binding miRNAs have been already described as over-expressed in solid and hematologic tumors. Moreover, the down-regulation of ETV6 is associated with alteration of cell growth and hematopoiesis. Due to these evidences, c.*514C>T in 3'UTR of ETV6 could be considered as a new mutation involved in FAMS predisposition. Disclosures No relevant conflicts of interest to declare.

scholarly journals M-DATA: A Statistical Approach to Jointly Analyzing De Novo Mutations for Multiple Traits

2021 ◽  
Author(s):  
Yuhan Xie ◽  
Mo Li ◽  
Weilai Dong ◽  
Wei Jiang ◽  
Hongyu Zhao
Keyword(s):  
Statistical Power ◽  
De Novo ◽  
Expectation Maximization Algorithm ◽  
De Novo Mutation ◽  
Joint Analysis ◽  
De Novo Mutations ◽  
Multiple Traits ◽  
Disease Etiology ◽  
Degree Of Association ◽  
Shared Risk

Recent studies have demonstrated that multiple early-onset diseases have shared risk genes, based on findings from de novo mutations (DMNs). Therefore, we may leverage information from one trait to improve statistical power to identify genes for another trait. However, there are few methods that can jointly analyze DNMs from multiple traits. In this study, we develop a framework called M-DATA (Multi-trait framework for De novo mutation Association Test with Annotations) to increase the statistical power of association analysis by integrating data from multiple correlated traits and their functional annotations. Using the number of DNMs from multiple diseases, we develop a method based on an Expectation-Maximization algorithm to both infer the degree of association between two diseases as well as to estimate the gene association probability for each disease. We apply our method to a case study of jointly analyzing data from congenital heart disease (CHD) and autism. Our method was able to identify 23 genes from joint analysis, including 12 novel genes, which is substantially more than single-trait analysis, leading to novel insights into CHD disease etiology.

Sign in / Sign up

Export Citation Format

Share Document