Convergent Evolution of Conserved Mitochondrial Pathways Underlies Repeated Adaptation to Extreme Environments

Extreme environments test the limits of life; yet, some organisms thrive in harsh conditions. Extremophile lineages inspire questions about how organisms can tolerate physiochemical stressors and whether the repeated colonization of extreme environments is facilitated by predictable and repeatable evolutionary innovations. We identified the mechanistic basis underlying convergent evolution of tolerance to hydrogen sulfide (H2S)—a toxicant that impairs mitochondrial function—across evolutionarily independent lineages of a fish (Poecilia mexicana, Poeciliidae) from H2S-rich springs. Using comparative biochemical and physiological analyses, we found that mitochondrial function is maintained in the presence of H2S in sulfide spring P. mexicana, but not ancestral lineages from nonsulfidic habitats, due to convergent adaptations in the primary toxicity target and a major detoxification enzyme. Genome-wide local ancestry analyses indicated that convergent evolution of increased H2S tolerance in different populations is likely caused by a combination of selection on standing genetic variation and de novo mutations. At a macroevolutionary scale, H2S tolerance in 10 independent lineages of sulfide spring fishes across multiple genera of Poeciliidae is correlated with the convergent modification and expression changes of genes associated with H2S toxicity and detoxification. Our results demonstrate that the modification of highly conserved physiological pathways associated with essential mitochondrial processes mediates tolerance to physiochemical stress. In addition, the same pathways, genes, and—in some instances—codons are implicated in H2S adaptation in lineages that span 40 million years of evolution.Significance StatementSome organisms can tolerate environments lethal for most others, but we often do not know what adaptations allow them to persist and whether the same mechanisms underly adaptation in different lineages exposed to the same stressors. Investigating fish inhabiting springs rich in toxic hydrogen sulfide (H2S), we show that tolerance is mediated by the modification of pathways that are inhibited by H2S and those that can detoxify it. Sulfide spring fishes across multiple genera have evolved similar modifications of toxicity targets and detoxification pathways, despite abundant lineage-specific variation. Our study highlights how constraints associated with the physiological consequences of a stressor limit the number of adaptive solutions and lead to repeatable evolutionary outcomes across organizational and evolutionary scales.

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Convergent evolution of conserved mitochondrial pathways underlies repeated adaptation to extreme environments

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2004223117 ◽

2020 ◽

Vol 117 (28) ◽

pp. 16424-16430 ◽

Cited By ~ 2

Author(s):

Ryan Greenway ◽

Nick Barts ◽

Chathurika Henpita ◽

Anthony P. Brown ◽

Lenin Arias Rodriguez ◽

...

Keyword(s):

Mitochondrial Function ◽

Convergent Evolution ◽

De Novo ◽

Extreme Environments ◽

De Novo Mutations ◽

Poecilia Mexicana ◽

Genome Wide ◽

Different Populations ◽

Mechanistic Basis ◽

Harsh Conditions

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Epigenetic Inheritance is Gated by Naive Pluripotency and Dppa2

10.1101/2021.05.11.443595 ◽

2021 ◽

Author(s):

Valentina Carlini ◽

Cristina Policarpi ◽

Jamie A Hackett

Keyword(s):

De Novo ◽

Epigenetic Inheritance ◽

Developmental Model ◽

Lineage Specification ◽

Chromatin States ◽

Genome Wide ◽

Mechanistic Basis ◽

Endogenous Loci ◽

Epigenetic Editing

Environmental factors can trigger cellular responses that propagate across mitosis or even generations. Perturbations to the epigenome could underpin such acquired changes, however, the extent and contexts in which modified chromatin states confer heritable memory in mammals is unclear. Here we exploit a modular epigenetic editing strategy to establish de novo heterochromatin domains (epialleles) at endogenous loci and track their inheritance in a developmental model. We find that naive pluripotent phases systematically erase ectopic domains of heterochromatin via active mechanisms, which acts as an intergenerational safeguard against transmission of epialleles. Upon lineage specification however, acquired chromatin states can be probabilistically inherited under selectively favourable conditions, including propagation of p53 silencing through in vivo development. Using genome-wide CRISPR screening, we identify the mechanisms that block heritable silencing memory in pluripotent cells, and demonstrate removal of Dppa2 unlocks the potential for epigenetic inheritance uncoupled from DNA sequence. Our study outlines a mechanistic basis for how epigenetic inheritance is restricted in mammals, and reveals genomic- and developmental- contexts in which heritable memory is feasible.

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De novo assembly of a Tibetan genome and identification of novel structural variants associated with high altitude adaptation

10.1101/753186 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ouzhuluobu ◽

Yaoxi He ◽

Haiyi Lou ◽

Chaoying Cui ◽

Lian Deng ◽

...

Keyword(s):

High Altitude ◽

De Novo ◽

Population Analysis ◽

Extreme Environments ◽

Structural Variants ◽

Base Pairs ◽

High Quality ◽

Genome Wide ◽

Long Read ◽

Altitude Adaptation

AbstractStructural variants (SVs) may play important roles in human adaption to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50 length of 58.80 Mb. The ZF1 assembly filled 80 remaining N-gaps (0.25 Mb in total length) in the reference human genome (GRCh38). Markedly, we detected 17,900 SVs, among which the ZF1-specific SVs are enriched in GTPase activity that is required for activation of the hypoxic pathway. Further population analysis uncovered a 163-bp intronic deletion in the MKL1 gene showing large divergence between highland Tibetans and lowland Han Chinese. This deletion is significantly associated with lower systolic pulmonary arterial pressure, one of the key adaptive physiological traits in Tibetans. Moreover, with the use of the high quality de novo assembly, we observed a much higher rate of genome-wide archaic hominid (Altai Neanderthal and Denisovan) shared non-reference sequences in ZF1 (1.32%-1.53%) compared to other East Asian genomes (0.70%-0.98%), reflecting a unique genomic composition of Tibetans. One such archaic-hominid shared sequence, a 662-bp intronic insertion in the SCUBE2 gene, is enriched and associated with better lung function (the FEV1/FVC ratio) in Tibetans. Collectively, we generated the first high-resolution Tibetan reference genome, and the identified SVs may serve as valuable resources for future evolutionary and medical studies.

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A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation

Genome Medicine ◽

10.1186/s13073-019-0694-y ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 10

Author(s):

Hannah Demond ◽

Zahra Anvar ◽

Bahia Namavar Jahromi ◽

Angela Sparago ◽

Ankit Verma ◽

...

Keyword(s):

Dna Methylation ◽

De Novo ◽

Hydatidiform Mole ◽

Human Oocyte ◽

Imprinted Genes ◽

High Coverage ◽

Genome Wide ◽

A Genome ◽

Mechanistic Basis ◽

Methylation Defects

Abstract Background Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. The rarity of these disorders and the possibility that methylation defects originate in oocytes have made these questions very challenging to address. Methods Single-cell bisulphite sequencing (scBS-seq) was used to assess methylation in oocytes from a patient with BiCHM identified to be homozygous for an inactivating mutation in the human SCMC component KHDC3L. Genome-wide methylation analysis of a preimplantation embryo and molar tissue from the same patient was also performed. Results High-coverage scBS-seq libraries were obtained from five KHDC3Lc.1A>G oocytes, which revealed a genome-wide deficit of DNA methylation compared with normal human oocytes. Importantly, germline differentially methylated regions (gDMRs) of imprinted genes were affected similarly to other sequence features that normally become methylated in oocytes, indicating no selectivity towards imprinted genes. A range of methylation losses was observed across genomic features, including gDMRs, indicating variable sensitivity to defects in the SCMC. Genome-wide analysis of a pre-implantation embryo and molar tissue from the same patient showed that following fertilisation methylation defects at imprinted genes persist, while most non-imprinted regions of the genome recover near-normal methylation post-implantation. Conclusions We show for the first time that the integrity of the SCMC is essential for de novo methylation in the female germline. These findings have important implications for understanding the role of the SCMC in DNA methylation and for the origin of imprinting defects, for counselling affected families, and will help inform future therapeutic approaches.

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Faculty Opinions recommendation of Genome-wide signatures of convergent evolution in echolocating mammals.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718099172.793484543 ◽

2013 ◽

Author(s):

Christopher Gregg

Keyword(s):

Convergent Evolution ◽

Genome Wide

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Faculty Opinions recommendation of Genome-wide profiling of heritable and de novo STR variations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727556430.793546826 ◽

2018 ◽

Author(s):

Melanie Bahlo

Keyword(s):

De Novo ◽

Genome Wide

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Inhibition of Kynurenine Metabolism and Its Effect in Mitochondrial Function in Hepatocellular Carcinoma

Innovation in Aging ◽

10.1093/geroni/igaa057.410 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 124-125

Author(s):

Raul Castro-Portuguez ◽

Samuel Freitas ◽

George Sutphin

Keyword(s):

Hepatocellular Carcinoma ◽

Mitochondrial Function ◽

De Novo ◽

Principal Component ◽

Kynurenine Pathway ◽

The Cancer Genome Atlas ◽

Wilcoxon Test ◽

Nad Synthesis ◽

Significant Difference ◽

Kynurenine Metabolism

Abstract Hepatocellular carcinoma (HCC) is the most prevalent cancer in the liver. The majority of ingested tryptophan is processed in the liver through the kynurenine pathway, the endpoint of which is de novo NAD+ biosynthesis. Dysregulation of tryptophan-kynurenine metabolism and NAD+ synthesis may promote mitochondrial malfunction, tumor reprogramming, and carcinogenesis. Using a publicly available gene expression dataset from liver hepatocellular carcinoma (LIHC) samples available through The Cancer Genome Atlas (TCGA; n = 371), we employed Principal Component Analysis (PCA), hierarchical clustering, gene-pattern expression profiling, and survival analysis to cluster patients and determine overall survival. Our analysis of genes encoding kynurenine pathway enzymes determined that patients with high QPRT expression had a poor prognosis with decreased median survival, with no effect on the maximum survival. There is a significant difference in the survival between patients with high QPRT expression relative to patients with high HAAO/AFMID expression (HR = 1.2, [95% CI 0.5-1.8] P = 0.0181, Gehan-Breslow-Wilcoxon Test). Patients with high QPRT expression have higher survival rates compared with low QPRT expression (HR = 1.4, [95% CI 0.9-2.2] P = 0.0344, Gehan-Breslow-Wilcoxon Test). To test the consequences of kynurenine-pathway inhibition in mitochondrial function and morphology we use 4-Cl-3HAA, an irreversible HAAO inhibitor, and observed a small increase in mitochondrial fragmentation in HepG2 cells after 24 hours of treatment. We conclude that kynurenine metabolism may be useful as a biomarker to predict patient prognosis among HCC patients. In ongoing work, we are testing QPRT inhibitors in cell culture as a potential adjuvant for chemotherapies.

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Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes

Cell Death and Disease ◽

10.1038/s41419-020-03213-2 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Jing-dong Zhou ◽

Ting-juan Zhang ◽

Zi-jun Xu ◽

Zhao-qun Deng ◽

Yu Gu ◽

...

Keyword(s):

Cancer Progression ◽

Myelodysplastic Syndromes ◽

Bisulfite Sequencing ◽

De Novo ◽

Dna Hypermethylation ◽

Reduced Representation ◽

Targeted Bisulfite Sequencing ◽

Specific Pcr ◽

Genome Wide ◽

Potential Biomarker

AbstractThe potential mechanism of myelodysplastic syndromes (MDS) progressing to acute myeloid leukemia (AML) remains poorly elucidated. It has been proved that epigenetic alterations play crucial roles in the pathogenesis of cancer progression including MDS. However, fewer studies explored the whole-genome methylation alterations during MDS progression. Reduced representation bisulfite sequencing was conducted in four paired MDS/secondary AML (MDS/sAML) patients and intended to explore the underlying methylation-associated epigenetic drivers in MDS progression. In four paired MDS/sAML patients, cases at sAML stage exhibited significantly increased methylation level as compared with the matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involving in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were involved in MDS progression. Targeted bisulfite sequencing further identified that aberrant GFRA1, IRX1, NPY, and ZNF300 methylation were frequent events in an additional group of de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Subsequently, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was confirmed by real-time quantitative methylation-specific PCR. It was illustrated that ZNF300 methylation could act as a potential biomarker for the diagnosis and prognosis in MDS and AML patients. Functional experiments demonstrated the anti-proliferative and pro-apoptotic role of ZNF300 overexpression in MDS-derived AML cell-line SKM-1. Collectively, genome-wide DNA hypermethylation were frequent events during MDS progression. Among these changes, ZNF300 methylation, a regulator of ZNF300 expression, acted as an epigenetic driver in MDS progression. These findings provided a theoretical basis for the usage of demethylation drugs in MDS patients against disease progression.

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A publicly available repository of ROH islands reveals signatures of selection in different livestock and pet species

Genetics Selection Evolution ◽

10.1186/s12711-020-00599-7 ◽

2021 ◽

Vol 53 (1) ◽

Author(s):

Wim Gorssen ◽

Roel Meyermans ◽

Steven Janssens ◽

Nadine Buys

Keyword(s):

Association Studies ◽

Genome Wide Association Studies ◽

Single Nucleotide ◽

Future Studies ◽

Snp Data ◽

Animal Populations ◽

Genome Wide ◽

Starting Point ◽

Different Populations ◽

Signatures Of Selection

Abstract Background Runs of homozygosity (ROH) have become the state-of-the-art method for analysis of inbreeding in animal populations. Moreover, ROH are suited to detect signatures of selection via ROH islands and are used in other applications, such as genomic prediction and genome-wide association studies (GWAS). Currently, a vast amount of single nucleotide polymorphism (SNP) data is available online, but most of these data have never been used for ROH analysis. Therefore, we performed a ROH analysis on large medium-density SNP datasets in eight animal species (cat, cattle, dog, goat, horse, pig, sheep and water buffalo; 442 different populations) and make these results publicly available. Results The results include an overview of ROH islands per population and a comparison of the incidence of these ROH islands among populations from the same species, which can assist researchers when studying other (livestock) populations or when looking for similar signatures of selection. We were able to confirm many known ROH islands, for example signatures of selection for the myostatin (MSTN) gene in sheep and horses. However, our results also included multiple other ROH islands, which are common to many populations and not identified to date (e.g. on chromosomes D4 and E2 in cats and on chromosome 6 in sheep). Conclusions We are confident that our repository of ROH islands is a valuable reference for future studies. The discovered ROH island regions represent a unique starting point for new studies or can be used as a reference for future studies. Furthermore, we encourage authors to add their population-specific ROH findings to our repository.

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