scholarly journals Functional Architecture of Deleterious Genetic Variants in the Genome of a Wrangel Island Mammoth

2020 ◽  
Vol 12 (3) ◽  
pp. 48-58 ◽  
Author(s):  
Erin Fry ◽  
Sun K Kim ◽  
Sravanthi Chigurapti ◽  
Katelyn M Mika ◽  
Aakrosh Ratan ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Small Population ◽  
Deleterious Mutations ◽  
Developmental Defects ◽  
Wrangel Island ◽  
Relict Populations ◽  
Deleterious Alleles ◽  
Large Populations ◽  
Functional Consequences

Abstract Woolly mammoths were among the most abundant cold-adapted species during the Pleistocene. Their once-large populations went extinct in two waves, an end-Pleistocene extinction of continental populations followed by the mid-Holocene extinction of relict populations on St. Paul Island ∼5,600 years ago and Wrangel Island ∼4,000 years ago. Wrangel Island mammoths experienced an episode of rapid demographic decline coincident with their isolation, leading to a small population, reduced genetic diversity, and the fixation of putatively deleterious alleles, but the functional consequences of these processes are unclear. Here, we show that a Wrangel Island mammoth genome had many putative deleterious mutations that are predicted to cause diverse behavioral and developmental defects. Resurrection and functional characterization of several genes from the Wrangel Island mammoth carrying putatively deleterious substitutions identified both loss and gain of function mutations in genes associated with developmental defects (HYLS1), oligozoospermia and reduced male fertility (NKD1), diabetes (NEUROG3), and the ability to detect floral scents (OR5A1). These data suggest that at least one Wrangel Island mammoth may have suffered adverse consequences from reduced population size and isolation.

scholarly journals Functional architecture of deleterious genetic variants in the Wrangel Island mammoth genome

2017 ◽  
Author(s):  
Erin Fry ◽  
Sun K. Kim ◽  
Sravanthi Chigurapti ◽  
Katelyn M. Mika ◽  
Aakrosh Ratan ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Small Population ◽  
Developmental Defects ◽  
Wrangel Island ◽  
Relict Populations ◽  
Deleterious Alleles ◽  
Large Populations ◽  
Population Sizes ◽  
Functional Consequences

Woolly mammoths were among the most abundant cold adapted species during the Pleistocene. Their once large populations went extinct in two waves, an end-Pleistocene extinction of continental populations followed by the mid-Holocene extinction of relict populations on St. Paul Island ~5,600 years ago and Wrangel Island ~4,000 years ago. Wrangel Island mammoths experienced an episode of rapid demographic decline coincident with their isolation, leading to a small population, reduced genetic diversity, and the fixation of putatively deleterious alleles, but the functional consequences of these processes are unclear. Here we show that the Wrangel Island mammoth accumulated many putative deleterious mutations that are predicted to cause diverse behavioral and developmental defects. Resurrection and functional characterization of Wrangel Island mammoth genes carrying these substitutions identified both loss and gain of function mutations in genes associated with developmental defects (HYLS1), oligozoospermia and reduced male fertility (NKD1), diabetes (NEUROG3), and the ability to detect floral scents (OR5A1). These results suggest that Wrangel Island mammoths may have suffered adverse consequences from their reduced population sizes and isolation.

scholarly journals OsChz1 acts as a histone chaperone in modulating chromatin organization and genome function in rice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kangxi Du ◽  
Qiang Luo ◽  
Liufan Yin ◽  
Jiabing Wu ◽  
Yuhao Liu ◽  
...  
Keyword(s):  
Nucleosome Occupancy ◽  
Functional Characterization ◽  
Histone Chaperone ◽  
Recognition Mechanism ◽  
Developmental Defects ◽  
Dynamic Regulation ◽  
Genome Wide ◽  
Domain Protein ◽  
Acidic Region

Abstract While the yeast Chz1 acts as a specific histone-chaperone for H2A.Z, functions of CHZ-domain proteins in multicellular eukaryotes remain obscure. Here, we report on the functional characterization of OsChz1, a sole CHZ-domain protein identified in rice. OsChz1 interacts with both the canonical H2A-H2B dimer and the variant H2A.Z-H2B dimer. Within crystal structure the C-terminal region of OsChz1 binds H2A-H2B via an acidic region, pointing to a previously unknown recognition mechanism. Knockout of OsChz1 leads to multiple plant developmental defects. At genome-wide level, loss of OsChz1 causes mis-regulations of thousands of genes and broad alterations of nucleosome occupancy as well as reductions of H2A.Z-enrichment. While OsChz1 associates with chromatin regions enriched of repressive histone marks (H3K27me3 and H3K4me2), its loss does not affect the genome landscape of DNA methylation. Taken together, it is emerging that OsChz1 functions as an important H2A/H2A.Z-H2B chaperone in dynamic regulation of chromatin for higher eukaryote development.

scholarly journals Evolution of Drift Robustness in Small Populations

2016 ◽  
Author(s):  
Thomas LaBar ◽  
Christoph Adami
Keyword(s):  
Mathematical Modeling ◽  
Experimental Evolution ◽  
Small Population ◽  
Small Populations ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
Mutational Robustness ◽  
Large Populations ◽  
Slightly Deleterious Mutations ◽  
Population Sizes

AbstractMost mutations are deleterious and cause a reduction in population fitness known as the mutational load. In small populations, weakened selection against slightly-deleterious mutations results in an additional fitness reduction. Many studies have established that populations can evolve a reduced mutational load by evolving mutational robustness, but it is uncertain whether small populations can evolve a reduced susceptibility to drift-related fitness declines. Here, using mathematical modeling and digital experimental evolution, we show that small populations do evolve a reduced vulnerability to drift, or “drift robustness”. We find that, compared to genotypes from large populations, genotypes from small populations have a decreased likelihood of small-effect deleterious mutations, thus causing small-population genotypes to be drift-robust. We further show that drift robustness is not adaptive, but instead arises because small populations preferentially adapt to drift-robust fitness peaks. These results have implications for genome evolution in organisms with small population sizes.

scholarly journals Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Hirokazu Kimura ◽  
Raymond M Paranal ◽  
Neha Nanda ◽  
Laura D Wood ◽  
James R Eshleman ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Ductal Adenocarcinoma ◽  
Proliferation Assay ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Deleterious Alleles ◽  
Increased Risk ◽  
Uncertain Significance

Pathogenic germline CDKN2A variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). CDKN2A variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of CDKN2A VUSs is needed to reclassify variants and inform clinical management. 29 germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. 12 of the 29 CDKN2A VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of CDKN2A VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic/likely pathogenic CDKN2A in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, CDKN2A VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.

scholarly journals Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting

2021 ◽  
Author(s):  
Nasim Biglari ◽  
Isabella Gaziano ◽  
Jonas Schumacher ◽  
Jan Radermacher ◽  
Lars Paeger ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Energy State ◽  
Functional Characterization ◽  
Anatomical Distribution ◽  
Electrophysiological Properties ◽  
Functional Consequences ◽  
Glucagon Like Peptide 1 ◽  
Differential Ability

AbstractPro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus represent key regulators of metabolic homeostasis. Electrophysiological and single-cell sequencing experiments have revealed a remarkable degree of heterogeneity of these neurons. However, the exact molecular basis and functional consequences of this heterogeneity have not yet been addressed. Here, we have developed new mouse models in which intersectional Cre/Dre-dependent recombination allowed for successful labeling, translational profiling and functional characterization of distinct POMC neurons expressing the leptin receptor (Lepr) and glucagon like peptide 1 receptor (Glp1r). Our experiments reveal that POMCLepr+ and POMCGlp1r+ neurons represent largely nonoverlapping subpopulations with distinct basic electrophysiological properties. They exhibit a specific anatomical distribution within the arcuate nucleus and differentially express receptors for energy-state communicating hormones and neurotransmitters. Finally, we identify a differential ability of these subpopulations to suppress feeding. Collectively, we reveal a notably distinct functional microarchitecture of critical metabolism-regulatory neurons.

scholarly journals Functional characterization of peroxisome biogenic proteins Pex5 and Pex7 of Drosophila

2018 ◽  
Author(s):  
Francesca Di Cara ◽  
Richard A. Rachubinski ◽  
Andrew J. Simmonds
Keyword(s):  
Human Fibroblasts ◽  
Functional Characterization ◽  
Early Death ◽  
Peroxisome Biogenesis ◽  
Developmental Defects ◽  
Peroxisomal Targeting ◽  
Embryonic Nervous System ◽  
Bona Fide ◽  
Targeting Signals

ABSTRACTPeroxisomes are ubiquitous membrane-enclosed organelles involved in lipid processing and reactive oxygen detoxification. Mutations in human peroxisome biogenesis genes (Peroxin, PEX) cause progressive developmental disabilities and, in severe cases, early death. PEX5 and PEX7 are receptors that recognize different peroxisomal targeting signals called PTS1 and PTS2, respectively, and traffic proteins to the peroxisomal matrix. We characterized mutants of Drosophila melanogaster Pex5 and Pex7 and found that adult animals are affected in lipid processing. Moreover, Pex5 mutants exhibited severe developmental defects in the embryonic nervous system and muscle, similar to what is observed in humans with Pex5 mutations, while Pex7 fly mutants were weakly affected in brain development, suggesting different roles for Pex7 in fly and human. Of note, although no PTS2-containing protein has been identified in Drosophila, Pex7 from Drosophila can function as a bona fide PTS2 receptor because it can rescue targeting of the PTS2-containing protein Thiolase to peroxisomes in PEX7 mutant human fibroblasts.

scholarly journals ACE2 Netlas: In-silico functional characterization and drug-gene interactions of ACE2 gene network to understand its potential involvement in COVID-19 susceptibility

2020 ◽  
Author(s):  
Gita A Pathak ◽  
Frank R Wendt ◽  
Aranyak Goswami ◽  
Flavio De Angelis ◽  
Renato Polimanti ◽  
...  
Keyword(s):  
Gene Network ◽  
Functional Characterization ◽  
Gene Interaction ◽  
Biological Properties ◽  
Angiotensin Converting Enzyme 2 ◽  
Interaction Database ◽  
Functional Consequences ◽  
Multi Level ◽  
Ace2 Gene

AbstractAngiotensin-converting enzyme-2 (ACE2) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed a multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their over-represented biological properties in the context of COVID-19.The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains (p<4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (p<4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others.Considering genetic variants within ± 10 kb of ACE2-network genes we characterized functional consequences (among others) using miRNA binding-site targets. MiRNAs affected by ACE2-network variants revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. With respect to variants mapped to the ACE2-network, we observed COVID-19 related associations in RORA, SLC12A6 and SLC6A19 genes.Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at https://gpwhiz.github.io/ACE2Netlas/

scholarly journals Deleterious mutations in a hybrid zone: can mutational load decrease the barrier to gene flow?

2002 ◽  
Vol 80 (3) ◽  
pp. 197-204 ◽  
Author(s):  
NICOLAS BIERNE ◽  
THOMAS LENORMAND ◽  
FRANÇOIS BONHOMME ◽  
PATRICE DAVID
Keyword(s):  
Gene Flow ◽  
Hybrid Zone ◽  
Small Population ◽  
Structured Populations ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
Migration Rates ◽  
Linkage Disequilibria ◽  
Deleterious Alleles ◽  
Population Sizes

The aim of this paper is to investigate the effect of deleterious mutations in a hybrid zone maintained by selection against hybrids. In such zones, linkage disequilibria among hybrid depression loci, resulting from a balance between migration and selection, are crucial in maintaining the barrier because they allow each locus, in addition to its own selection coefficient, to cumulate indirect selective effects from other loci. Deleterious alleles produce heterosis and increase by this means the effective migration rate in structured populations. In a hybrid zone, they therefore contribute to decrease linkage disequilibria as well as the barrier to gene flow imposed by hybrid depression. However, deleterious mutations have no effect: (i) when selection against hybrids is weak, because linkage disequilibria are small even without heterosis in this case, or (ii) when selection against hybrids is so strong that it overwhelms heterosis. On the other hand, with moderate selection against hybrids, the decrease in the strength of the barrier due to heterosis may reach detectable levels, although it requires relatively small population sizes and/or migration rates. The effect is expected to be small and only within small genomes where loci are tightly linked can it become strong. Nevertheless, neglecting mutational load may to some extent obscure the estimations of selective parameters based either on artificial F1 crosses or on cline characteristics.

scholarly journals Evolutionary analysis and functional characterization of SiBRI1 as a Brassinosteroid receptor gene in foxtail millet

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhiying Zhao ◽  
Sha Tang ◽  
Yiming Zhang ◽  
Jingjing Yue ◽  
Jiaqi Xu ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Expression Patterns ◽  
Functional Characterization ◽  
Foxtail Millet ◽  
Evolutionary Analysis ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Leaf Phenotype ◽  
Signaling Function

AbstractBrassinosteroids (BRs) play important roles in plant growth and development. Although BR receptors have been intensively studied in Arabidopsis, those in foxtail millet remain largely unknown. Here, we show that the BR signaling function of BRASSINOSTEROID INSENSITIVE 1 (BRI1) is conserved between Arabidopsis and foxtail millet, a new model species for C4 and Panicoideae grasses. We identified four putative BR receptor genes in the foxtail millet genome: SiBRI1, SiBRI1-LIKE RECEPTOR KINASE 1 (SiBRL1), SiBRL2 and SiBRL3. Phylogenetic analysis was used to classify the BR receptors in dicots and monocots into three branches. Analysis of their expression patterns by quantitative real-time PCR (qRT-PCR) showed that these receptors were ubiquitously expressed in leaves, stems, dark-grown seedlings, roots and non-flowering spikelets. GFP fusion experiments verified that SiBRI1 localized to the cell membrane. We also explored the SiBRI1 function in Arabidopsis through complementation experiments. Ectopic overexpression of SiBRI1 in an Arabidopsis BR receptor loss-of-function mutant, bri1-116, mostly reversed the developmental defects of the mutant. When SiBRI1 was overexpressed in foxtail millet, the plants showed a drooping leaf phenotype and root development inhibition, lateral root initiation inhibition, and the expression of BR synthesis genes was inhibited. We further identified BRI1-interacting proteins by immunoprecipitation (IP)-mass spectrometry (MS). Our results not only demonstrate that SiBRI1 plays a conserved role in BR signaling in foxtail millet but also provide insight into the molecular mechanism of SiBRI1.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

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