Advanced genetics (Hoboken, N.J.)最新文献

{"title":"The missing person in gene-environment interactions","authors":"Oluwatobiloba Osikoya,&nbsp;Myles Axton","doi":"10.1002/ggn2.10041","DOIUrl":"10.1002/ggn2.10041","url":null,"abstract":"<p>Genetics was supposed to move epidemiology beyond the original “Table 1 error” of assuming ancestry as surrogate genotype and ethnicity as surrogate environmental exposures—and to deliver precision in health prediction and healthcare.<span>¹</span> Without methods to prioritize research around a person's everyday exposures and experiences of disease at scale, even sophisticated genetic epidemiology will deliver only an outline of contributory factors. Indeed, genetic research might even worsen existing ancestry-based health disparities in common and rare monogenic diseases.</p><p>Taking Sickle Cell Disease (SCD) as the classic example of a monogenic disease caused by a single mutation, a Perspective<span>²</span> in this issue of the journal suggests how an international collaboration can take advantage of the range of individual experiences of SCD in resource rich—but unequal—and less well-resourced environments to understand how a single mutation results in such a complex range of environmentally dependent experiences of disease and disability. At least for rarer but highly penetrant monogenic conditions with a small range of allelic variation that may be possible. Insights into the divergent phenotypes of SCD may be achieved by aggregating data globally to inform the research methods used to understand how gene-environment interactions result in different health outcomes. These collaborative research efforts may in turn ameliorate the effects of health disparities for people with rare diseases or people in any population living with conditions where there is a strong genetic component. The proposed approach is rooted in the detailed experience of individuals sharing a genotype. To make it useful for research the reporting needs to be in units suitable for statistical methods. The duration or frequency of an episode of disease requiring intervention is a universal measure of disease experience that is useful across the diversity of reporting, adaptable to differential missingness in data, and useful despite the use of reporting instruments of types that greatly exceed the variation in genotyping technologies and analytic pipelines.</p><p>One of the insights in this Perspective is the conceptual use of individual health timelines recording the temporal correlation and intensity of factors influencing health status.<span>²</span> These factors can be intrinsic (mutation, genotype, admixture) episodic (altitude, exercise, hospitalization) and continuing (geographic location, family, and community). There will be much redundancy and missingness in these datasets, but the aggregate will be rich in data to be mined for their patterns of correlation and causation. Since individuals with SCD will have most at stake in symptom mitigation, incentives for participation and guided self-reporting should be introduced in the methodology in its design.</p><p>The authors have chosen pain to model which is apt because it is a","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10507591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sickle cell disease is a global prototype for integrative research and healthcare","authors":"Charmaine D. M. Royal,&nbsp;Michael Babyak,&nbsp;Nirmish Shah,&nbsp;Shantanu Srivatsa,&nbsp;Kearsley A. Stewart,&nbsp;Paula Tanabe,&nbsp;Ambroise Wonkam,&nbsp;Monika Asnani","doi":"10.1002/ggn2.10037","DOIUrl":"10.1002/ggn2.10037","url":null,"abstract":"<p>Differences in health outcomes and treatment responses within and between global populations have been well documented. There is growing recognition of the need to move beyond simple inventories and descriptions of these differences and our linear explanations for them, and gain a better understanding of the multifaceted systems and networks underlying them in order to develop more precise and effective remedies. Typical targets for such integrative research have been common multifactorial diseases. We propose sickle cell disease, one of the most common monogenic diseases, as an ideal candidate for elucidating the complexity of the influences of endogenous and exogenous factors on disease pathophysiology, phenotypic diversity, and variations in responses to treatments at both the individual and population levels. We provide data-informed representations of diverse contributors to sickle cell disease complications that could guide innovative efforts to advance scientific knowledge, clinical practice, and policy formulation related to the disease; help improve outcomes for people worldwide with sickle cell disease; and inform approaches to studying and addressing other diseases.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10512805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of literature searching tools for curation of mismatch repair gene variants in hereditary colon cancer","authors":"Varun Kaushik,&nbsp;John-Paul Plazzer,&nbsp;Finlay Macrae","doi":"10.1002/ggn2.10039","DOIUrl":"10.1002/ggn2.10039","url":null,"abstract":"<p>Pathogenic constitutional genomic variants in the mismatch repair (MMR) genes are the drivers of Lynch syndrome; optimal variant interpretation is required for the management of suspected and confirmed cases. The International Society for Hereditary Gastrointestinal Tumours (InSiGHT) provides expert classifications for MMR variants for the US National Human Genome Research Institute's (NHGRI) ClinGen initiative and interprets variants with discordant classifications and those of uncertain significance (VUSs). Given the onerous nature of extracting information related to variants, literature searching tools which harness artificial intelligence may aid in retrieving information to allow optimum variant classification. In this study, we described the nature of discordance in a sample of 80 variants from a list of variants requiring updating by InSiGHT for ClinGen by comparing their existing InSiGHT classifications with the various submissions for each variant on the US National Centre for Biotechnology Information's (NCBI) ClinVar database. To identify the potential value of a literature searching tool in extracting information related to classification, all variants were searched for using a traditional method (Google Scholar) and literature searching tool (Mastermind) independently. Descriptive statistics were used to compare: the number of articles before and after screening for relevance and the number of relevant articles unique to either method. Relevance was defined as containing the variant in question as well as data informing variant interpretation. A total of 916 articles were returned by both methods and Mastermind averaged four relevant articles per search compared to Google Scholar's three. Of relevant Mastermind articles, 193/308 (62.7%) were unique to it, compared to 87/202, (43.0%) for Google Scholar. For 24 variants, either or both methods found no information. All 6/80 (20%) variants with pathogenic or likely pathogenic InSiGHT classifications have newer VUS assertions on ClinVar. Our study demonstrated that for a sample of variants with varying discordant interpretations, Mastermind was able to return on average, a more relevant and unique literature search. Google Scholar was able to retrieve information that Mastermind did not, which supports a conclusion that Mastermind could play a complementary role in literature searching for classification. This work will aid InSiGHT in its role of classifying MMR variants.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10512804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embryonic lethality and defective mammary gland development of activator-function impaired conditional knock-in Erbb3V943R mice","authors":"Kate Senger,&nbsp;Wenlin Yuan,&nbsp;Meredith Sagolla,&nbsp;Jonas Doerr,&nbsp;Brad Bolon,&nbsp;James Ziai,&nbsp;Kai-Hui Sun,&nbsp;Soren Warming,&nbsp;Merone Roose-Girma,&nbsp;Na Zhang,&nbsp;Lucinda Tam,&nbsp;Robert J. Newman,&nbsp;Subhra Chaudhuri,&nbsp;Aju Antony,&nbsp;Leonard D. Goldstein,&nbsp;Steffen Durinck,&nbsp;Bijay S. Jaiswal,&nbsp;Daniel Lafkas,&nbsp;Zora Modrusan,&nbsp;Somasekar Seshagiri","doi":"10.1002/ggn2.10036","DOIUrl":"https://doi.org/10.1002/ggn2.10036","url":null,"abstract":"<p>ERBB3 is a pseudokinase domain-containing member of the ERBB family of receptor tyrosine kinases (RTKs). Following ligand binding, ERBB receptors homo- or hetero-dimerize, leading to a head-to-tail arrangement of the intracellular kinase domains, where the “receiver” kinase domain of one ERBB is activated by the “activator” domain of the other ERBB in the dimer. In ERBB3, a conserved valine at codon 943 (V943) in the kinase C-terminal domain has been shown to be important for its function as an “activator” kinase <i>in vitro</i>. Here we report a knock-in mouse model where we have modified the endogenous <i>Erbb3</i> allele to allow for tissue-specific conditional expression of <i>Erbb3</i>^<i>V943R</i> (<i>Erbb3</i>^{<i>CKI-V943R</i>}). Additionally, we generated an <i>Erbb3</i>^<i>D850N</i> (<i>Erbb3</i>^{<i>CKI-D850N</i>}) conditional knock-in mouse model where the conserved aspartate in the DFG motif of the pseudokinase domain was mutated to abolish any potential residual kinase activity. While <i>Erbb3</i>^{<i>D850N/D850N</i>} animals developed normally, homozygous <i>Erbb3</i>^{<i>V943R/V943R</i>} expression during development resulted in embryonic lethality. Further, tissue specific expression of <i>Erbb3</i>^{<i>V943R/V943R</i>} in the mammary gland epithelium following its activation using <i>MMTV-Cre</i> resulted in delayed elongation of the ductal network during puberty. Single-cell RNA-seq analysis of <i>Erbb3</i>^{<i>V943R/V943R</i>} mammary glands showed a reduction in a specific subset of fibrinogen-producing luminal epithelial cells.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92303850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular underpinnings of fertility: Genetic approaches in Caenorhabditis elegans","authors":"Xue Mei,&nbsp;Andrew W. Singson","doi":"10.1002/ggn2.10034","DOIUrl":"https://doi.org/10.1002/ggn2.10034","url":null,"abstract":"<p>The study of mutations that impact fertility has a catch-22. Fertility mutants are often lost since they cannot simply be propagated and maintained. This has hindered progress in understanding the genetics of fertility. In mice, several molecules are found to be required for the interactions between the sperm and egg, with JUNO and IZUMO1 being the only known receptor pair on the egg and sperm surface, respectively. In <i>Caenorhabditis elegans</i>, a total of 12 proteins on the sperm or oocyte have been identified to mediate gamete interactions. Majority of these genes were identified through mutants isolated from genetic screens. In this review, we summarize the several key screening strategies that led to the identification of fertility mutants in <i>C</i>. <i>elegans</i> and provide a perspective about future research using genetic approaches. Recently, advancements in new technologies such as high-throughput sequencing and Crispr-based genome editing tools have accelerated the molecular, cell biological, and mechanistic analysis of fertility genes. We review how these valuable tools advance our understanding of the molecular underpinnings of fertilization. We draw parallels of the molecular mechanisms of fertilization between worms and mammals and argue that our work in <i>C</i>. <i>elegans</i> complements fertility research in humans and other species.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92315587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic transcriptome landscape in the song nucleus HVC between juvenile and adult zebra finches","authors":"Zhimin Shi,&nbsp;Zeyu Zhang,&nbsp;Lana Schaffer,&nbsp;Zhi Huang,&nbsp;Lijuan Fu,&nbsp;Steven Head,&nbsp;Terry Gaasterland,&nbsp;Xiu-Jie Wang,&nbsp;XiaoChing Li","doi":"10.1002/ggn2.10035","DOIUrl":"10.1002/ggn2.10035","url":null,"abstract":"<p>Male juvenile zebra finches learn to sing by imitating songs of adult males early in life. The development of the song control circuit and song learning and maturation are highly intertwined processes, involving gene expression, neurogenesis, circuit formation, synaptic modification, and sensory-motor learning. To better understand the genetic and genomic mechanisms underlying these events, we used RNA-Seq to examine genome-wide transcriptomes in the song control nucleus HVC of male juvenile (45 d) and adult (100 d) zebra finches. We report that gene groups related to axon guidance, RNA processing, lipid metabolism, and mitochondrial functions show enriched expression in juvenile HVC compared to the rest of the brain. As juveniles mature into adulthood, massive gene expression changes occur. Expression of genes related to amino acid metabolism, cell cycle, and mitochondrial function is reduced, accompanied by increased and enriched expression of genes with synaptic functions, including genes related to G-protein signaling, neurotransmitter receptors, transport of small molecules, and potassium channels. Unexpectedly, a group of genes with immune system functions is also developmentally regulated, suggesting potential roles in the development and functions of HVC. These data will serve as a rich resource for investigations into the development and function of a neural circuit that controls vocal behavior.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10512801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Active DNA demethylation—The epigenetic gatekeeper of development, immunity, and cancer","authors":"Rahul Prasad,&nbsp;Timothy J. Yen,&nbsp;Alfonso Bellacosa","doi":"10.1002/ggn2.10033","DOIUrl":"10.1002/ggn2.10033","url":null,"abstract":"<p>DNA methylation is a critical process in the regulation of gene expression with dramatic effects in development and continually expanding roles in oncogenesis. 5-Methylcytosine was once considered to be an inherited and stably repressive epigenetic mark, which can be only removed by passive dilution during multiple rounds of DNA replication. However, in the past two decades, physiologically controlled DNA demethylation and deamination processes have been identified, thereby revealing the function of cytosine methylation as a highly regulated and complex state—not simply a static, inherited signature or binary on-off switch. Alongside these fundamental discoveries, clinical studies over the past decade have revealed the dramatic consequences of aberrant DNA demethylation. In this review we discuss DNA demethylation and deamination in the context of 5-methylcytosine as critical processes for physiological and physiopathological transitions within three states—development, immune maturation, and oncogenic transformation; and we describe the expanding role of DNA demethylating drugs as therapeutic agents in cancer.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10505784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging mechanisms—A perspective mostly from Drosophila","authors":"Amy Tsurumi,&nbsp;Willis X. Li","doi":"10.1002/ggn2.10026","DOIUrl":"10.1002/ggn2.10026","url":null,"abstract":"<p>A mechanistic understanding of the natural aging process, which is distinct from aging-related disease mechanisms, is essential for developing interventions to extend lifespan or healthspan. Here, we discuss current trends in aging research and address conceptual and experimental challenges in the field. We examine various molecular markers implicated in aging with an emphasis on the role of heterochromatin and epigenetic changes. Studies in model organisms have been advantageous in elucidating conserved genetic and epigenetic mechanisms and assessing interventions that affect aging. We highlight the use of <i>Drosophila</i>, which allows controlled studies for evaluating genetic and environmental contributors to aging conveniently. Finally, we propose the use of novel methodologies and future strategies using <i>Drosophila</i> in aging research.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10874742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling selection signatures in a single dog breed suggests recent selection for morphological and behavioral traits","authors":"Juliane Friedrich,&nbsp;Andrea Talenti,&nbsp;Per Arvelius,&nbsp;Erling Strandberg,&nbsp;Marie J. Haskell,&nbsp;Pamela Wiener","doi":"10.1002/ggn2.10024","DOIUrl":"10.1002/ggn2.10024","url":null,"abstract":"<p>Strong selection has resulted in substantial morphological and behavioral diversity across modern dog breeds, which makes dogs interesting model animals to study the underlying genetic architecture of these traits. However, results from between-breed analyses may confound selection signatures for behavior and morphological features that were coselected during breed development. In this study, we assess population genetic differences in a unique resource of dogs of the same breed but with systematic behavioral selection in only one population. We exploit these different breeding backgrounds to identify signatures of recent selection. Selection signatures within populations were found on chromosomes 4 and 19, with the strongest signals in behavior-related genes. Regions showing strong signals of divergent selection were located on chromosomes 1, 24, and 32, and include candidate genes for both physical features and behavior. Some of the selection signatures appear to be driven by loci associated with coat color (Chr 24; <i>ASIP</i>) and length (Chr 32; <i>FGF5</i>), while others showed evidence of association with behavior. Our findings suggest that signatures of selection within dog breeds have been driven by selection for morphology and behavior. Furthermore, we demonstrate that combining selection scans with association analyses is effective for dissecting the traits under selection.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10874744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How can aging be reversed? Exploring rejuvenation from a damage-based perspective","authors":"Bohan Zhang,&nbsp;Vadim N. Gladyshev","doi":"10.1002/ggn2.10025","DOIUrl":"10.1002/ggn2.10025","url":null,"abstract":"<p>Advanced age is associated with accumulation of damage and other deleterious changes and a consequential systemic decline of function. This decline affects all organs and systems in an organism, leading to their inadaptability to the environment, and therefore is thought to be inevitable for humans and most animal species. However, in vitro and in vivo application of reprogramming strategies, which convert somatic cells to induced pluripotent stem cells, has demonstrated that the aged cells can be rejuvenated. Moreover, the data and theoretical considerations suggest that reversing the biological age of somatic cells (from old to young) and de-differentiating somatic cells into stem cells represent two distinct processes that take place during rejuvenation, and thus they may be differently targeted. We advance a stemness-function model to explain these data and discuss a possibility of rejuvenation from the perspective of damage accumulation. In turn, this suggests approaches to achieve rejuvenation of cells in vitro and in vivo.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ggn2.10025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10508961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}