bioRxiv - Genetics最新文献_第4页

Stochasticity in dietary restriction-mediated lifespan outcomes in Drosophila 果蝇饮食限制介导的寿命结果的随机性

bioRxiv - Genetics Pub Date : 2024-09-12 DOI: 10.1101/2024.09.06.611756

Olivia L Mosley, Joel A Villa, Advaitha Kamalakkannan, Eliyashaib James, Jessica M Hoffman, Yang Lyu

{"title":"Stochasticity in dietary restriction-mediated lifespan outcomes in Drosophila","authors":"Olivia L Mosley, Joel A Villa, Advaitha Kamalakkannan, Eliyashaib James, Jessica M Hoffman, Yang Lyu","doi":"10.1101/2024.09.06.611756","DOIUrl":"https://doi.org/10.1101/2024.09.06.611756","url":null,"abstract":"Dietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories, represents an attempt to unify DR protocols in Drosophila and to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ad libitum, or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Heterosis across an environmental and genetic space 跨越环境和遗传空间的异质性

bioRxiv - Genetics Pub Date : 2024-09-12 DOI: 10.1101/2024.09.06.611759

Gabrielle D Sandstedt, Catherine A Rushworth

{"title":"Heterosis across an environmental and genetic space","authors":"Gabrielle D Sandstedt, Catherine A Rushworth","doi":"10.1101/2024.09.06.611759","DOIUrl":"https://doi.org/10.1101/2024.09.06.611759","url":null,"abstract":"When genetically divergent lineages meet again in secondary contact, hybrids may suffer negative, fitness-reducing consequences, or benefit from positive genetic interactions that result in increased fitness. Empirical studies of heterosis, a phenomenon in which hybrids outperform their inbred progenitors, are of great interest in agriculture, but are less often performed in wild systems. In this study, we leverage Boechera retrofracta, a primarily self-fertilizing wildflower species, to explore how population divergence influences fitness effects upon secondary contact. We integrated genomic data and a large-scale fitness experiment to compare fitness and heterozygosity between outbred and inbred progeny of B. retrofracta. We show that interpopulation hybrids have increased overwintering survival compared to inbred individuals, indicative of heterosis. The magnitude of heterosis varied across genotypes and different environments, with overwintering survival increasing with genetic distance between parents. Sliding window analyses of genotyping by sequencing data show that heterozygosity varies across the genome of two species, B. retrofracta and the commonly co-occurring species Boechera stricta. We next compared these data with de novo F2s (intrapopulation, interpopulation, and interspecific crosses), as well as with wild-collected interpopulation cross B. retrofracta and interspecific B. stricta x B. retrofracta hybrids. Wild-collected interspecific hybrids appear to be F1s, while wild-collected intraspecific B. retrofracta are consistent with more complex crossing patterns. Because outcrossing is associated with a transition to asexuality in this group, this suggests different mechanisms underlie asexuality in hybrid and non-hybrid lineages. These findings underscore the potential differences in the role of heterosis between genetic groups at different stages of divergence and its relevance following hybridization in nature.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Widespread naturally variable human exons aid genetic interpretation 人类外显子的广泛自然变异有助于基因解读

bioRxiv - Genetics Pub Date : 2024-09-11 DOI: 10.1101/2024.09.09.612029

Hannah Jacobs, Bram Gorissen, Jeremy Guez, Masahiro Kanai, Hilary Finucane, Christopher Burge

引用次数: 0

Imputed DNA methylation outperforms measured loci associations with smoking and chronological age 推算的 DNA 甲基化与吸烟和实际年龄的关系优于测量的基因位点关系

bioRxiv - Genetics Pub Date : 2024-09-10 DOI: 10.1101/2024.09.05.611501

Anne Richmond, Jure Mur, Sarah Harris, Janie Corley, Hannah R Elliott, Chris N Foley, Eilis Hannon, Zhana Kuncheva, Josine Min, Mahdi Moqri, Magatte Ndiaye, Benjamin Sun, Catalina Vallejos, Kejun Ying, Vadim N Gladyshev, Simon R Cox, Daniel L. McCartney, Riccardo Marioni

引用次数: 0

Preschool musicality is associated with school-age communication abilities through genes related to rhythmicity 学龄前乐感通过与节奏感相关的基因与学龄期交流能力相关联

bioRxiv - Genetics Pub Date : 2024-09-09 DOI: 10.1101/2024.09.09.611603

Lucía de Hoyos, Ellen Verhoef, Aysu Okbay, Janne R Vermeulen, Celeste Figaroa, Miriam Lense, Simon E. Fisher, Reyna L Gordon, Beate St Pourcain

{"title":"Preschool musicality is associated with school-age communication abilities through genes related to rhythmicity","authors":"Lucía de Hoyos, Ellen Verhoef, Aysu Okbay, Janne R Vermeulen, Celeste Figaroa, Miriam Lense, Simon E. Fisher, Reyna L Gordon, Beate St Pourcain","doi":"10.1101/2024.09.09.611603","DOIUrl":"https://doi.org/10.1101/2024.09.09.611603","url":null,"abstract":"Early-life musical engagement is an understudied but developmentally important and heritable precursor of later (social) communication and language abilities. This study aims to uncover the aetiological mechanisms linking musical to communication abilities. We derived polygenic scores (PGS) for self-reported beat synchronisation abilities (PGSrhythmicity) in children (N≤6,737) from the Avon Longitudinal Study of Parents and Children and tested their association with preschool musical (0.5-5 years) and school-age (social) communication and cognition-related abilities (9-12 years). We further assessed whether relationships between preschool musicality and school-age communication are shared through PGSrhythmicity, using structural equation modelling techniques. PGSrhythmicity were associated with preschool musicality (Nagelkerke-R2=0.70-0.79%), and school-age communication and cognition-related abilities (R2=0.08-0.41%), but not social communication. We identified links between preschool musicality and school-age speech- and syntax-related communication abilities as captured by known genetic influences underlying rhythmicity (shared effect β=0.0065(SE=0.0021), p=0.0016), above and beyond general cognition, strengthening support for early music intervention programmes.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrating Phenomic Selection Using Single-Kernel Near-Infrared Spectroscopy and Genomic Selection for Corn Breeding Improvement 利用单核近红外光谱进行表观选择与基因组选择相结合，促进玉米育种改良

bioRxiv - Genetics Pub Date : 2024-09-08 DOI: 10.1101/2024.09.07.611678

Rafaela Prado Graciano, Marco Antonio Peixoto, Kristen A. Leach, Noriko Suzuki, Jeff Gustin, A. Mark Settles, Paul R. Armstrong, Marcio FR Resende

{"title":"Integrating Phenomic Selection Using Single-Kernel Near-Infrared Spectroscopy and Genomic Selection for Corn Breeding Improvement","authors":"Rafaela Prado Graciano, Marco Antonio Peixoto, Kristen A. Leach, Noriko Suzuki, Jeff Gustin, A. Mark Settles, Paul R. Armstrong, Marcio FR Resende","doi":"10.1101/2024.09.07.611678","DOIUrl":"https://doi.org/10.1101/2024.09.07.611678","url":null,"abstract":"Phenomic Selection (PS) is a cost-effective method proposed for predicting complex traits and enhancing genetic gain in breeding programs. The statistical procedures are similar to those utilized in genomic selection (GS) models, but molecular markers data are replaced with phenomic data, such as near-infrared spectroscopy (NIRS). However, the use of NIRS applied to PS typically utilized destructive sampling or collected data after the establishment of selection experiments in the field. Here, we explored the application of PS using non-destructive, single-kernel NIRS in a sweet corn breeding program, focusing on predicting future, unobserved field-based traits of economic importance, including ear and vegetative traits. Three models were employed on a diversity panel: G-BLUP and P-BLUP models, which used relationship matrices based on SNP and NIRS data, and a combined model. The genomic relationship matrices were evaluated with varying numbers of SNPs. Additionally, the P-BLUP model trained on the diversity panel was used to select doubled haploid (DH) lines for germination before planting, with predictions validated using observed data. The findings indicate that PS generated good predictive ability (e.g., 0.46 for plant height) and effectively distinguished between high and low germination rates in untested DH lines. Although GS generally outperformed PS, the model combining both information yielded the highest predictive ability, with considerably higher accuracies than GS when low marker densities were used. This study highlights the potential of NIRS both to achieve genetic gain where GS may not be feasible and to maintain/improve accuracy with SNP-based information while reducing genotyping costs.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

High Resolution Class I HLA -A, -B, and -C Diversity in Eastern and Southern African Populations 非洲东部和南部人群中高分辨率 I 类 HLA -A、-B 和 -C 的多样性

bioRxiv - Genetics Pub Date : 2024-09-08 DOI: 10.1101/2024.09.04.611164

Zaza Ndhlovu, Alabi W Banjoko, Tiza Ng'uni, Nitalia Naidoo, Veron Ramsuran, Olivier Hyrien

{"title":"High Resolution Class I HLA -A, -B, and -C Diversity in Eastern and Southern African Populations","authors":"Zaza Ndhlovu, Alabi W Banjoko, Tiza Ng'uni, Nitalia Naidoo, Veron Ramsuran, Olivier Hyrien","doi":"10.1101/2024.09.04.611164","DOIUrl":"https://doi.org/10.1101/2024.09.04.611164","url":null,"abstract":"Africa remains significantly underrepresented in high-resolution Human Leukocyte Antigen (HLA) data, despite being one of the most genetically diverse regions in the world. This critical gap in genetic information poses a substantial barrier to HLA-based research on the continent. In this study, Class I HLA data from Eastern and Southern African populations were analyzed to assess genetic diversity across the region. We examined allele and haplotype frequency distributions, deviations from Hardy-Weinberg Equilibrium (HWE), linkage disequilibrium (LD), and conducted neutrality tests of homozygosity across various populations. Additionally, the African HLA data were compared to those of Caucasian and African American populations using the Jaccard index and multidimensional scaling (MDS) methods. The study revealed that South African populations exhibited 50.4% more genetic diversity within the Class I HLA region compared to other African populations. Zambia showed an estimated 36.5% genetic diversity, with Kenya, Rwanda and Uganda showing 35.7%, 34.2%, and 31.1%, respectively. Furthermore, an analysis of in-country diversity among different tribes indicated an average Class I HLA diversity of 25.7% in Kenya, 17% in Rwanda, 2.8% in South Africa, 13.6% in Uganda, and 6.5% in Zambia. The study also highlighted the genetic distinctness of Caucasian and African American populations compared to African populations. Notably, the differential frequencies of disease-promoting and disease-preventing HLA alleles across these populations emphasize the urgent need to generate high-quality HLA data for all regions of Africa and its major ethnic groups. Such efforts will be crucial in enhancing healthcare outcomes across the continent.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance 对人类胰岛素受体外结构域进行深度突变扫描，为胰岛素抵抗的精准治疗提供依据

bioRxiv - Genetics Pub Date : 2024-09-08 DOI: 10.1101/2024.09.07.611782

Vahid Aslanzadeh, Gemma V Brierley, Rupa Kumar, Hasan Cubuk, Corinne Vigouroux, Kenneth A Matreyek, Grzegorz Kudla, Robert K Semple

{"title":"Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance","authors":"Vahid Aslanzadeh, Gemma V Brierley, Rupa Kumar, Hasan Cubuk, Corinne Vigouroux, Kenneth A Matreyek, Grzegorz Kudla, Robert K Semple","doi":"10.1101/2024.09.07.611782","DOIUrl":"https://doi.org/10.1101/2024.09.07.611782","url":null,"abstract":"The insulin receptor (INSR) entrains tissue growth and metabolism to nutritional conditions. Complete loss of function in humans leads to extreme insulin resistance and infantile mortality, while loss of 80-90% function permits longevity of decades. Even low-level activation of severely compromised receptors, for example by anti-receptor monoclonal antibodies, thus offers the potential for decisive clinical benefit. A barrier to genetic diagnosis and translational research is the increasing identification of INSR variants of uncertain significance. We employed saturation mutagenesis coupled to multidimensional flow-based assays to stratify approximately 14,000 INSR extracellular domain missense variants by cell surface expression, insulin binding, and insulin- or monoclonal antibody-stimulated signaling. The resulting function scores correlate strongly with clinical syndromes, offer insights into dynamics of insulin binding, and reveal novel potential gain-of-function variants. This INSR sequence-function map has high biochemical, diagnostic and translational utility, aiding rapid identification of variants amenable to activation by non-canonical INSR agonists.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identifying deleterious noncoding variation through gain and loss of CTCF binding activity 通过 CTCF 结合活性的增减识别有害的非编码变异

bioRxiv - Genetics Pub Date : 2024-09-08 DOI: 10.1101/2024.09.04.609712

Colby Tubbs, Mary Lauren Benton, Evonne McArthur, John A. Capra, Douglas M. Ruderfer

{"title":"Identifying deleterious noncoding variation through gain and loss of CTCF binding activity","authors":"Colby Tubbs, Mary Lauren Benton, Evonne McArthur, John A. Capra, Douglas M. Ruderfer","doi":"10.1101/2024.09.04.609712","DOIUrl":"https://doi.org/10.1101/2024.09.04.609712","url":null,"abstract":"Noncoding single nucleotide variants are the predominant class of genetic variation in whole genome sequencing and are key drivers of phenotypic variation. However, their functional annotation remains challenging. To address this, we develop a hypothesis-driven functional annotation scheme for CTCF binding sites given CTCFs critical roles in gene regulation and extensive profiling in regulatory datasets. We synthesize CTCFs binding patterns at 1,063,879 genomic loci across 214 biological contexts into a summary metric, which we refer to as binding activity. We find that binding activity is significantly enriched for both conserved nucleotides (Pearson R = 0.31, p < 2.2 x 10-16) and sequences that contain high-quality CTCF binding motifs (Pearson R = 0.63, p = 2.9 x 10-12). We then integrate binding activity with high confidence change in precision weight matrix scores. By applying this framework to 1,253,330 SNVs in gnomAD, we explore signatures of selection acting against the disruption of CTCF binding. We find a strong, positive relationship between the mutability adjusted proportion of singletons (MAPS) metric and the loss of CTCF binding at loci with high in vitro activity (Pearson R = 0.67, p = 1.5 x 10-14). To contextualize these findings, we apply MAPS to other functional classes of variation and find that a subset of 198,149 loss of CTCF binding variants are observed as infrequently as missense variants. This work implicates these thousands of rare, noncoding variants that disrupt CTCF binding for further functional studies while providing a blueprint for the interpretable annotation of noncoding variants.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancer activation from transposable elements in extrachromosomal DNA 染色体外 DNA 中转座子激活的增强子

bioRxiv - Genetics Pub Date : 2024-09-08 DOI: 10.1101/2024.09.04.611262

Katerina Kraft, Sedona E Murphy, Matthew G Jones, Quanming Shi, Aarohi Bhargava-Shah, Christy Luong, King L Hung, Britney J He, Rui Li, Seung K Park, Natasha E Weiser, Jens Luebeck, Vineet Bafna, Jef D Boeke, Paul S. Mischel, Alistair N Boettiger, Howard Y Chang

{"title":"Enhancer activation from transposable elements in extrachromosomal DNA","authors":"Katerina Kraft, Sedona E Murphy, Matthew G Jones, Quanming Shi, Aarohi Bhargava-Shah, Christy Luong, King L Hung, Britney J He, Rui Li, Seung K Park, Natasha E Weiser, Jens Luebeck, Vineet Bafna, Jef D Boeke, Paul S. Mischel, Alistair N Boettiger, Howard Y Chang","doi":"10.1101/2024.09.04.611262","DOIUrl":"https://doi.org/10.1101/2024.09.04.611262","url":null,"abstract":"Extrachromosomal DNA (ecDNA) is a hallmark of aggressive cancer, contributing to both oncogene amplification and tumor heterogeneity. Here, we used Hi-C, super-resolution imaging, and long-read sequencing to explore the nuclear architecture of MYC-amplified ecDNA in colorectal cancer cells. Intriguingly, we observed frequent spatial proximity between ecDNA and 68 repetitive elements which we called ecDNA-interacting elements or EIEs. To characterize a potential regulatory role of EIEs, we focused on a fragment of the L1M4a1#LINE/L1 which we found to be co-amplified with MYC on ecDNA, gaining enhancer-associated chromatin marks in contrast to its normally silenced state. This EIE, in particular, existed as a naturally occurring structural variant upstream of MYC, gaining oncogenic potential in the transcriptionally permissive ecDNA environment. This EIE sequence is sufficient to enhance MYC expression and is required for cancer cell fitness. These findings suggest that silent repetitive genomic elements can be reactivated on ecDNA, leading to functional cooption and amplification. Repeat element activation on ecDNA represents a mechanism of accelerated evolution and tumor heterogeneity and may have diagnostic and therapeutic potential.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0