Pub Date : 2024-09-12DOI: 10.1101/2024.09.06.611756
Olivia L Mosley, Joel A Villa, Advaitha Kamalakkannan, Eliyashaib James, Jessica M Hoffman, Yang Lyu
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.
膳食限制（DR）被广泛认为是延长不同物种健康寿命的最有效方法之一，但越来越明显的是，DR 介导的长寿受到生物和非生物因素的影响。我们建议，该领域目前的优先事项应包括了解这些因素的相对贡献，以阐明 DR 产生有益影响的机制。我们在两个实验室开展的工作代表了统一果蝇 DR 方案和研究 DR 随机效应的一种尝试。在 64 对生存数据（DR/自由饮食或 AL）中，我们发现 DR 并不能普遍延长寿命。具体来说，我们观察到 DR 只在 26.7%（17/64）的配对中显著延长了寿命。我们的汇总数据显示，DR 组和 AL 组之间的总体寿命差异具有统计学意义，但 DR 下寿命延长的中位数（7.1%）很小。随机因素和基因型掩盖了 DR 的影响。未来旨在全面了解 DR 依赖性机制的研究工作应侧重于揭示遗传和环境因素之间的相互作用。这对于开发延长健康寿命的个性化干预措施和优化针对个体遗传特征的饮食建议至关重要。
{"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":"168 1","pages":""},"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}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.06.611759
Gabrielle D Sandstedt, Catherine A Rushworth
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.
当基因不同的品系在二次接触中再次相遇时，杂交种可能会产生负面影响，降低适应性，也可能从积极的基因相互作用中获益，从而提高适应性。杂交是指杂交种优于其近交祖先的一种现象，对杂交的实证研究在农业领域引起了极大的兴趣，但在野生系统中却较少进行。在本研究中，我们利用一种主要为自花授粉的野花物种 Boechera retrofracta，探索种群分化如何影响二次接触后的适合度效应。我们整合了基因组数据和大规模的适应性实验，比较了B. retrofracta外交后代和近交后代的适应性和杂合度。我们发现，与近交个体相比，种群间杂交种的越冬存活率更高，这表明存在异质性。不同基因型和不同环境下的异质性程度不同，越冬存活率随亲本间遗传距离的增加而增加。对基因分型测序数据的滑动窗口分析表明，杂合度在两个物种（B. retrofracta 和常见的共生物种 Boechera stricta）的基因组中各不相同。接下来，我们将这些数据与新的 F2（种群内、种群间和种间杂交）以及野生采集的种群间杂交 B. retrofracta 和种间 B. stricta x B. retrofracta 杂交种进行了比较。野生采集的种间杂交种似乎是 F1s，而野生采集的种内 B. retrofracta 与更复杂的杂交模式一致。由于杂交与该群体向无性繁殖的过渡有关，这表明杂交和非杂交品系的无性繁殖具有不同的机制。这些发现强调了处于不同分化阶段的遗传群体之间异交作用的潜在差异及其在自然界杂交后的相关性。
{"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":"16 1","pages":""},"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}
Pub Date : 2024-09-11DOI: 10.1101/2024.09.09.612029
Hannah Jacobs, Bram Gorissen, Jeremy Guez, Masahiro Kanai, Hilary Finucane, Christopher Burge
Most mammalian genes undergo alternative splicing. The splicing of some exons has been acquired or lost in specific mammalian lineages, but differences in splicing within the human population are poorly characterized. Using GTEx tissue transcriptomes from 838 individuals, we identified 56,415 exons which are included in mRNAs in some individuals but entirely excluded from others, which we term 'naturally variable exons' (NVEs). NVEs impact three quarters of protein-coding genes, occur at all population frequencies, and are often absent from reference annotations. NVEs are more abundant in genes depleted of genetic loss-of-function mutations and aid in the interpretation of causal genetic variants. Genetic variants modulate the splicing of many NVEs, and 5'UTR and coding-region NVEs are often associated with increased and decreased gene expression, respectively. Together, our findings characterize abundant splicing variation in the human population, with implications for a range of human genetic analyses.
{"title":"Widespread naturally variable human exons aid genetic interpretation","authors":"Hannah Jacobs, Bram Gorissen, Jeremy Guez, Masahiro Kanai, Hilary Finucane, Christopher Burge","doi":"10.1101/2024.09.09.612029","DOIUrl":"https://doi.org/10.1101/2024.09.09.612029","url":null,"abstract":"Most mammalian genes undergo alternative splicing. The splicing of some exons has been acquired or lost in specific mammalian lineages, but differences in splicing within the human population are poorly characterized. Using GTEx tissue transcriptomes from 838 individuals, we identified 56,415 exons which are included in mRNAs in some individuals but entirely excluded from others, which we term 'naturally variable exons' (NVEs). NVEs impact three quarters of protein-coding genes, occur at all population frequencies, and are often absent from reference annotations. NVEs are more abundant in genes depleted of genetic loss-of-function mutations and aid in the interpretation of causal genetic variants. Genetic variants modulate the splicing of many NVEs, and 5'UTR and coding-region NVEs are often associated with increased and decreased gene expression, respectively. Together, our findings characterize abundant splicing variation in the human population, with implications for a range of human genetic analyses.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179731","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}
Pub Date : 2024-09-10DOI: 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
Multi-locus signatures of blood-based DNA methylation are well-established biomarkers for lifestyle and health outcomes. Here, we focus on two CpGs that are strongly associated with age and smoking behaviour. Imputing these loci via epigenome-wide CpGs results in stronger associations with outcomes in external datasets compared to directly measured CpGs. If extended epigenome-wide, CpG imputation could augment historic arrays and recently-released, inexpensive but lower-content arrays, thereby yielding better-powered association studies.
基于血液的 DNA 甲基化的多焦点特征是生活方式和健康结果的公认生物标志物。在这里，我们重点研究与年龄和吸烟行为密切相关的两个 CpGs。与直接测量的 CpGs 相比，通过全表观基因组的 CpGs 对这些位点进行推算，会发现它们与外部数据集中的结果有更强的关联。如果在整个表观基因组范围内推广，CpG 估算可以增强历史阵列和最近发布的廉价但含量较低的阵列，从而产生更好的关联研究。
{"title":"Imputed DNA methylation outperforms measured loci associations with smoking and chronological age","authors":"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","doi":"10.1101/2024.09.05.611501","DOIUrl":"https://doi.org/10.1101/2024.09.05.611501","url":null,"abstract":"Multi-locus signatures of blood-based DNA methylation are well-established biomarkers for lifestyle and health outcomes. Here, we focus on two CpGs that are strongly associated with age and smoking behaviour. Imputing these loci via epigenome-wide CpGs results in stronger associations with outcomes in external datasets compared to directly measured CpGs. If extended epigenome-wide, CpG imputation could augment historic arrays and recently-released, inexpensive but lower-content arrays, thereby yielding better-powered association studies.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179733","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}
Pub Date : 2024-09-09DOI: 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
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.
早年的音乐活动是日后（社交）沟通和语言能力的重要遗传前兆，但对其研究不足。本研究旨在揭示音乐与沟通能力之间的遗传机制。我们从 "雅芳父母与儿童纵向研究"（Avon Longitudinal Study of Parents and Children）中得出了儿童（人数≤6737）自我报告的节拍同步能力（PGSrhythmicity）的多基因分数（PGS），并测试了这些分数与学龄前音乐能力（0.5-5 岁）和学龄期（社交）沟通及认知相关能力（9-12 岁）之间的关系。我们使用结构方程模型技术进一步评估了学龄前音乐性和学龄期沟通能力之间的关系是否通过 PGSrhythmicity 得到了共享。PGSrhythmicity 与学龄前乐感（Nagelkerke-R2=0.70-0.79%）、学龄期沟通和认知相关能力（R2=0.08-0.41%）相关，但与社会沟通无关。我们确定了学龄前乐感与学龄期语言和句法相关沟通能力之间的联系，这种联系是由节奏性的已知遗传影响因素所决定的（共享效应β=0.0065（SE=0.0021），p=0.0016），超出了一般认知的范围，从而加强了对早期音乐干预计划的支持。
{"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 (PGS<sub>rhythmicity</sub>) 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 PGS<sub>rhythmicity</sub>, using structural equation modelling techniques. PGS<sub>rhythmicity</sub> were associated with preschool musicality (Nagelkerke-R<sup>2</sup>=0.70-0.79%), and school-age communication and cognition-related abilities (R<sup>2</sup>=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":"83 1","pages":""},"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}
Pub Date : 2024-09-08DOI: 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
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.
{"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":"12 1","pages":""},"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}
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.
{"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":"51 1","pages":""},"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}
Pub Date : 2024-09-08DOI: 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
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.
{"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":"58 1","pages":""},"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}
Pub Date : 2024-09-08DOI: 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
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.
{"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":"9 1","pages":""},"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}
Pub Date : 2024-09-08DOI: 10.1101/2024.09.04.609712
Colby Tubbs, Mary Lauren Benton, Evonne McArthur, John A. Capra, Douglas M. Ruderfer
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.
非编码单核苷酸变异是全基因组测序中最主要的一类遗传变异，也是表型变异的主要驱动因素。然而，对它们进行功能注释仍然具有挑战性。鉴于 CTCF 在基因调控中的关键作用以及调控数据集的广泛剖析，我们开发了一种假设驱动的 CTCF 结合位点功能注释方案。我们将 214 种生物背景下 1,063,879 个基因组位点上的 CTCFs 结合模式综合成一个总结性指标，我们称之为结合活性。我们发现，结合活性在保守核苷酸（Pearson R = 0.31，p < 2.2 x 10-16）和包含高质量 CTCF 结合图案的序列（Pearson R = 0.63，p = 2.9 x 10-12）中都有明显的富集。然后，我们将结合活性与精确度权重矩阵得分中的高置信度变化进行整合。通过将这一框架应用于 gnomAD 中的 1,253,330 个 SNVs，我们探索了针对 CTCF 结合破坏的选择特征。我们发现，在具有高体外活性的基因位点上，突变性调整单体比例（MAPS）指标与 CTCF 结合的丧失之间存在着强烈的正相关关系（Pearson R = 0.67，p = 1.5 x 10-14）。为了说明这些发现的背景，我们将 MAPS 应用于其他功能类变异，发现在 198,149 个 CTCF 结合丧失变异中，有一个子集与错义变异一样不常被观察到。这项工作将这数千个破坏 CTCF 结合的罕见非编码变异与进一步的功能研究联系起来，同时为非编码变异的可解释性注释提供了一个蓝图。
{"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":"15 1","pages":""},"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}
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