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I want to discuss both the Single Nucleotide Polymorphism (SNP) Consortium and the Human Genome Project. I am afraid most of my presentation will be thin on law and possibly too high on rhetoric. Having been engaged in a personal and direct way with these issues as a trained scientist, I find it quite difficult to be always as objective as I ought to be.
Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)–mutant low-grade glioma (LGG). Here, we reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1 R132H -driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.
The commercially important speciesLutjanus campechanus(Northern/Gulf red snapper) andLutjanus purpureus(Southern/Caribbean red snapper) are the protagonists of a decade’s long taxonomic debate over their species delimitation, due in part to partial habitat overlap, extensive morphological similarity, and the lack of resolution when applying canonically reliable DNA barcoding approaches. In this study, we leveraged publicly available RAD-Seq data forL. campechanusandL. purpureusto identify species-informative single‐nucleotide polymorphisms (SNPs) at the genome scale that were successful in distinguishing the Northern and Southern red snappers, while also detecting individuals exhibiting introgression. This 4-step empirical approach demonstrates the value of applying novel bioinformatics pipelines to existing genome-scale data to maximize the distillation of informative subsets. Our results facilitate economically relevant species identification in addition to confirming or challenging species identifications for specimens with data in public databases. These findings and their applications will benefit future sustainability strategies and broader research questions surrounding these overfished and evolutionarily entangled snapper species.
White sturgeon (Acipenser transmontanus) are the largest freshwater fish in North America, with reproducing populations in the Sacramento-San Joaquin, Fraser, and Columbia River Basins. Of these, the Columbia River is the largest, but it is also highly fragmented by hydroelectric dams, and many segments are characterized by declining abundance and persistent recruitment failure. Efforts to conserve and supplement these fish requires an understanding of their spatial genetic structure. Here, we assembled a large set of samples from throughout the Columbia River Basin, along with representative collections from adjacent basins, and genotyped them using a panel of 325 single-nucleotide markers. Results from individual- and group-based analyses of these data indicate that white sturgeon in the uppermost Columbia River Basin, in the Kootenai and upper Snake Rivers, are the most distinct, while the remaining populations downstream in the basin can be described as a genetic gradient consistent with an isolation-by-distance effect. Notably, the population in the lowest reaches of the Columbia River is more distinct from the middle or upper reaches than from outside basins, and suggests historically a higher or more recent gene exchange through coastal routes than with populations in the interior Columbia Basin. Nonetheless, proximal reaches were generally only marginally or non-significantly divergent, suggesting that transplanting larvae or juveniles from nearby sources poses relatively little risk of outbreeding depression. Indeed, we inferred examples of dispersal between reaches via close-kin mark-recapture and genetic mark-recapture that indicate movement between nearby reaches is not unusual. Samples from the Kootenai and upper Snake Rivers exhibited notably lower genetic diversity than the remaining samples as a result of population bottlenecks, genetic drift, and/or historical divergence. Conservation actions, such as supplementation, are underway to maintain population viability and will require balanced efforts to increase demographic abundance while maintaining genetic diversity.
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Neither microscopical hair comparisons nor mitochondrial DNA sequencing alone, or together, constitutes a basis for personal identification. Due to these limitations, a complementary technique to compare questioned and known hair shafts was investigated. Recently, scientists from Lawrence Livermore National Laboratory's Forensic Science Center and other collaborators developed a peptide profiling technique, which can infer non-synonymous single nucleotide polymorphisms (SNPs) preserved in hair shaft proteins as single amino acid polymorphisms (SAPs). In this study, peptide profiling was evaluated to determine if it can meet forensic expectations when samples are in limited quantities with the possibility that hair samples collected from different areas of a single donor’s scalp (i.e., single source) might not exhibit the same SAP profile. The average dissimilarity, percent differences in SAP profiles within each source, ranged from 0% difference to 29%. This pilot study suggests that more work is needed before peptide profiling of hair can be considered for forensic comparisons.
Populus euphratica is a dominant tree species in desert riparian forests and possesses extraordinary adaptation to salinity stress. Exploration of its genomic variation and molecular underpinning of salinity tolerance is important for elucidating population evolution and identifying stress-related genes. Here, we identify approximately 3.15 million single nucleotide polymorphisms using whole-genome resequencing. The natural populations of P. euphratica in northwest China are divided into four distinct clades that exhibit strong geographical distribution patterns. Pleistocene climatic fluctuations and tectonic deformation jointly shaped the extant genetic patterns. A seed germination rate-based salinity tolerance index was used to evaluate seed salinity tolerance of P. euphratica and a genome-wide association study was implemented. A total of 38 single nucleotide polymorphisms were associated with seed salinity tolerance and were located within or near 82 genes. Expression profiles showed that most of these genes were regulated under salt stress, revealing the genetic complexity of seed salinity tolerance. Furthermore, DEAD-box ATP-dependent RNA helicase 57 and one undescribed gene (CCG029559) were demonstrated to improve the seed salinity tolerance in transgenic Arabidopsis. These results provide new insights into the demographic history and genetic architecture of seed salinity tolerance in desert poplar.
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The seasonal timing of the transition from vegetative to reproductive growth has a major impact on biomass accumulation in switchgrass. Late-flowering switchgrass cultivars produce greater biomass, a critical trait for sustainable bioenergy production. Genomic prediction (GP) may allow rapid selection of late-flowering individuals with reduced time and expense for field evaluations. To evaluate GP, two flowering time traits (heading date and anthesis date) were collected on 1532 genotypes from four breeding populations: Midwest, Gulf, Atlantic, and Hybrid. These were sequenced using genotype-by-sequencing (530,792 single-nucleotide polymorphisms). Predictive ability of single-trait and multi-trait models were evaluated by cross-validation, by prediction of a progeny trial (n = 122), and through prediction of yield performance in a parallel experiment (n = 52). Predictive ability was not improved by sharing information among breeding groups. Overall, multi-trait models provided an advantage during cross-validation, but a smaller advantage during progeny prediction. Within populations, GP resulted in lower per-cycle progress than previously reported field evaluations (3.1 vs. 5.0 day –1 cycle –1 ). However, GP cycles are potentially much faster than field evaluations. When directly predicting biomass yield, the Hybrid training population had a predictive ability of 0.54–0.63. This reinforces the strong linkage between biomass yields in swards and flowering time. Furthermore, these results highlight the value of GP for rapid yield improvement in switchgrass, particularly in a breeding program designed to share information between biomass yield trials and low-cost flowering time evaluations.
Abstract Human hair contains minimal intact nuclear DNA for human identification in forensic and archaeological applications. In contrast, proteins offer a pathway to exploit hair evidence for human identification owing to their persistence, abundance, and derivation from DNA. Individualizing single nucleotide polymorphisms (SNPs) are often conserved as single amino acid polymorphisms in genetically variant peptides (GVPs). Detection of GVP markers in the hair proteome via high-resolution tandem mass spectrometry permits inference of SNPs with known statistical probabilities. To adopt this approach for forensic investigations, hair proteomic variation and its effects on GVP identification must first be characterized. This research aimed to assess variation in single-inch head, arm, and pubic hair, and discover body location-invariant GVP markers to distinguish individuals. Comparison of protein profiles revealed greater body location-specific variation in keratin-associated proteins and intracellular proteins, allowing body location differentiation. However, robust GVP markers derive primarily from keratins that do not exhibit body location-specific differential expression, supporting GVP identification independence from hair proteomic variation at the various body locations. Further, pairwise comparisons of GVP profiles with 8 SNPs demonstrated greatest interindividual variation and high intraindividual consistency, enabling similar differentiative potential of individuals using single hairs irrespective of body location origin.
Heat shock transcription factors (Hsfs), which function as the activator of heat shock proteins (Hsps), play multiple roles in response to environmental stress and the development of plants. The Hsf family had experienced gene expansion via whole-genome duplication from a single cell algae to higher plants. Yet, how the Hsf gene family went through evolutionary divergence after genome duplication is unknown. As a model wood species, Populus trichocarpa is widely distributed in North America with various ecological and climatic environments. In this study, we used P. trichocarpa as materials and identified the expression divergence of the PtHsf gene family in developmental processes, such as dormant bud formation and opening, catkins development, and in response to environments. Through the co-expression network, we further discovered the divergent co-expressed genes that related to the functional divergence of PtHsf . Then, we studied the alternative splicing events, single nucleotide polymorphism distribution and tertiary structures of members of the PtHsf gene family. In addition to expression divergence, we uncovered the evolutionary divergence in the protein level which may be important to new function formations and for survival in changing environments. This study comprehensively assessed the evolutionary divergence of a member of the PtHsf gene family after genome duplication, paving the way for further gene function analysis and genetic engineering.
Rapid advancements in technologies provide various tools to analyze fruit crop genomes to better understand genetic diversity and relationships and aid in breeding. Genome-wide single nucleotide polymorphism (SNP) genotyping arrays offer highly multiplexed assays at a relatively low cost per data point. We report the development and validation of 1.4M SNP Axiom® Citrus HD Genotyping Array (Citrus 15AX 1 and Citrus 15AX 2) and 58K SNP Axiom® Citrus Genotyping Arrays for Citrus and close relatives. SNPs represented were chosen from a citrus variant discovery panel consisting of 41 diverse whole-genome re-sequenced accessions of Citrus and close relatives, including eight progenitor citrus species. SNPs chosen mainly target putative genic regions of the genome and are accurately called in both Citrus and its closely related genera while providing good coverage of the nuclear and chloroplast genomes. Reproducibility of the arrays was nearly 100%, with a large majority of the SNPs classified as the most stringent class of markers, “PolyHighResolution” (PHR) polymorphisms. Concordance between SNP calls in sequence data and array data average 98%. Phylogenies generated with array data were similar to those with comparable sequence data and little affected by 3 to 5% genotyping error. Both arrays are publicly available.
Consumption of buffalofish has been sporadically associated with Haff disease-like illnesses involving sudden onset muscle pain and weakness due to skeletal muscle rhabdomyolysis, but determination of precisely which species are associated with these illnesses has been impeded by a lack of species-specific DNA-based markers. Here, three closely related species of buffalofish native to the Mississippi River Basin (Ictiobus bubalus, Ictiobus cyprinellus and Ictiobus niger) that have previously proven genetically indistinguishable using both mitochondrial and nuclear single-locus sequencing were reliably discriminated using low-coverage whole genome sequencing (‘genome skimming’). Using 44 specimens representing the three species collected from the mid/upper (Missouri) and lower (Louisiana) regions of the species’ native ranges, the SISRS (Site Identification from Short Read Sequences) bioinformatics pipeline was adapted to (1) identify over 620Mbp of putatively homologous nuclear sequence data and (2) isolate over 140,000 single-nucleotide polymorphisms (SNPs) that supported accurate species delimitation, all without the use of a reference genome or annotation data. These sites were used to classify Ictiobus spp. samples with genome-skim data, along with a larger set (n = 67) where ultraconserved elements (UCEs) were sequenced. Analyses of whole mitochondrial data revealed more limited signal. Nearly all samples matched their purported species based on morphologic identification, but two Missouri samples morphologically identified as I. niger grouped with samples of I. bubalus, albeit with significant enrichment of I. niger SNPs. To our knowledge this is the first report of a DNA-based tool to reliably discriminate these three morphologically distinct species.
Genetic structure within marine species may be driven by local adaptation to their environment, or alternatively by historical processes, such as geographic isolation. The gulfs and seas bordering the Arabian Peninsula offer an ideal setting to examine connectivity patterns in coral reef fishes with respect to environmental gradients and vicariance. The Red Sea is characterized by a unique marine fauna, historical periods of desiccation and isolation, as well as environmental gradients in salinity, temperature, and primary productivity that vary both by latitude and by season. The adjacent Arabian Sea is characterized by a sharper environmental gradient, ranging from extensive coral cover and warm temperatures in the southwest, to sparse coral cover, cooler temperatures, and seasonal upwelling in the northeast. Reef fish, however, are not confined to these seas, with some Red Sea fishes extending varying distances into the northern Arabian Sea, while their pelagic larvae are presumably capable of much greater dispersal. These species must therefore cope with a diversity of conditions that invoke the possibility of steep clines in natural selection. Here, we test for genetic structure in two widespread reef fish species (a butterflyfish and surgeonfish) and eight range-restricted butterflyfishes across the Red Sea and Arabian Sea using genome-wide single nucleotide polymorphisms. We performed multiple matrix regression with randomization analyses on genetic distances for all species, as well as reconstructed scenarios for population subdivision in the species with signatures of isolation. We found that (a) widespread species displayed more genetic subdivision than regional endemics and (b) this genetic structure was not correlated with contemporary environmental parameters but instead may reflect historical events. We propose that the endemic species may be adapted to a diversity of local conditions, but the widespread species are instead subject to ecological filtering where different combinations of genotypes persist under divergent ecological regimes.
Evidence recovery is challenging where an explosion has occurred. Though hair evidence may be sufficiently robust to be recovered at the site, forensic analysis underutilizes the matrix by relying on morphological analysis. Where DNA is compromised, particularly in hair, protein-based human identification presents a promising alternative. Detection of amino acid polymorphisms in hair proteins as genetically variant peptides (GVPs) permits the inference of individualizing single nucleotide polymorphisms for identification. However, an explosive blast may damage hair proteins and compromise GVP identification. This work evaluates effects of an explosive blast on the hair proteome and GVP identification, investigates microscopy as a predictor of proteome profiling success in recovered hairs to improve analysis throughput, and quantifies discriminative power in damaged hairs. The proteomics dataset has been deposited into the ProteomeXchange Consortium (PXD017427). With the exception of degradation in keratins K75, K80, K40, and keratin-associated protein KAP10-11 as markers of hair cuticular damage, corroborated by scanning electron microscopic analysis, minimal hair proteome degradation following explosion allowed successful proteome profiling of single hairs regardless of morphological damage. Finally, GVP identification remained independent of explosion conditions, permitting similar discriminative power between exploded and undamaged hairs. These findings lend greater confidence to GVP analysis in one-inch hairs for forensic identification and provide information about hair protein localization.
Genome–wide association studies (GWAS) have great promise for identifying the loci that contribute to adaptive variation, but the complex genetic architecture of many quantitative traits presents a substantial challenge.We measured 14 morphological and physiological traits and identified single nucleotide polymorphism (SNP)–phenotype associations in a Populus trichocarpa population distributed from California, USA to British Columbia, Canada. We used whole–genome resequencing data of 882 trees with more than 6.78 million SNPs, coupled with multitrait association to detect polymorphisms with potentially pleiotropic effects. Candidate genes were validated with functional data.Broad–sense heritability (H2) ranged from 0.30 to 0.56 for morphological traits and 0.08 to 0.36 for physiological traits. In total, 4 and 20 gene models were detected using the single–trait and multitrait association methods, respectively. Several of these associations were corroborated by additional lines of evidence, including co–expression networks, metabolite analyses, and direct confirmation of gene function through RNAi.Multitrait association identified many more significant associations than single–trait association, potentially revealing pleiotropic effects of individual genes. Furthermore, this approach can be particularly useful for challenging physiological traits such as water–use efficiency or complex traits such as leaf morphology, for which we were able to identify credible candidate genes by combining multitrait association with gene co–expression and co–methylation data.
Genomic structural mutations, especially deletions, are an important source of variation in many species and can play key roles in phenotypic diversification and evolution. Previous work in many plant species has identified multiple instances of structural variations (SVs) occurring in or near genes related to stress response and disease resistance, suggesting a possible role for SVs in local adaptation. Sorghum [Sorghum bicolor (L.) Moench] is one of the most widely grown cereal crops in the world. It has been adapted to an array of different climates as well as bred for multiple purposes, resulting in a striking phenotypic diversity. In this study, we identified genome-wide SVs in the Biomass Association Panel, a collection of 347 diverse sorghum genotypes collected from multiple countries and continents. Using Illumina-based, short-read whole-genome resequencing data from every genotype, we found a total of 24,648 SVs, including 22,359 deletions. The global site frequency spectrum of deletions and other types of SVs fit a model of neutral evolution, suggesting that the majority of these mutations were not under any types of selection. Clustering results based on single nucleotide polymorphisms separated the genotypes into eight clusters which largely corresponded with geographic origins, with many of the large deletions we uncovered being unique to a single cluster. Even though most deletions appeared to be neutral, a handful of cluster-specific deletions were found in genes related to biotic and abiotic stress responses, supporting the possibility that at least some of these deletions contribute to local adaptation in sorghum.