ABSTRACT
Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, "in-a-dish" genotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.
Subject(s)
Genetic Predisposition to Disease , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/genetics , Organoids , Genetic Association Studies , Alleles , LiverABSTRACT
The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
Subject(s)
Immunologic Deficiency Syndromes , Nerve Tissue Proteins , Ubiquitins , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Female , Male , NF-kappa B/metabolism , Ubiquitin-Protein Ligases/genetics , Inflammation/immunology , Inflammation/genetics , B-Lymphocytes/immunology , Loss of Function Mutation , Fibroblasts/metabolism , Fibroblasts/immunology , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Animals , Mice , AllelesABSTRACT
Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.
Subject(s)
Growth and Development , Mosaicism , Spermatozoa/metabolism , Adolescent , Aging/blood , Alleles , Clone Cells , Cohort Studies , Humans , Male , Models, Biological , Mutation/genetics , Risk Factors , Time Factors , Young AdultABSTRACT
3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.
Subject(s)
3' Untranslated Regions/genetics , Biological Evolution , Disease/genetics , Genome-Wide Association Study , Algorithms , Alleles , Gene Expression Regulation , Genes, Reporter , Genetic Variation , Humans , Phenotype , Polymorphism, Single Nucleotide/genetics , Polyribosomes/metabolism , Quantitative Trait Loci/genetics , RNA/geneticsABSTRACT
Searching for factors to improve knockin efficiency for therapeutic applications, biotechnology, and generation of non-human primate models of disease, we found that the strand exchange protein RAD51 can significantly increase Cas9-mediated homozygous knockin in mouse embryos through an interhomolog repair (IHR) mechanism. IHR is a hallmark of meiosis but only occurs at low frequencies in somatic cells, and its occurrence in zygotes is controversial. Using multiple approaches, we provide evidence for an endogenous IHR mechanism in the early embryo that can be enhanced by RAD51. This process can be harnessed to generate homozygotes from wild-type zygotes using exogenous donors and to convert heterozygous alleles into homozygous alleles without exogenous templates. Furthermore, we identify additional IHR-promoting factors and describe features of IHR events. Together, our findings show conclusive evidence for IHR in mouse embryos and describe an efficient method for enhanced gene conversion.
Subject(s)
DNA Repair/genetics , Gene Conversion , Rad51 Recombinase/metabolism , Alleles , Animals , Base Sequence , CRISPR-Associated Protein 9/metabolism , Calcium-Binding Proteins/metabolism , Cell Cycle Proteins/metabolism , Chromosomes, Mammalian/genetics , DNA Breaks, Double-Stranded , Embryo, Mammalian , Female , Genetic Loci , Homologous Recombination/genetics , Homozygote , Humans , INDEL Mutation/genetics , Mice, Inbred C57BL , Mosaicism , Nuclear Proteins/metabolism , Polymorphism, Single Nucleotide/genetics , Ribonucleoproteins/metabolism , Zygote/metabolismABSTRACT
Selfish centromere DNA sequences bias their transmission to the egg in female meiosis. Evolutionary theory suggests that centromere proteins evolve to suppress costs of this "centromere drive." In hybrid mouse models with genetically different maternal and paternal centromeres, selfish centromere DNA exploits a kinetochore pathway to recruit microtubule-destabilizing proteins that act as drive effectors. We show that such functional differences are suppressed by a parallel pathway for effector recruitment by heterochromatin, which is similar between centromeres in this system. Disrupting the kinetochore pathway with a divergent allele of CENP-C reduces functional differences between centromeres, whereas disrupting heterochromatin by CENP-B deletion amplifies the differences. Molecular evolution analyses using Murinae genomes identify adaptive evolution in proteins in both pathways. We propose that centromere proteins have recurrently evolved to minimize the kinetochore pathway, which is exploited by selfish DNA, relative to the heterochromatin pathway that equalizes centromeres, while maintaining essential functions.
Subject(s)
Centromere Protein B/metabolism , Centromere/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Alleles , Amino Acid Sequence , Animals , Biological Evolution , CRISPR-Cas Systems/genetics , Centromere Protein A/metabolism , Chromosomal Proteins, Non-Histone/chemistry , Chromosomes, Mammalian/metabolism , Female , Heterochromatin/metabolism , Kinetochores/metabolism , Male , Mice, Inbred C57BL , Models, Biological , Oocytes/metabolism , Protein DomainsABSTRACT
Both transcription and three-dimensional (3D) architecture of the mammalian genome play critical roles in neurodevelopment and its disorders. However, 3D genome structures of single brain cells have not been solved; little is known about the dynamics of single-cell transcriptome and 3D genome after birth. Here, we generated a transcriptome (3,517 cells) and 3D genome (3,646 cells) atlas of the developing mouse cortex and hippocampus by using our high-resolution multiple annealing and looping-based amplification cycles for digital transcriptomics (MALBAC-DT) and diploid chromatin conformation capture (Dip-C) methods and developing multi-omic analysis pipelines. In adults, 3D genome "structure types" delineate all major cell types, with high correlation between chromatin A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first post-natal month. In neurons, 3D genome is rewired across scales, correlated with gene expression modules, and independent of sensory experience. Finally, we examine allele-specific structure of imprinted genes, revealing local and chromosome (chr)-wide differences. These findings uncover an unknown dimension of neurodevelopment.
Subject(s)
Brain/growth & development , Genome , Sensation/genetics , Transcription, Genetic , Alleles , Animals , Animals, Newborn , Cell Lineage/genetics , Chromatin/metabolism , Gene Expression Regulation, Developmental , Gene Ontology , Gene Regulatory Networks , Genetic Loci , Genomic Imprinting , Mice , Multigene Family , Neuroglia/metabolism , Neurons/metabolism , Transcriptome/genetics , Visual Cortex/metabolismABSTRACT
Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%-5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.
Subject(s)
Ion Channels/metabolism , Iron/metabolism , Black or African American , Aging/metabolism , Alleles , Animals , Cohort Studies , Erythrocyte Count , Erythropoiesis , Gain of Function Mutation/genetics , Hepatocytes/metabolism , Hepcidins/blood , Hepcidins/metabolism , Humans , Iron/blood , Iron Overload/metabolism , Macrophages/metabolism , Mechanotransduction, Cellular , Mice, Inbred C57BL , Phagocytosis , Phenotype , Stress, PhysiologicalABSTRACT
Understanding the functional consequences of single-nucleotide variants is critical to uncovering the genetic underpinnings of diseases, but technologies to characterize variants are limiting. Here, we leverage CRISPR-Cas9 cytosine base editors in pooled screens to scalably assay variants at endogenous loci in mammalian cells. We benchmark the performance of base editors in positive and negative selection screens, identifying known loss-of-function mutations in BRCA1 and BRCA2 with high precision. To demonstrate the utility of base editor screens to probe small molecule-protein interactions, we screen against BH3 mimetics and PARP inhibitors, identifying point mutations that confer drug sensitivity or resistance. We also create a library of single guide RNAs (sgRNAs) predicted to generate 52,034 ClinVar variants in 3,584 genes and conduct screens in the presence of cellular stressors, identifying loss-of-function variants in numerous DNA damage repair genes. We anticipate that this screening approach will be broadly useful to readily and scalably functionalize genetic variants.
Subject(s)
Gene Editing , Genetic Variation , High-Throughput Nucleotide Sequencing , Alleles , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Base Sequence , Catalytic Domain , Cell Line, Tumor , Humans , Loss of Function Mutation , Mutagenesis/genetics , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Point Mutation/genetics , Poly(ADP-ribose) Polymerases/chemistry , Poly(ADP-ribose) Polymerases/genetics , Reproducibility of Results , Selection, Genetic , bcl-X Protein/geneticsABSTRACT
Divergence of gene function is a hallmark of evolution, but assessing functional divergence over deep time is not trivial. The few alleles available for cross-species studies often fail to expose the entire functional spectrum of genes, potentially obscuring deeply conserved pleiotropic roles. Here, we explore the functional divergence of WUSCHEL HOMEOBOX9 (WOX9), suggested to have species-specific roles in embryo and inflorescence development. Using a cis-regulatory editing drive system, we generate a comprehensive allelic series in tomato, which revealed hidden pleiotropic roles for WOX9. Analysis of accessible chromatin and conserved cis-regulatory sequences identifies the regions responsible for this pleiotropic activity, the functions of which are conserved in groundcherry, a tomato relative. Mimicking these alleles in Arabidopsis, distantly related to tomato and groundcherry, reveals new inflorescence phenotypes, exposing a deeply conserved pleiotropy. We suggest that targeted cis-regulatory mutations can uncover conserved gene functions and reduce undesirable effects in crop improvement.
Subject(s)
Genes, Plant , Genetic Pleiotropy/genetics , Homeodomain Proteins/genetics , Plant Proteins/genetics , Regulatory Sequences, Nucleic Acid/genetics , Alleles , Arabidopsis/genetics , CRISPR-Cas Systems/genetics , Chromatin/metabolism , Gene Expression Regulation, Plant , Inflorescence/genetics , Solanum lycopersicum/genetics , Mutagenesis , Plant Development/genetics , Plants, Genetically Modified/genetics , Plants, Genetically Modified/growth & development , Plants, Genetically Modified/metabolism , Promoter Regions, Genetic , Solanaceae/genetics , Solanaceae/growth & developmentABSTRACT
T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection, but the repertoire of naturally processed and presented viral epitopes on class I human leukocyte antigen (HLA-I) remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post infection using mass spectrometry. We found HLA-I peptides derived not only from canonical open reading frames (ORFs) but also from internal out-of-frame ORFs in spike and nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and individuals with COVID-19 that exceeded responses to canonical peptides, including some of the strongest epitopes reported to date. Whole-proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights, as well as the discovery of out-of-frame ORF epitopes, will facilitate selection of peptides for immune monitoring and vaccine development.
Subject(s)
Epitopes, T-Lymphocyte/immunology , Histocompatibility Antigens Class I/immunology , Open Reading Frames/genetics , Peptides/immunology , Proteome/immunology , SARS-CoV-2/immunology , A549 Cells , Alleles , Amino Acid Sequence , Animals , Antigen Presentation/immunology , COVID-19/immunology , COVID-19/virology , Female , HEK293 Cells , Humans , Kinetics , Male , Mice , Peptides/chemistry , T-Lymphocytes/immunologyABSTRACT
In this issue of Cell, Zuccaro and colleagues show that on-target Cas9-mediated double-strand breaks cause chromosome loss or mis-repair of the disease allele in > 90% of human embryos. End joining repair pathways dominate, causing small insertions or deletions, which raises serious questions about using double-strand breaks for "gene surgery".
Subject(s)
DNA Breaks, Double-Stranded , DNA End-Joining Repair , Alleles , CRISPR-Cas Systems , Chromosomes , HumansABSTRACT
Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, but they are still understudied. Here we present a comprehensive analysis of structural variation in the Human Genome Diversity panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify, in total, 126,018 variants, 78% of which were not identified in previous global sequencing projects. Some reach high frequency and are private to continental groups or even individual populations, including regionally restricted runaway duplications and putatively introgressed variants from archaic hominins. By de novo assembly of 25 genomes using linked-read sequencing, we discover 1,643 breakpoint-resolved unique insertions, in aggregate accounting for 1.9 Mb of sequence absent from the GRCh38 reference. Our results illustrate the limitation of a single human reference and the need for high-quality genomes from diverse populations to fully discover and understand human genetic variation.
Subject(s)
Genetics, Population , Genomic Structural Variation , Alleles , Databases, Genetic , Gene Dosage , Gene Duplication , Gene Frequency/genetics , Genetic Variation , Genome, Human , HumansABSTRACT
Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.
Subject(s)
Antigens, Neoplasm/immunology , Epitopes/immunology , Neoplasms/immunology , Alleles , Antigen Presentation/immunology , Cohort Studies , Humans , Peptides/immunology , Programmed Cell Death 1 Receptor , Reproducibility of ResultsABSTRACT
Structural variants (SVs) underlie important crop improvement and domestication traits. However, resolving the extent, diversity, and quantitative impact of SVs has been challenging. We used long-read nanopore sequencing to capture 238,490 SVs in 100 diverse tomato lines. This panSV genome, along with 14 new reference assemblies, revealed large-scale intermixing of diverse genotypes, as well as thousands of SVs intersecting genes and cis-regulatory regions. Hundreds of SV-gene pairs exhibit subtle and significant expression changes, which could broadly influence quantitative trait variation. By combining quantitative genetics with genome editing, we show how multiple SVs that changed gene dosage and expression levels modified fruit flavor, size, and production. In the last example, higher order epistasis among four SVs affecting three related transcription factors allowed introduction of an important harvesting trait in modern tomato. Our findings highlight the underexplored role of SVs in genotype-to-phenotype relationships and their widespread importance and utility in crop improvement.
Subject(s)
Crops, Agricultural/genetics , Gene Expression Regulation, Plant , Genomic Structural Variation , Solanum lycopersicum/genetics , Alleles , Cytochrome P-450 Enzyme System/genetics , Ecotype , Epistasis, Genetic , Fruit/genetics , Gene Duplication , Genome, Plant , Genotype , Inbreeding , Molecular Sequence Annotation , Phenotype , Plant Breeding , Quantitative Trait Loci/geneticsABSTRACT
The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4+ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS.
Subject(s)
HLA-DR Serological Subtypes/immunology , Multiple Sclerosis/immunology , T-Lymphocytes/immunology , Adult , Aged , Alleles , Antigens/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Cells, Cultured , Cross Reactions/immunology , Female , Humans , Immunologic Memory , Male , Middle Aged , Monocytes/immunology , Peptides/immunology , Proteome/metabolism , Young AdultABSTRACT
Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.
Subject(s)
Metabolic Diseases/genetics , MicroRNAs/genetics , Adipocytes, Brown/pathology , Adiposity , Alleles , Animals , Cell Differentiation , Cell Line , Cells, Cultured , Diet, High-Fat , Energy Metabolism , Epigenesis, Genetic , Genetic Loci , Glucose/metabolism , Homeostasis , Humans , Hypertrophy , Insulin Resistance , Leptin/deficiency , Leptin/metabolism , Male , Mammals/genetics , Mice, Inbred C57BL , Mice, Obese , MicroRNAs/metabolism , Obesity/genetics , Oligonucleotides/metabolism , Species SpecificityABSTRACT
Correction of disease-causing mutations in human embryos holds the potential to reduce the burden of inherited genetic disorders and improve fertility treatments for couples with disease-causing mutations in lieu of embryo selection. Here, we evaluate repair outcomes of a Cas9-induced double-strand break (DSB) introduced on the paternal chromosome at the EYS locus, which carries a frameshift mutation causing blindness. We show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame. Notably, about half of the breaks remain unrepaired, resulting in an undetectable paternal allele and, after mitosis, loss of one or both chromosomal arms. Correspondingly, Cas9 off-target cleavage results in chromosomal losses and hemizygous indels because of cleavage of both alleles. These results demonstrate the ability to manipulate chromosome content and reveal significant challenges for mutation correction in human embryos.
Subject(s)
Alleles , CRISPR-Associated Protein 9/metabolism , Chromosomes, Human/genetics , Embryo, Mammalian/metabolism , Animals , Base Sequence , Blastocyst/metabolism , Cell Cycle/genetics , Cell Line , Chromosome Deletion , DNA Breaks, Double-Stranded , DNA End-Joining Repair/genetics , Embryo Implantation/genetics , Eye Proteins/genetics , Fertilization , Gene Editing , Gene Rearrangement/genetics , Genetic Loci , Genome, Human , Genotype , Heterozygote , Human Embryonic Stem Cells/metabolism , Humans , INDEL Mutation/genetics , Mice , Mitosis , Open Reading Frames/genetics , Polymorphism, Single Nucleotide/geneticsABSTRACT
Recent developments in genetics and genomics are providing a detailed and systematic characterization of the genetic underpinnings of common metabolic diseases and traits, highlighting the inherent complexity within systems for homeostatic control and the many ways in which that control can fail. The genetic architecture underlying these common metabolic phenotypes is complex, with each trait influenced by hundreds of loci spanning a range of allele frequencies and effect sizes. Here, we review the growing appreciation of this complexity and how this has fostered the implementation of genome-scale approaches that deliver robust mechanistic inference and unveil new strategies for translational exploitation.
Subject(s)
Metabolic Diseases/etiology , Metabolic Diseases/genetics , Alleles , Chromosome Mapping , Gene Frequency/genetics , Genetic Predisposition to Disease , Genetic Variation/genetics , Genome-Wide Association Study , Humans , Phenotype , Quantitative Trait LociABSTRACT
Complex multicellular organisms, such as mammals, express two complete sets of chromosomes per nucleus, combining the genetic material of both parents. However, epigenetic studies have demonstrated violations to this rule that are necessary for mammalian physiology; the most notable parental allele expression phenomenon is genomic imprinting. With the identification of endogenous imprinted genes, genomic imprinting became well-established as an epigenetic mechanism in which the expression pattern of a parental allele influences phenotypic expression. The expanding study of genomic imprinting is revealing a significant impact on brain functions and associated diseases. Here, we review key milestones in the field of imprinting and discuss mechanisms and systems in which imprinted genes exert a significant role.