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Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 (TBK1) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg228→His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72, TBK1, and TDP-43 connects three different facets of FTD-ALS into one coherent pathway. [ABSTRACT FROM AUTHOR]

The article discusses a study which describes the genomic epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a dataset of genomes from several African countries and overseas territories. Topics include a brief background on the spread of the coronavirus which originated in Wuhan, China in 2019, an overview of the genomic surveillance efforts in Africa from the onset of the pandemic, and data on Africa's contribution to the international spread of the virus.

The article discusses the challenges in predicting pathogenic protein variants, with a particular focus on the AlphaMissense variant effect predictor (VEP) machine-learning algorithm. Topics discussed include the limitations of interpreting genetic mutations, the integration of protein structural information within AlphaMissense, and the potential for computational advancements to improve genetic diagnosis.

NEWS Carola Vinuesa woke up early on 5 June in London, around 3 a.m., when colleagues from Australia called the clinical geneticist with big news: Kathleen Folbigg, who on only circumstantial evidence was famously convicted of killing her four young children and jailed 2 decades ago, had just been pardoned by New South Wales and set free. Vinuesa enlisted a colleague, Todor Arsov, to visit Folbigg in prison and get a DNA sample. I was so happy, for Kathleen first of all, but for science [too]", says Vinuesa, who now runs a lab at the Francis Crick Institute. [Extracted from the article]

Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach that aggregates phenotypes on the basis of patterns described by Mendelian diseases.We mapped the clinical features of 1204 Mendelian diseases into phenotypes captured from the electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In an initial validation, PheRS distinguished cases and controls of five Mendelian diseases. Applying PheRS to 21,701 genotyped individuals uncovered 18 associations between rare variants and phenotypes consistent with Mendelian diseases. In 16 patients, the rare genetic variants were associated with severe outcomes such as organ transplants. PheRS can augment rare-variant interpretation and may identify subsets of patients with distinct genetic causes for common diseases. [ABSTRACT FROM AUTHOR]

The article discusses the release of data by the research project UK Biobank (UKB), which includes health and genetics data on people in Great Britain. Topics include links between genetic markers and diseases, research access to data from the project, and criticism of the project due to the large percentage of people of Northern European ancestry in the database as a factor in its polygenic risk scores for diseases.

The article offers information on high-throughput genotyping platforms to identify single-nucleotide polymorphisms to study human diseases associated with common genetic variation. It discusses genome-wide association studies to generate the classification of genetic diseases and common allelic variants in noncoding regions with small effect sizes and complex interactions.

Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown.We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9. STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention. [ABSTRACT FROM AUTHOR]

Analysis of the pattern of proteins or messenger RNAs (mRNAs) in histological tissue sections is a cornerstone in biomedical research and diagnostics. This typically involves the visualization of a few proteins or expressed genes at a time. We have devised a strategy, which we call "spatial transcriptomics," that allows visualization and quantitative analysis of the transcriptome with spatial resolution in individual tissue sections. By positioning histological sections on arrayed reverse transcription primers with unique positional barcodes, we demonstrate high-quality RNA-sequencing data with maintained two-dimensional positional information from the mouse brain and human breast cancer. Spatial transcriptomics provides quantitative gene expression data and visualization of the distribution of mRNAs within tissue sections and enables novel types of bioinformatics analyses, valuable in research and diagnostics. [ABSTRACT FROM AUTHOR]

The article discusses the U.S. consumer genetics company 23andMe's role in collecting DNA samples and analyzing them for their relations with diseases, including the company's efforts to develop drugs to treat diseases. An overview of 23andMe's co-founder and chief executive officer (CEO) Anne Wojcicki is provided.

According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data have sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant coexpression patterns, symptom similarity, and comorbidity, whereas diseases residing in separated network neighborhoods are phenotypically distinct. These tools represent an interactome-based platform to predict molecular commonalities between phenotypically related diseases, even if they do not share primary disease genes. [ABSTRACT FROM AUTHOR]

Biosynthesis of ubiquinones requires the intramembrane UbiA enzyme, an archetypal member of a superfamily of prenyltransferases that generates lipophilic aromatic compounds. Mutations in eukaryotic superfamily members have been linked to cardiovascular degeneration and Parkinson's disease. To understand how quinones are produced within membranes, we report the crystal structures of an archaeal UbiA in its apo and substrate-bound states at 3.3 and 3.6 angstrom resolution, respectively. The structures reveal nine transmembrane helices and an extramembrane cap domain that surround a large central cavity containing the active site. To facilitate the catalysis inside membranes, UbiA has an unusual active site that opens laterally to the lipid bilayer. Our studies illuminate general mechanisms for substrate recognition and catalysis in the UbiA superfamily and rationalize disease-related mutations in humans. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous fatuities with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn's disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders. [ABSTRACT FROM AUTHOR]

Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk. [ABSTRACT FROM AUTHOR]

Viperin is an interferon-inducible protein that is directly induced in cells by human cytomegalovirus (HCMV) infection. Why HCMV would induce viperin, which has antiviral activity, is unknown. We show that HCMV-induced viperin disrupts cellular metabolism to enhance the infectious process. Viperin interaction with the viral protein vMIA resulted in viperin relocalization from the endoplasmic reticulum to the mitochondria. There, viperin interacted with the mitochondrial trifunctional protein that mediates β-oxidation of fatty acids to generate adenosine triphosphate (ATP). This interaction with viperin, but not with a mutant lacking the viperin iron-sulfur cluster-binding motif, reduced cellular ATP generation, which resulted in actin cytoskeleton disruption and enhancement of infection. This function of viperin, which was previously attributed to vMIA, suggests that HCMV has coopted viperin to facilitate the infectious process. [ABSTRACT FROM AUTHOR]

Copy number variants affect both disease and normal phenotypic variation, but those lying within heavily duplicated, highly identical sequence have been difficult to assay. By analyzing short-read mapping depth for 159 human genomes, we demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kilobase pairs, ranging from 0 to 48 copies. We identified 4.1 million "singly unique nucleotide" positions informative in distinguishing specific copies and used them to genotype the copy and content of specific para logs within highly duplicated gene families. These data identify human-specific expansions in genes associated with brain development, reveal extensive population genetic diversity, and detect signatures consistent with gene conversion in the human species. Our approach makes -1000 genes accessible to genetic studies of disease association. [ABSTRACT FROM AUTHOR]

Loss-of-function genetic screens in model organisms have elucidated numerous biological processes, but the diploid genome of mammalian cells has precluded large-scale gene disruption. We used insertional mutagenesis to develop a screening method to generate null alleles in a human cell line haploid for all chromosomes except chromosome 8. Using this approach, we identified host factors essential for infection with influenza and genes encoding important elements of the biosynthetic pathway of diphthamide, which are required for the cytotoxic effects of diphtheria toxin and exotoxin A. We also identified genes needed for the action of cytolethal distending toxin, including a cell-surface protein that interacts with the toxin. This approach has both conceptual and practical parallels with genetic approaches in haploid yeast. [ABSTRACT FROM AUTHOR]

Studies correlating genetic variation to gene expression facilitate the interpretation of common human phenotypes and disease. As functional variants may be operating in a tissue-dependent manner, we performed gene expression profiting and association with genetic variants (single-nucleotide polymorphisms) on three cell types of 75 individuals. We detected cell type--specific genetic effects, with 69 to 80% of regulatory variants operating in a cell type-specific manner, and identified multiple expressive quantitative trait led (eQTLs) per gene, unique or shared among cell types and positively correlated with the number of transcripts per gene. Cell type-specific eQTLs were found at larger distances from genes and at lower effect size, similar to known enhancers. These data suggest that the complete regulatory variant repertoire can only be uncovered in the context of cell-type specificity. [ABSTRACT FROM AUTHOR]

The article discusses the disease cystic fibrosis (CF), which is an inherited disease with a short life expectancy, and the progress that researchers have made in finding a cure. An example is given of geneticist Mitch Drumm who paired up with colleague Francis Collins and began experimenting with a gene-hunting technique designed by Collins. The team chose cystic fibrosis (CF) as their test case eventually collaborating with Canadian research group that had cloned a CF gene called the cystic fibrosis transmembrane conductance regulator (CFTR). Topics include how gene discovery transformed researchers' understanding of CF's pathology, how early success in CF research led scientists to conclude a cure was imminent, and the failure of gene therapy.

Ubiquitin-mediated proteolysis regulates all aspects of cellular function, and defects in this process are associated with human diseases. The limited number of identified ubiquitin ligase-substrate pairs is a major bottleneck in the ubiquitin field. We established and applied genetic technologies that combine global protein stability (GPS) profiling and genetic perturbation of E3 activity to screen for substrates of the Skp1-cullin-F-box (SCF) ubiquitin ligase in mammalian cells. Among the >350 potential substrates identified, we found most known SCF targets and many previously unknown substrates involved in cell cycle, apoptosis, and signaling pathways. Exploring cell cycle-stage stability, we found that several substrates used the SCF and other E3s in different cell cycle stages. Our results demonstrate the potential of these technologies as general platforms for the global discovery of E3-substrate regulatory networks. [ABSTRACT FROM AUTHOR]

Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases. We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead. [ABSTRACT FROM AUTHOR]

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia. [ABSTRACT FROM AUTHOR]

The article reports on a 3.0 angstrom resolution structure of a complex between p110± and a polypeptide that has the p110±-binding domains of p85±, a protein that is needed for its enzymatic activity. p110± is the catalytic subunit of a phosphatidylinositol 3-kinase, which is one of the two most commonly mutated oncogenes in human tumors. The structure reveals that many of the mutations are found at residues located at the interfaces between p110± and p85± or between the kinase domain of p110± and other domains found in the catalytic subunit.

Many maternally inherited and incurable neuromyopathies are caused by mutations in mitochondrial (mt) transfer RNA (tRNA) genes. Kinetoplastid protozoa, including Leishmania, have evolved specialized systems for importing nucleus-encoded tRNAs into mitochondria. We found that the Leishmania RNA import complex (RIC) could enter human cells by a caveolin-1-dependent pathway, where it induced import of endogenous cytosolic tRNAs, including tRNALys, and restored mitochondrial function in a cybrid harboring a mutant mt tRNALys (MT-TK) gene. The use of protein complexes to modulate mitochondrial function may help in the management of such genetic disorders. [ABSTRACT FROM AUTHOR]

The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we determined the sequence of well-annotated human protein-coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ∼90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology. [ABSTRACT FROM AUTHOR]

Addresses the major challenges and opportunities facing the research community in its effort to dissect the molecular basis of human disease. Genome variations monitoring; Genome-wide screening of gene transcript variations; Detection of metabolic disease pathways; Phenotypic variations in simplex diseases; Genetic background of complex disorders; Genetic information in health care.

Analyzes the genetic aspects in the transmission of HIV and the progression of AIDS in HIV-positive individuals with a structural variant of the chemokine receptor CX...CR1. Factors which are responsible for the risk of HIV infection and HIV disease progression; Screening of the CX...CR1 coding sequence for mutations in the blood of HIV patients; Analysis of chromosomes responsible for the disease progression.

Presents a study of the gene encoding interferon regulatory factor-1 (IRF-1). Mapping IRF-1 to chromosome 5q31.1; Performing a Southern blot and quantitative slot-blot analyses on DNA samples from 11 patients with leukemia; Fluorescence in situ chromosomal hybridization (FISH) studies; Unusual instability of the 5q region; More.

Presents a study of myotonic dystrophy (DM), an autosomal-dominant disorder. Correlation of an amplification of an unstable trinucleotide CTG repeat with a more severe DM phenotype; CTG repeats and the transmission of the DM allele; Halpotype data of six polymorphic markers in the DM gene region; More.

Describes research into a synthetic gene constructed that contains a zinc finger region of the Wilms' tumor locus (WTL). Identification of specific DNA binding site; Similarities to sequence recognized by the early growth response-1 (EGR-1) gene product; Results of mutation; Possible role of the WTL protein at DNA binding site.

Discusses advances in molecular biology and biotechnology and how they are creating many possibilities for deoxyribonucleic acid (DNA) diagnostics. Analysis of nucleic acids; Automation of DNA diagnostic procedures; Applications.

Report on familial polyposiscoli (FPC) as caused by an autosomal dominant gene on chromosome 5; proposal that colorectal cancer in the general population arises from loss or inactivation of the FPC gene, analogous to recessive tumor genes in retinoblastoma and Wilms' tumor.

Application of molecular biology by means of linkage analysis and DNA probes demonstrate chromosomal localization of genes responsible for Huntington's Disease, Duchenne Dystrophy, manic-depressive illness, autosomal recessive disorders, myotonic dystrophy, familial amyloidotic polyneuropathy, Alzheimer's disease, neurofibromatosis, retinoblastoma, brain tumors, meningioma and Lesch-Nyhan disease.

Describes advances in the application of molecular genetics into the study of cardiovascular disease. Inherited cardiac arrhythmias; Familial cardiomyopathies; Inherited vascular diseases; Presymptomatic diagnosis and prognosis.

Discusses the genetic dissection of complex traits. Methodologies; Limitations; Applications to biological problems; Genetic epidemiology; Association studies; Experimental crosses; Statistical significance; Gene cloning that underlie complex traits.

Discusses research into the role of a defect in genetic recombination that may cause ataxia-telangiectasia (A-T), an inherited human disease associated with neurologic degeneration, immune dysfunction and high cancer risk. Interference with immune gene rearrangements and the repair of DNA damage; How recombination was studied in A-T and control human fibroblast lines; High spontaneous intrachromosomal recombination rates; Implications.

Discusses the results of experiments with gene fusions which shows that gene `lasl' is essential for high expression of elastase, one of the virulence factors produced by the organism `Pseudomonas aeruginosa,' an opportunistic human pathogen. Requirement of the transcriptional activator LasR; Role of the `lasl' gene in the synthesis of a molecule called `Pseudomonas' autoinducer (PAI); How PAI provides a means of cell-to-cell communication; More.

Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that, the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somaticalty mutated in two tumors. Examination of 27 additional oligodendrogtiomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes. [ABSTRACT FROM AUTHOR]

The article discusses microarrays as a vital tool in microRNA research. MicroRNAs are tiny non-coding stretches of genetic material that regulate messenger RNA (mRNA). According to the author microarrays are the best methods for reading the microRNA "fingerprints," which are unique to disease states, but that the field is gaining popularity and presenting challenges for commercial microarray makers due to increasing competition. An in-depth discussion regarding the state of microarray manufacturing in the U.S. as part of the effort to keep pace with the evolving field of microRNA research is presented. An overview of several companies that manufacture microarrays and offer microRNA analysis services, such as U.S. companies Agilent Technologies and LC Sciences is also discussed.

The article assesses on the issue concerning the ethics on protecting genetic information. According to the authors, a proper balance between encouraging genomic research and protecting privacy and confidentiality of research participants will not be easily attained. They assert that a completely open access model will rarely be defensible when sufficient amounts of genomic data are present to be unique. Nevertheless, they view that a variety of controlled-access model can be employed as well as keeping the risk of identifying individuals low. Furthermore, they stress that the protection of identifiability is obligatory to maintain the trust among the people. Details regarding the tactics for de-identifying genomic data are presented, as well as the provisions of access to genomic data.

The article focuses on research related to human genomics that discusses single cell gene expression. It is noted that the majority of chromatin accessibility data lacks single-cell resolution, which has limited the researchers' ability to find patterns such as the cell types that are most relevant to each common disease.

The article present a research on the human genetic variation and population history from 929 diverse genomes. Topics discussed include structure of genetic variation in human species; how it was shaped by past population separations, admixture, adaptation, size changes and gene flow from archaic human groups; and the genetic separation between present-day human populations. Also mentions about resource with relevance to population history, medical genetics, anthropology and linguistics.

The article reports that the increasing ability to analyze fetal DNA from maternal blood should lead to better prenatal diagnoses of genetic disease--and confront future parents with tough information and choices. Diana Bianchi, a prenatal geneticist at Tufts University School of Medicine in Boston and one of a small number of researchers who have spent more than a decade trying to detect sex and genetic disorders from fetal cells and DNA in a mother's blood, states that such tests aren't yet considered scientifically and ethically vetted. However, noninvasive fetal diagnosis are the latest trend. Researchers have already used fetal DNA from maternal blood to successfully test for genes inherited from a father that cause diseases such as cystic fibrosis and the blood disorder thalassemia. For now, researchers are grappling with how to get a clear, consistent signal from a relatively few molecules of fetal DNA sequence floating in a sea of maternal DNA. The researchers have noted that the current techniques would have to improve before blood-borne fetal cells could provide reliable diagnoses.

This article briefly reports various recent developments and research studies in assessing treatment methods for Tourett's syndrome. Research in this regard is now unearthing both genetic and environmental triggers and pointing the way to better treatments. When Purdue University neurobiologist Peter Hollenbeck lectures in front of his 400-student cell biology class, the symptoms of his Tourette syndrome, the up-and-down movements of one arm, the twists of his head, the barely audible sounds, virtually disappear. The cause of Tourette syndrome has been controversial ever since Georges Gilles de la Tourette, a neurologist who shared a mentor with Sigmund Freud at the Salpêtrière Hospital in Paris, first described the condition in 1885.

Presents letters to the editor, discussing Materials published in the periodical "Science," in the previous six months or issues of general interest . Probes into the basics of genetic modification; Discusses about genetically modified organisms.

Focuses on human DNA sequence research which identifies risk genes by using single-nucleotide polymorphisms (SNP). Description of SNP as the most common mutations in the genome; Improvements in SNP mapping studies; Separation of disease-related SNP from the noise of irrelevant genetic variation. INSET: SNP-ing Drugs to Size, by T.G..