Featured Publications: June - December 2016

Gene discovery by chemical mutagenesis and whole-genome sequencing in Dictyostelium.

Cells of the social amoeba D. discoideum aggregate and develop into multicellular structures upon starvation. A self-recognition system that utilizes two polymorphic transmembrane proteins, TgrB1 and TgrC1, allows the cells to cooperate with their kin. Cells that carry incompatible alleles of TgrB1 and TgrC1 fail to develop into multicellular structures. The paper by Li, et al., which appears in the September 2016 issue of Genome Research, used such cells as a background for selection of genetic suppressors that can develop despite the mismatch between TgrB1 and TgrC1. Using low levels of chemical mutagenesis to generate the suppressors, and whole-genome sequencing to identify them, Li et al. discovered mutations that outline a signal transduction pathway that mediates the allorecognition response.

A cholinergic basal forebrain feeding circuit modulates appetite suppression.

Scientists in the Benjamin Arenkiel laboratory have discovered a cluster of cells in an unexpected area of the brain that could play a powerful role in regulating appetite and eating habits. Cholinergic neurons located in the mouse basal forebrain, produce acetylcholine, a chemical that helps brain cells transmit information to one another. These neurons use the same pathways in the brain as nicotine, a known appetite suppressant, suggesting that targeting such pathways may provide therapeutic approaches toward treating eating disorders. In a report published in the October 2016 issue of Nature, it is reported that an impairment of cholinergic signalling increased food intake and resulted in severe obesity, whereas enhanced cholinergic signalling had the opposite effect and decreased food consumption.

DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells

In a study published in the September 2016 issue of Nature Genetics, a team of investigators led by Drs. Peggy Goodell and Xiaotian Zhang explore the importance for blood development of the proteins DNMT3A and TET2 that regulate DNA methylation marks, encoding “epigenetic” information that help control when and where genes are expressed. By deleting one or the other protein, the investigators were able to map which protein impacted which regions of the genome, and gain insight into how loss of these proteins contributes to leukemia development.

Featured Publications: January - May 2016

Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta.

Osteogenesis imperfecta is a debilitating genetic disorder characterized by low bone mass, increased bone brittleness and fractures, and better pharmacological therapies are needed. While dominant OI is mostly caused by mutations in the genes encoding type I collagen, recessive forms of OI can be caused by mutations in CRTAP that is involved in post-translational collagen modification. In a study published in the Journal of Bone and Mineral Research, Dr. Ingo Grafe together with other scientists show that treatment of Crtap-/- mice, which recapitulate the human phenotype, with a sclerostin-inhibiting antibody (Scl-Ab; Amgen Inc/UCB Pharma) improves bone mass, bone strength, and bone formation. These findings suggest that Scl-Ab treatment may be a promising new treatment option for patients with recessive OI.

An ultra-dense library resource for rapid deconvolution of mutations that cause phenotypes in Escherichia coli.

Forward genetic screens in microbial models have led molecular-biological discovery but are virtually abandoned at present because of the labor of the mapping step. In this paper published in Nucleic Acids Research, scientists in the Susan Rosenberg Laboratory outline a high-throughput method and resource for mapping which of many random mutations, identified by whole-genome sequencing, causes screened phenotypes in Escherichia coli. “Deconvoluter” libraries of intergenic insertions of selectable markers allow rapid separation of phenotype-causing screenable mutations by a simple bacteriophage-induced gene-replacement strategy.  This resource makes forward-genetic screens with mapping-by-sequencing, “forward genomics”, fast, simple and easy in E. coli and may be adapted for other microbial models.

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations

Breakdown of muscle tissue, also termed as rhabdomyolysis is a serious condition which can be life-threatening. The underlying genetic etiology of rhabdomyolysis is unknown in about half of all pediatric cases. In a study published in The American Journal of Human Genetics, Dr. Seema Lalani along with other scientists show that bi-allelic mutations in TANGO2 is responsible for recurrent episodes of muscle breakdown and cardiac arrhythmia in children. The findings suggest that two specific variants in TANGO2 are present as low-frequency heterozygous alleles in the Hispanic and European populations, causing considerable morbidity in the homozygotes in these populations.

A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.

Left-sided congenital cardiac lesions are among the most common and most medically challenging forms of congenital heart disease. Although genetic factors are known to play a role in their development, the underlying genetics are complex and poorly understood. In a study published in Human Molecular Genetics, Dr. Neil Hanchard and the other authors demonstrate by using two multi-national cohorts of more than 1,000 patient samples that the contribution to the disease of genetic variants commonly observed in the population is moderately high. We also identified common variants on chromosome 20 and chromosome 1 that are strongly associated with susceptibility to LSLs. These regions contain multiple genes known to be involved in cardiac development, and thus offer new biological candidates for future exploration.

Capture-based high-coverage NGS: a powerful tool to uncover a wide spectrum of mutation types

Currently, chromosomal microarray, karyotyping, and next generation sequencing (NGS) are used to detect copy number variants (CNVs), translocations, and single nucleotide variants (SNV), respectively. To perform all these procedures for comprehensive diagnosis is costly and time consuming. Dr. Wong and her team have developed an effective single step approach by using loose filtering parameters to assess raw data from target capture deep NGS. In a paper published in Genetics in Medicine, the authors show that this approach allowed simultaneous detection of all types of mutations, including SNVs, CNVs, translocations, and breakpoints.

Featured Publications: October - December 2015

December 2015: Mutations in the transcriptional repressor REST predispose to Wilms tumor

Wilms tumor is the most common childhood renal cancer, with one in 10,000 affected. While significant advances in the understanding of Wilms tumor pathogenesis have been made over the last 30 years, the genetic and mechanistic causes of the disease remain unclear. In a study published in Nature Genetics, scientists in the Westbrook lab provide new insight into the role of the REST gene in human cancers and identify it as a novel predisposition gene that accounts for approximately 2% of familial Wilms tumor cases.

December 2015: De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

Meier-Gorlin Syndrome is associated with the classic triad of primordial dwarfism, microtia, and absent patella. Previously, this disorder has been associated with biallelic pathogenic variants in one of five genes (ORC1, ORC4ORC6CDT1CDT6) encoding proteins involved in the pre-replication complex. In this study published in the American Journal of Human Genetics, the authors report three patients with Meier-Gorlin Syndrome who have de novo pathogenic variants in GMNN, which encodes geminin, an inhibitor of DNA replication. They present data supporting that these pathogenic variants in GMNN increase protein stability and result in an autosomal dominant form of Meier-Gorlin Syndrome.

December 2015: Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations.

Although it is common to refer to a particular gene's role in a given disease, what often matters is the specific alteration of the gene that may have no effect, render its product nonfunctional or enhance its normal activity. In cancer, tumors acquire frequent mutations in known cancer genes as well as a long "tail" of mutations that occur only rarely. Many of these tail mutations may be unimportant while others could reveal important biological vulnerabilities of cancers that inspire new therapies. In a paper published in Cancer Research, the Ken Scott laboratory describes a high-throughput method for the engineering and screening for cancer activity by many “barcoded” mutations in parallel. They used their platform to study numerous rare mutations in a known cancer gene, PIK3CA, which encodes p110α subunit of the PI3K protein complex and is the most frequently mutated gene in cancer. The study demonstrated that PIK3CA mutations differed widely in their cancer-promoting tendency, and the presence of rare mutations may point to sensitivity of cancers to particular therapeutics.

December 2015: Molecular diagnostic experience of whole-exome sequencing in adult patients.

The development of Precision Medicine is fundamentally dependent on identifying the underlying genetic basis of disease in patients.  In this study published in Genetics in Medicine, the authors analyzed the use of diagnostic whole exome sequencing by physicians caring for adult patients. Their findings suggest that genetic disease is under-recognized in adults, that is it not always inherited but can occur ‘de novo’, and that there is much to learn about the complex genetic basis of disease in adult populations.

November 2015: AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow.

How cancer cells resist metabolic stress in the tumor microenvironment is a fundamental question in cancer biology. In a study published in Cell Stem Cell, researchers from the Nakada lab show that a metabolic checkpoint kinase called AMPK protects leukemia cells from metabolic stress present in the bone marrow. Strikingly, a slight increase in metabolic stress caused by dietary restriction made leukemia cells particularly dependent upon AMPK; as such, combinatorial treatment with an AMPK inhibitor and dietary restriction profoundly suppressed leukemogenesis. This work establishes that the metabolism of cancer cells can be targeted to make them vulnerable to physiological levels of metabolic stress.

November 2015: Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency.

Arginase deficiency is unique among the urea cycle disorders because this disorder is typically characterized by increased tone in the lower extremities, intellectual disability, and seizures rather than repeated episodes of hyperammonemia. Normalization of plasma arginine levels is the goal of treatment because metabolites of arginine are suspected to contribute to the neurologic complications. In a paper published in Human Molecular Genetics, the authors report that a pegylated human recombinant arginase 1 (AEB1102) reduces plasma arginine in mouse models of arginase deficiency and thus, may have potential in lowering plasma arginine levels in human patients with this disorder.

November 2015: Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.

Genomic disorders are caused by rare variant DNA rearrangements, which may disrupt the structural integrity of a gene or alter the copy number of dosage-sensitive genes by generating copy-number variants (CNVs) ranging from kilobases (kb) to megabases (Mb) in size. These structural variant (SV) or rearrangements of genomic DNA may be mediated by various molecular mechanisms and lead to variable phenotypes. In a study published in The American Journal of Human Genetics, scientists in the Lupski laboratory, focusing on both genotype-phenotype correlation and the underlying molecular mechanism, provided a systematic investigation of a group of subjects with genomic rearrangements that could lead to overlapping phenotypic outcomes blending clinical aspects of both Potocki-Lupski syndrome and Charcot-Marie-Tooth disease type 1A. This new disease entity, termed Yuan-Harel-Lupski syndrome (YUHAL; OMIM # 616652), occurred by the duplication encompassing two dosage-sensitive genes: PMP22 and RAI1.

Featured Publications: June - September 2015

September 2015: The spliceosome is a therapeutic vulnerability in MYC-driven cancer

Up to 40% of human cancers are driven by the oncogene MYC, yet therapeutic targeting of MYC has been unsuccessful to date. MYC is a transcription factor whose oncogenic activation has been shown to increase total RNA and protein production in many tissue and disease contexts. While such increases in RNA and protein may endow cancer cells with pro-tumorigenic functions, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly. In a study published in Nature, scientists in the Westbrook lab report that the RNA processing machinery called the spliceosome is critical for the survival of MYC-dependent cancer. Unlike normal cells, inhibition of the spliceosome in MYC-hyperactivated cells leads to global disruption of RNA processing and maturation, and deregulation of many essential cell processes. Their findings suggest that oncogenic MYC confers a stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

September 2015: USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

Mutations in MAGEL2 cause the neurodevelopmental disorder Schaaf-Yang syndrome. In a study published in Molecular Cell, researchers from the Schaaf laboratory and collaborators from UT Southwestern show that MAGEL2 interacts with USP7 and TRIM27 to maintain proper protein recycling and cellular homeostasis. Importantly, the study identifies USP7 as a novel disease gene for a condition that is clinically and molecularly related to Schaaf-Yang syndrome.

September 2015: Plasma metabolomic profiles enhance precision medicine for volunteers of normal health.

Precision medicine, taking account of human individuality in genes, environment, and lifestyle for early disease diagnosis and individualized therapy, has shown great promise to transform medical care. In this study published in the Proceedings of the National Academy of Sciences of the United States of America, the authors test the application of metabolomics in individual diagnosis. The results of this study demonstrate that metabolomics could be an effective approach to complement next generation sequencing (NGS) for disease risk analysis, disease monitoring, and drug management in our goal toward precision care.

August 2015: Olfaction Modulates Reproductive Plasticity through Neuroendocrine Signaling in Caenorhabditis elegans.

In nature, organisms must constantly sense and adapt to environmental changes. Phenotypic plasticity is a key mechanism that allows organisms to cope with changing environments. Reproduction is the most crucial aspect of an organism’s life cycle as it ensures the perpetuation of the species, and having plastic reproductive strategies maximizes reproductive success and the survival of offspring under different environmental conditions. In a paper published in Current Biology, research from the Wang lab showed that AWB olfactory neurons perceive odorant signals to adjust reproductive timing and senescence via neuropeptide signaling, revealing a neuroendocrine link between olfactory sensation and reproductive plasticity, and the power of smell to regulate reproductive aging for the first time.

August 2015: Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi)

JAG1 haploinsufficiency in humans results in a multisystem disorder known as Alagille Syndrome which is characterized by a congenital cholangiopathy of variable severity. In a study in Hepatology, Jafar-Nejad lab has described a liver phenotype associated with Jag1 heterozygosity in mice with many similarities to the Alagille syndrome cholangiopathy. Simultaneous loss of one copy of the glycosyltransferase gene Poglut1 suppresses the liver phenotypes in this model. This work establishes a framework for better understanding the pathophysiology of Alagille syndrome and a model to test potential therapeutic approaches for this disease.

July 2015: “The GATA transcription factor GtaC regulates early developmental gene expression dynamics in Dictyostelium.”

GtaC is a transcription factor that is necessary for early development in Dictyostelium. In a study published in the journal Nature Communications, the research team of Gad Shaulsky and Mariko Katoh-Kurasawa used two high-throughput methods to identify the genes regulated by GtaC. One method (RNA-seq) discovered genes that were mis-expressed when GtaC function was altered by mutations and the other method (ChIP-seq) discovered regions in the genome that were bound by GtaC. Intersecting the data from the two methods, the researchers found that GtaC regulates multiple physiological processes concordant with developmental progression in Dictyostelium.

July 2015: Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress.

The Bellen lab has identified mutations in 165 Drosophila genes whose loss-of-function cause neurodevelopmental and neurodegenerative defects. Interestingly, 32 of these are required for mitochondrial function. This study in PLoS Biology reports a novel mechanism of light induced degeneration of photoreceptor neurons due to an energy shortfall in three of these mutants. This is in contrast to the commonly observed oxidative stress in many other mitochondrial mutants that induce light independent degeneration. Hence, this and other studies reveal that mutations in genes that encode mitochondrial protein can cause the demise of neurons by affecting very different molecular events and that the course of the demise of neurons differ greatly in these mutants.

July 2015: Somatic mosaicism: implications for disease and transmission genetics.

A well-known feature of multicellular organisms, including humans, is that the genetic material of each cell within an individual is nearly identical. But as cells divide and accumulate mutations during development, the individual cellular DNA begins to differ, a phenomenon known as mosaicism. In this review published in the journal Trends in Genetics, scientists in Dr. Lupski's Laboratory explore recent advances in our understanding of how mosaicism can cause genetic disease as well as how mosaicism can lead to seemingly “new” mutations between generations and effect transmission genetics and recurrence risk for parents.

Featured Publications: January - May 2015

May 2015: Temporal regulation of kin recognition maintains recognition-cue diversity and suppresses cheating.

Evolutionary theory predicts that polymorphism in kin-recognition cues would be unstable because individuals carrying rare cues would be unable to benefit from social interactions, leading to loss of the genetic-cue diversity. In a study published in the journal, Nature Communications, Hsing-I Ho and Gad Shaulsky show that in Dictyostelium rare variants are initially excluded, but they subsequently rejoin the aggregate and produce spores. Thus, temporal regulation of recognition may sustain polymorphism in kin-recognition genes. 

May 2015: IL-33 activates tumor stroma to promote intestinal polyposis.

In a recent Proceedings of the National Academy of Science paper, researchers in the lab of Dr. Jason Heaney report that colorectal cancer tumor cells utilize a key mediator of immune responses in the intestine, Interleukin 33, to influence the function of their surrounding supporting cell. By borrowing an immune response signal, tumor epithelial cells have acquired the means to regulate the environment in which they develop so that it is favorable for their continued survival and growth.

April 2015: MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome.

Rett syndrome is a postnatal neurodevelopmental disorder caused by mutations in the gene that encodes methyl-CpG binding protein 2 (MeCP2). A perplexing feature of Rett is that affected individuals achieve developmental milestones for the first year but then regress and develop neurological problems. In a study published in the journal, Proceedings of the National Academy of Sciences of the United States of America, the authors show that MeCP2 function is paramount at non-CpG cytosines that are methylated in neurons after birth.

April 2015: Absence of heterozygosity due to template switching during replicative rearrangements.

Structural genomic rearrangements in humans can be highly complex due to the concomitant presence of copy number variation, genomic inversions and single-nucleotide variants due to an error prone repair mechanism based on DNA replication and template switching events. Importantly, all of these alterations may arise in the same event and cause a genomic disorder due to the contribution of either one (or more than one) of these de novo variants. This paper, published in the American Journal of Human Genetics, shows that such an error prone repair can occur post-zygotically in which case a patient may end up with a diploid copy of a chromosome inherited just from one parent in addition to the presence of the complex structural variant formed during repair – such ‘segmental uniparental disomy’ results in an absence of heterozygosity often Megabases in size and can thereby distort transmission genetics. Carriers of such complex variants have an increased chance of having a severe clinical phenotype because of the presence of a segmental uniparental disomy that can lead to imprinted diseases or to the expression of recessive traits.

March 2015: Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels.

Spinocerebellar ataxia type 1 is a neurodegenerative disease characterized by loss of balance, breathing difficulty, and premature death due to accumulation of glutamine-expanded ATAXIN1. In this study, published in Cell, the authors found that the RNA-binding protein PUM1 negatively regulates ATAXIN1 and that 50% reduction of PUM1 increases wild-type ATAXIN1 by 30% causing cerebellar degeneration that is rescued by normalizing ATAXIN1 levels. These data suggest that either deletion of PUM1 or duplication of ATAXIN1 might cause degenerative disorders.

March 2015: The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism.

ABAT is a key enzyme responsible for metabolism of neurotransmitter gamma-aminobutyric acid (GABA). Besse et al. report a novel and essential role for ABAT in a seemingly unrelated pathway, mitochondrial nucleoside salvage. This study, published in Cell Metabolism, points to a potential mechanism for the unexplained side effect caused by medication that targets ABAT.

Jan. 2015: Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration.

This paper, published in Cell, demonstrates the first link between altered brain metabolism and the process of neurodegeneration. Lipid droplets are cellular organelles that consists of a lipid (fat) core, surrounded by a protein bound membrane that have never been previously identified in the brain. Research from the Bellen lab has identified a novel mechanism by which lipid droplets accumulate in the brain as a harbinger for neurodegeneration. Importantly, administration of antioxidants can reduce the lipid accumulation and delay neurodegeneration.