1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Rewriting Human History and Empowering Indigenous Communities with Genome Editing Tools

      other

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Appropriate empirical-based evidence and detailed theoretical considerations should be used for evolutionary explanations of phenotypic variation observed in the field of human population genetics (especially Indigenous populations). Investigators within the population genetics community frequently overlook the importance of these criteria when associating observed phenotypic variation with evolutionary explanations. A functional investigation of population-specific variation using cutting-edge genome editing tools has the potential to empower the population genetics community by holding “just-so” evolutionary explanations accountable. Here, we detail currently available precision genome editing tools and methods, with a particular emphasis on base editing, that can be applied to functionally investigate population-specific point mutations. We use the recent identification of thrifty mutations in the CREBRF gene as an example of the current dire need for an alliance between the fields of population genetics and genome editing.

          Related collections

          Most cited references56

          • Record: found
          • Abstract: found
          • Article: not found

          Adapting to obesity with adipose tissue inflammation

          Adipose tissue inflammation is an adaptive response to overnutrition in the early stages of obesity, but later becomes maladaptive. Here, Reilly and Saltiel review the cellular and molecular mechanisms of obesity-induced inflammation in adipose tissue and discuss potential therapeutic approaches.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions

            Base editing is a recently developed approach to genome editing that uses a fusion protein containing a catalytically defective Streptococcus pyogenes Cas9, a cytidine deaminase, and an inhibitor of base excision repair to induce programmable, single-nucleotide changes in the DNA of living cells without generating double-strand DNA breaks, without requiring a donor DNA template, and without inducing an excess of stochastic insertions and deletions 1 . Here we report the development of five new C→T (or G→A) base editors that use natural and engineered Cas9 variants with different protospacer-adjacent motif (PAM) specificities to expand the number of sites that can be targeted by base editing by 2.5-fold. Additionally, we engineered new base editors containing mutated cytidine deaminase domains that narrow the width of the apparent editing window from approximately 5 nucleotides to as little as 1 to 2 nucleotides, enabling the discrimination of neighboring C nucleotides that would previously be edited with comparable efficiency, thereby doubling the number of disease-associated target Cs that can be corrected preferentially over nearby non-target Cs. Collectively, these developments substantially increase the targeting scope of base editing and establish the modular nature of base editors.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells.

              The β-haemoglobinopathies, such as sickle cell disease and β-thalassaemia, are caused by mutations in the β-globin (HBB) gene and affect millions of people worldwide. Ex vivo gene correction in patient-derived haematopoietic stem cells followed by autologous transplantation could be used to cure β-haemoglobinopathies. Here we present a CRISPR/Cas9 gene-editing system that combines Cas9 ribonucleoproteins and adeno-associated viral vector delivery of a homologous donor to achieve homologous recombination at the HBB gene in haematopoietic stem cells. Notably, we devise an enrichment model to purify a population of haematopoietic stem and progenitor cells with more than 90% targeted integration. We also show efficient correction of the Glu6Val mutation responsible for sickle cell disease by using patient-derived stem and progenitor cells that, after differentiation into erythrocytes, express adult β-globin (HbA) messenger RNA, which confirms intact transcriptional regulation of edited HBB alleles. Collectively, these preclinical studies outline a CRISPR-based methodology for targeting haematopoietic stem cells by homologous recombination at the HBB locus to advance the development of next-generation therapies for β-haemoglobinopathies.
                Bookmark

                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                12 January 2020
                January 2020
                : 11
                : 1
                : 88
                Affiliations
                [1 ]Department of Anthropology, University of California, San Diego, La Jolla, CA 92093, USA
                [2 ]Department of Global Health, University of California, San Diego, La Jolla, CA 92093, USA
                [3 ]Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA; krallapa@ 123456ucsd.edu
                Author notes
                [* ]Correspondence: pkfox@ 123456ucsd.edu (K.F.); akomor@ 123456ucsd.edu (A.C.K.)
                Author information
                https://orcid.org/0000-0003-4215-5273
                https://orcid.org/0000-0001-7402-1187
                https://orcid.org/0000-0001-5043-0998
                Article
                genes-11-00088
                10.3390/genes11010088
                7016644
                31940934
                c7621506-5f8c-4e18-ab23-6950fdefbe29
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 December 2019
                : 09 January 2020
                Categories
                Perspective

                base editing,population genetics,signatures of natural selection,functional genomics

                Comments

                Comment on this article