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Heritable Human Genome Editing (2020)

Chapter: Appendix C: Glossary

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Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Page 200
Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Page 201
Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Page 202
Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
×
Page 203
Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
×
Page 204
Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
×
Page 205
Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
×
Page 206
Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
×
Page 207
Suggested Citation:"Appendix C: Glossary." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
×
Page 208

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Appendix C Glossary Allele. A variant form of a gene at a particular locus on a chromosome. Different alleles can produce variations in inherited characteristics. Androgenetic haploid embryonic stem cells (AG-haESCs). Cells derived from embryos generated either by injecting sperm into oocytes from which the maternal chromosomes have been removed, or by fertilizing eggs and removing the female pronucleus. Aneuploidy. The presence of an abnormal number of chromosomes in a cell. Assisted reproductive technology (ART). A fertility treatment or procedure that involves laboratory handling of gametes (eggs and sperm) or embryos. Examples of ART include in vitro fertilization and intracytoplasmic sperm injection. Autosomal dominant. A pattern of inheritance in which an affected individual has one disease- causing copy of a gene and one copy of a gene with the non-disease-causing sequence, located on the autosomal chromosomes. The disease-causing copy of the gene determines the resultant phenotype. Humans have 22 pairs of autosomal chromosomes and one pair of sex chromosomes (see below). Autosomal recessive. A pattern of inheritance in which an affected individual has a disease- causing sequence in both copies of a gene located on an autosomal chromosome. A single disease-causing copy of the gene is insufficient to cause the phenotype. Blastocyst. A preimplantation embryo in placental mammals (occurring at about five days after fertilization in humans) having between 50 and 150 cells. The blastocyst consists of a sphere made up of an outer layer of cells (the trophectoderm), a fluid-filled cavity (the blastocoel or blastocyst cavity), and a cluster of cells in the interior (the inner cell mass). Cells from the inner cell mass, if grown in culture, can give rise to embryonic stem cell lines. Cas9 (CRISPR-associated protein 9). A specialized enzyme known as a nuclease that has the ability to cut DNA sequences. Cas9 makes up part of the “toolkit” for the CRISPR/Cas9 method of genome editing. Chromatin. The complex of DNA and proteins that forms chromosomes. Some of the proteins are structural, helping to organize and protect the DNA, while others are regulatory, acting to control whether genes are active or not, and to promote DNA replication or repair. Chromosome. A thread-like structure that contains a single length of DNA, usually carrying many hundreds of genes. This is packaged with proteins to form chromatin. The DNA within the complete set of chromosomes in each cell (23 pairs in humans) includes two copies of the genome, one from each parent. The chromosomes usually reside in the nucleus of a cell, except PREPUBLICATION COPY | UNCORRECTED PROOFS 200

during cell division, when the nuclear membrane breaks down and the chromosomes become condensed and can be visualized as discrete entities. Compound heterozygous. Having two different disease-causing alleles for the same disease. CRISPR (clustered regularly interspaced short palindromic repeats). A naturally occurring mechanism found in bacteria that involves the retention of fragments of foreign DNA, providing the bacteria with some immunity to viruses. The system is sometimes referred to as CRISPR/Cas9 to denote the entire gene-editing platform in which RNA homologous with the targeted gene is combined with Cas9 (CRISPR-associated protein 9), which is a DNA-cutting enzyme (nuclease) to form the “toolkit” for the CRISPR/Cas9 method of genome editing. Cultured cell. A cell maintained in a tissue culture allowing expansion of its numbers. De novo. From the Latin, meaning “of new.” As used in this report, describes mutations arising in the embryo that are not inherited from either parent. Deoxyribonucleic acid (DNA). A two-stranded molecule, arranged as a double helix, that contains the genetic instructions used in the development, functioning, and reproduction of all known living organisms. DNA cleavage. The process of introducing a double strand break in DNA. Diploid. Cells that contain a full set of DNA—half from each parent. In humans, diploid cells contain 46 chromosomes (in 23 pairs). DNA sequencing. A laboratory technique used to determine the sequence of bases (A, C, G, and T) in a DNA molecule. The DNA base sequence carries the information that a cell needs to assemble protein and RNA molecules. DNA sequence information is important in investigating the functions of genes. Dominant. A pattern of inheritance of a gene or trait in which, in a diploid cell, a single copy of a particular allele (a gene variant) confers a function independent of the nature of the second copy of the gene. Double-strand break (DSB). A break in the DNA double helix in which both strands are cut, as distinct from a single-strand break or “nick.” Edit. A change to genomic DNA sequence (e.g., insertion, deletion, substitution) resulting from the application of genome-editing components (e.g., nuclease, repair template). Embryo. An animal in the early stages of growth and differentiation that are characterized by cleavage (cell division of the fertilized egg), differentiation of fundamental cell types and tissues, and the formation of primitive organs and organ systems. In humans, this stage extends from shortly after fertilization to the end of the eighth week after conception, after which stage it becomes known as a fetus. PREPUBLICATION COPY | UNCORRECTED PROOFS 201

Embryonic stem cell (ESC, also known as ES cell). A primitive (undifferentiated) cell from the embryo that has the potential to become a wide variety of specialized cell types (that is, is pluripotent). It is a cultured cell derived from the inner cell mass of the blastocyst. An embryonic stem cell is not an embryo; by itself, it cannot produce the cell types, such as trophectoderm cells, necessary to give rise to a complete organism. Embryonic stem cells can be maintained as pluripotent cells in culture and induced to differentiate into many different cell types. Enhancement. Improving a condition or trait beyond a typical or normal level. Epigenetic effects. Changes to the chemical structure of DNA or the proteins that associate with DNA that can alter gene expression without changing the DNA sequence of a gene. For example, in the epigenetic phenomenon called genomic imprinting, molecules called methyl groups attach to DNA and alter gene expression according to parental origin. Epigenome. A set of genome-wide chemical modifications to DNA and to proteins that bind to DNA in the chromosomes that affect whether and how genes are expressed. Gamete. A reproductive cell (egg or sperm). Gametes are haploid (having only half the number of chromosomes found in somatic cells—23 in humans), and when two gametes unite at fertilization, the resulting one-cell embryo (the zygote) has the full number of chromosomes (46 in humans). Gene. A functional unit of heredity that is a segment of DNA in a specific site on a chromosome. A gene typically directs the formation of a protein or RNA molecule. Gene expression. The process by which RNA and proteins are made from the instructions encoded in genes. Gene expression is controlled by proteins and RNA molecules that bind to the genome or to the RNA copy and regulate their levels of production and the levels of their products. Alterations in gene expression change the functions of cells, tissues, organs, or whole organisms and sometimes result in observable characteristics associated with a particular gene. Gene therapy. Introduction of exogenous genes into cells with the goal of ameliorating a disease condition. Can also be referred to as gene addition therapy. Genetic variation. Differences in the sequence of DNA among people. Genome. The complete set of DNA possessed by an organism. In humans, the genome is organized into 23 pairs of homologous chromosomes and comprises approximately 6 billion base pairs. Genome editing. The process by which the genome sequence is changed through the intervention of a DNA break or other DNA modification. Genome-wide association studies. A way for scientists to identify genes involved in human disease. A genome-wide association study involves searching the genome for small variations, PREPUBLICATION COPY | UNCORRECTED PROOFS 202

called single-nucleotide polymorphisms (SNPs, pronounced “snips”), that occur more frequently in people who have a particular disease than in people who do not. Each study can look at hundreds or thousands of SNPs at the same time. Researchers use data from this type of study to pinpoint genes that may contribute to a person’s risk of developing a given disease. Genomics. The study of all the nucleotide sequences—including structural genes, regulatory sequences, and noncoding DNA segments—in the chromosomes of an organism or tissue sample. Genotype. Genetic constitution of an individual organism or cell. Germ cell. A sperm or egg cell Germline cell. A cell at any point in the lineage of cells that will give rise to a germ cell (see above). The germline is this lineage of cells. Eggs and sperm fuse during sexual reproduction to create an embryo, thus continuing the germline into the next generation. Guide RNA (gRNA). In CRISPR systems, a small RNA that combines with a Cas protein to form the complex that cuts DNA. The gRNA contains a sequence of approximately 20 bases that specifies the target to be cut. Haploid. Refers to a cell, usually a gamete or its immediate precursor, that has only one chromosome from each pair (a haploid cell in humans has a set of 23 chromosomes). In contrast, body cells (somatic cells) are diploid, having two sets of chromosomes (46 in humans). Heritable genetic change. Modifications to genes that could be passed down through generations. While heritable human genome editing would involve using editing reagents with germline cells, not all such editing is intended to be inherited. There is a distinction between research that is conducted only in a laboratory and making genetic changes in a clinical setting to establish a pregnancy. Heterozygous. Having two different variants (alleles) of a specific gene on the two homologous chromosomes of a cell or an organism. Homologous. (Of genes) having a shared genetic sequence. Homologous recombination. The recombining of two like DNA molecules, including a process by which gene targeting produces an alteration in a specific gene. Homology directed repair (HDR). A natural repair process used to repair broken DNA, which relies on a DNA “template” with homology to the broken stretch of DNA. This usually occurs during or after DNA synthesis, which provides this template. Homozygous. Having the same variant (allele) of a specific gene on both homologous chromosomes of a cell or an organism. PREPUBLICATION COPY | UNCORRECTED PROOFS 203

Human Fertilisation and Embryology Authority (HFEA). The U.K.’s independent regulator overseeing the use of germ cells and embryos in fertility treatment and research. The Human Fertilisation and Embryology Act is the law under which the authority operates and which it upholds. Implantation. The process by which an embryo becomes attached to the inside of the uterus (occurring at seven to 14 days after fertilization in typical pregnancies). In vitro. From the Latin, meaning “in glass.” Pertains to procedures performed in a laboratory dish or test tube, or in an artificial environment. In vitro fertilization (IVF). An assisted reproduction technique in which fertilization is accomplished outside of the body. In vivo. From the Latin, meaning “in the living.” Pertains to procedures performed in a natural environment, usually in the body of the subject. Indel. A sequence change caused by the insertion or deletion of DNA sequence. Induced pluripotent stem cell (iPSC). A cell type induced by the introduction or activation of genes conferring pluripotency and stem cell–like properties. For example, cells already committed to a particular fate (e.g., skin) can be induced to become pluripotent. This is useful in regenerative medicine, where iPSCs can be introduced back into the donor of the original cells with much less risk of transplant rejection. Institutional review board (IRB). An administrative body in an institution (such as a hospital or a university) established to protect the rights and welfare of human research participants who are recruited to participate in research activities conducted under the auspices of that institution. The IRB has the authority to approve, require modifications in, or disapprove research activities in its jurisdiction, as specified by both federal regulations and local institutional policy. Intended edit. A planned change to the genomic DNA sequence at the target resulting from the application of genome editing components (e.g., nuclease, repair template). In vitro gametogenesis (IVG). The use of stem cells to generate male or female gametes. Locus. (Of genes) The place where a gene is located on a chromosome Mitochondria. Small structures present in human cells that are the sites of important metabolic functions, including energy production. Mitochondrial DNA (mtDNA). The genetic material contained within the mitochondria. Mitochondrial replacement techniques (MRT). Treatment methods with the potential to reduce the transmission of abnormal mtDNA from a mother to her child, and thus avoid mitochondrial disease in the child and subsequent generations. PREPUBLICATION COPY | UNCORRECTED PROOFS 204

Monogenic disorder. A disorder that results from a mutation at a single genetic locus. A locus may be present on an autosome or on a sex chromosome, and it may be manifested in a dominant or a recessive mode. A monogenic disorder may also be referred to as a Mendelian disorder. Mosaicism. Variation among cells, such that the cells are not all the same—for example, in an embryo when not all of the cells are edited. Mutation. A change in a DNA sequence. Mutations can occur spontaneously during cell division or can be triggered by environmental stresses, such as sunlight, radiation, and chemicals. Non-homologous end joining (NHEJ). A natural repair process used to join the two ends of a broken DNA strand back together. This process is prone to errors in which short DNA sequences are introduced into the strand of DNA. Nuclease. An enzyme that can cut through DNA or RNA strands. Off-target event (or off-target edit). When a genome-editing nuclease alters a DNA sequence at a location other than the one to which it was targeted. This can occur because the off-target sequence is similar, but not identical to, the intended target sequence. On-target event (or on-target edit). Editing of the DNA at a specified, targeted location in the genome. Oocyte. A developing egg; usually a large and immobile cell. Pathogenic variant. A genetic alteration that increases an individual's susceptibility or predisposition to a certain disease or disorder. Penetrance. The proportion of people who have a particular genetic change (such as a mutation in a specific gene) and exhibit signs and symptoms of a genetic disorder. If some people who have the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Phenotype. Observable properties of an organism that are influenced by both its genotype and its environment. Polygenic inheritance. A pattern of inheritance that occurs when one characteristic is controlled by two or more genes. Preimplantation genetic testing (PGT). Involves checking the genes or chromosomes of early embryos for a specific genetic condition. During PGT, a single cell or a small number of cells is removed from the embryo at the eight-cell or blastocyst stage and DNA is isolated and genotyped by sensitive methods, such as the polymerase chain reaction. PREPUBLICATION COPY | UNCORRECTED PROOFS 205

Pronucleus. The haploid nucleus of an oocyte or sperm, either prior to fertilization or immediately after fertilization, before the sperm and egg nuclei have fused into a single diploid nucleus. Recessive. A recessive allele of a gene is one whose effects are masked by the second allele present in a diploid cell or organism, which is referred to as dominant. Recombinant DNA. A recombinant DNA molecule is made up of DNA sequences that have been artificially modified or joined together (recombined) so that the new genetic sequence differs from naturally occurring genetic material. Repair template. A nucleic acid sequence used to direct cellular DNA repair pathways to incorporate specific DNA sequence changes at or near a target site. Ribonucleic acid (RNA). A single-stranded molecule that transmits and regulates the DNA’s instructions for the development, functioning, and reproduction of all known living organisms. Sex chromosome. A type of chromosome that participates in sex determination. Humans and most other mammals have two sex chromosomes, X and Y. A female has two X chromosomes in each cell, while a male has an X chromosome and a Y chromosome in each cell. Single nucleotide polymorphism (SNP). A variant DNA sequence in which the purine or pyrimidine base of a single nucleotide has been replaced by another such base. Somatic cell. Any cell of a plant or animal other than a reproductive cell or its precursor. In Latin, “soma” means “body.” Spermatogonial stem cells (SSCs). The self-replicating precursors of sperm cells. Target sequence. A nucleic acid sequence subject to intentional binding, modification, or cleavage. The alteration induced at the target site can be a “desired on-target event” or an “unwanted on-target event.” The latter events are often due to non-homology end joining (NHEJ)–mediated DNA repair processes. Transcription. Making an RNA copy from a gene or other DNA sequence. Transcription is the first step in gene expression. Transcription activator–like effector nuclease (TALEN). An artificial nuclease composed of an endodeoxyribonuclease fused to DNA-binding domains of transcription activator–like effectors (TALEs) that cleave DNA at a defined distance from TALE recognition sequences. For example, a TALEN may refer to a pair of TALE-FokI fusion proteins that must dimerize on opposite strands of DNA adjacent to a target site for cleavage. Translation. The process of forming a protein molecule from information contained in a messenger RNA—a step in gene expression following transcription (the copying of RNA from DNA). PREPUBLICATION COPY | UNCORRECTED PROOFS 206

Translational pathway (clinical). The series of steps that a technology would need to go through to proceed from basic research to clinical use. Tripronuclear embryos. Egg cells that are fertilized by two sperm cells instead of one, precluding them from developing into a fetus. Trophectoderm. The outer layer of the developing blastocyst that will ultimately form the embryonic side of the placenta. Unintended edit. A change to the genomic DNA sequence at a location distinct from the target sequence, which results from the application of genome editing components (e.g., nuclease, repair template). Variant. Distinct forms of a gene present in a population that can differ somewhat in function, with some being advantageous to the organism and some being deleterious or neutral. Vector. A vehicle that transfers a gene into a new site (analogous to insect vectors that transfer a virus or parasite into a new animal host). Vectors used in molecular cell biology and genetic engineering include plasmids and modified viruses engineered to carry and express genes of interest in target cells. The most clinically relevant viral vectors for gene transfer include retroviral, lentiviral, adenoviral, and adeno-associated viral vectors. Whole-genome sequencing (WGS). A laboratory process that determines the complete DNA sequence of an organism’s genome at a single time. X-linked disease. A disease caused by a mutation in a gene on the X chromosome. The phenotype will be expressed in females who are homozygous for the gene mutation and in males. Females with just one copy of the mutated gene are carriers. Zinc-finger nuclease (ZFN). A class of engineered enzymes including both a DNA-binding domain and a DNA-cleavage enzyme that can be used as a genome editing tool. Zygote. The single, fertilized cell that results from the combination of parental gametes—the egg and sperm. REFERENCES Human Fertilisation and Embryology Authority (HFEA). 2014. Third Scientific Review of the Safety and Efficacy of Methods to Avoid Mitochondrial Disease through Assisted Conception: 2014 Update. NASEM (National Academies of Sciences, Engineering, and Medicine). 2017a. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. NASEM. 2017b. An Evidence Framework for Genetic Testing. Washington, DC: The National Academies Press. PREPUBLICATION COPY | UNCORRECTED PROOFS 207

National Cancer Institute. NCI Dictionary of Genetics Terms. Available at https://www.cancer.gov/publications/dictionaries/genetics-dictionary; accessed July 24, 2020. National Human Genome Research Institute. Talking Glossary of Genetic Terms. Available at https://www.genome.gov/genetics-glossary; accessed July 24, 2020. National Institute of Standards and Technology. Genome Editing Consortium Lexicon. ISO/CD 5058-1 Biotechnology. Genome Editing. Part 1: Terminology (in development). https://www.iso.org/standard/80679.html. PREPUBLICATION COPY | UNCORRECTED PROOFS 208

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Heritable human genome editing - making changes to the genetic material of eggs, sperm, or any cells that lead to their development, including the cells of early embryos, and establishing a pregnancy - raises not only scientific and medical considerations but also a host of ethical, moral, and societal issues. Human embryos whose genomes have been edited should not be used to create a pregnancy until it is established that precise genomic changes can be made reliably and without introducing undesired changes - criteria that have not yet been met, says Heritable Human Genome Editing.

From an international commission of the U.S. National Academy of Medicine, U.S. National Academy of Sciences, and the U.K.'s Royal Society, the report considers potential benefits, harms, and uncertainties associated with genome editing technologies and defines a translational pathway from rigorous preclinical research to initial clinical uses, should a country decide to permit such uses. The report specifies stringent preclinical and clinical requirements for establishing safety and efficacy, and for undertaking long-term monitoring of outcomes. Extensive national and international dialogue is needed before any country decides whether to permit clinical use of this technology, according to the report, which identifies essential elements of national and international scientific governance and oversight.

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