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Human Genetics Concepts and Applications Ninth Edition RICKI LEWIS 22 Genomics PowerPoint® Lecture Outlines Prepared by Johnny El-Rady, University of South Florida Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Introduction • Biotechnology is the use or alteration of cells or biological molecules for specific applications • A transgenic organism has DNA from different species • Recombinant DNA comes from more than one type of organism • Both are possible because of the universality of the genetic code Introduction Figure 19.1 Mice containing the jellyfish gene for green fluorescent protein (GFP) What is Patentable? • To qualify for patent protection, a transgenic organism must be new, useful, and non-obvious • Patent law has had to evolve to keep up with modern biotechnology • A DNA sequence alone does not warrant patent protection • - It must be useful as a tool for research or as a novel or improved product, such as a diagnostic test or drug What is Patentable? • A new problem for patenting DNA stems from the shift in focus of the entire field from a single-gene to a genome-wide approach • Especially problematic are: • - “Panels” of tests • - “Direct-to-consumer” genetic tests that scan client’s DNA for many thousands of SNPs The “Patent Thicket” • Term used to describe the need to license patents for every SNP or snippet of DNA • Suggested ways around this: • - Allow DNA to be patented only for use in diagnostic tests • - Exempt individuals from litigation if they use patented DNA sequences • A broader action is to ban patenting any DNA or its encoded proteins Horses vs. Zebras Figure 20.1 Horses vs. Zebras • Medical students are told early on, “When you hear hoofbeats, think horses, not zebras.” • Single-gene disorders, however, are often zebras • Medical geneticists are trained to see the big picture • - Can solve a medical mystery by putting together the pieces Genetic Counseling • Addresses medical, psychological, sociological, and ethical issues • A genetic counselor has medical, scientific, and communication skills • Genetic counseling began in pediatrics, and prenatal care, and has become specialized • The field has even infiltrated public policy as genetic testing has become widespread Genetic Counselors • The US only has about 3,000 • Provide information to individuals, couples expecting children, and families about: • - Modes of inheritance • - Disease risks and symptoms • - Available tests and treatments • Interpret direct-to-consumer genetic tests and assist other health care professionals with genetic information in their practices Genetic Counselors • When genetic counseling began, it was “nondirective” • - The practitioner did not offer an opinion or suggest a course of action, but presented options • A more recent definition of the role of the genetic counselor is “shared deliberation and decision making between the counselor and client” Figure 20.2 Genetic Testing • Genetic tests diagnose and predict the course of a disease and predict and monitor response to treatment • Using them widely must balance two traits • 1) Genetic determinism: our tendency to blame all ills on our genes • 2) Identifying ways to change our lifestyles to compensate for factors that we cannot control Newborn Screening • Usually tests for inborn errors of metabolism • Are not genetic tests, but instead they use tandem mass spectrometry to identify unusual metabolites or chemical imbalances that indicate a certain disease • The American College of Medical Genetics recommends testing for 29 disorders • - However, the actual number of tests varies by state • The field of newborn screening began in 1961 with the Guthrie test for phenylketonuria (PKU) • - It detects phenylalanine, which builds up in affected individuals • In 1963, a specialized diet became available • The diet is difficult to follow, but does prevent mental retardation • After diet’s success, genetic tests expanded • Some states perform DNA tests on newborns as well as biochemical tests Direct-To-Consumer Genetic Testing • Companies market DNA-based tests for traits, susceptibilities, and genetic diseases to the general public • The Clinical Laboratory Improvement Amendments (CLIA) control genetic testing • DTC tests presented as information, not diagnoses, may not be regulated • Unawareness of incomplete penetrance is one complication of DTC genetic testing Nutrigenetics Testing • Some DTC testing company websites offer genetic tests along with questionnaires about diet, exercise, and lifestyle habits • The company then sends a “nutrigenetics” profile with dietary suggestions and pitches to purchase supplements • However, many of these companies provide inaccurate information • - Some suggestions are even dangerous Matching Patient to Drug • A pharmacogenetic test detects a variant of a single gene that affects drug metabolism • A pharmacogenomic test detects variants of multiple genes or gene expression patterns that affect drug metabolism • These are often considered together under the umbrella term “personalized medicine” • - Help physicians to select the best drugs for individual patients Treating Genetic Disease • Treatments have evolved through stages • 1) Removing an affected body part • 2) Replacing an affected body part or biochemical with material from a donor • 3) Delivering pure, human proteins derived from recombinant DNA technology to compensate for the effects of a mutation • 4) Gene therapy, to replace mutant alleles Treating The Phenotype • Lysosomal storage diseases are a subclass of inborn errors of metabolism • Treatments are based on understanding metabolic pathways • - If any enzyme is deficient or its activity blocked, the substrate builds up and the product is deficient • There are three general approaches for counteracting these diseases Figure 20.3 Gene Therapy • Altering genes theoretically can provide a longer-lasting effect than treating symptoms • The first efforts focused on inherited disorders with a known mechanism, even though the conditions are rare • Gene therapy now is targeting more common illnesses, such as heart disease and cancers Gene Therapy • Germline gene therapy • - Gamete or zygote alteration; heritable; not done in humans; creates transgenic organisms • Somatic gene therapy • - Corrects only the cells that a disease affects; not heritable Table 20.7 Table 20.8 Invasiveness of Gene Therapy • Ex vivo gene therapy is applied to cells outside of body that are then returned • In situ gene therapy occurs directly on accessible body parts • In vivo gene therapy is applied directly to an interior body part • - The most invasive Gene Therapy: OTC, Ornithine Transcarbamylase • Deficiency of OTC is inherited as an Xlinked recessive mutation • OTC normally breaks down amino acids present in protein • Lack of OTC allows buildup of ammonia, which damages brain function • Low-protein diets and ammonia-binding drugs are used to treat OTC deficiency Gene Therapy: OTC, Ornithine Transcarbamylase Clinical trials to treat OTC deficiency were established using adenovirus as a vector for the normal OTC gene Jesse Gelsinger (18 yrs old)had a mild OTC deficiency, volunteered for the OTC gene therapy trial and was accepted Four days after gene therapy Jesse died from an overwhelming immune reaction and associated complications ( he had a virus in his body and was asymptomatic) OTC Gene Therapy Figure 20.7 • This led to a suspension of several gene therapy trials. • The death drew particular attention to safety since Jesse had not been very ill.. • Should gene therapy continue? • What about those disorders without any cure or treatment? Gene Therapy: Leber’s Congenital Amaurosis II • • • • Most severe form of blindness Inherited as autosomal recessive disease Mutation is in a gene called RPE64 Gene therapy first tried on Briard dogs, who have the same mutation as humans • - It was then tried on four young adults, and later on 8-year old Corey Haas • - So far it is working! He can see! Gene Therapy: Leber’s Congenital Amaurosis II Figure 20.9 Perspective on Gene Therapy • Great promise, but slower than expected • More complex than expected • - Gene interactions • - Appropriate vectors • - Adequately targeting and sustaining therapeutic effects • - Safety issues Savior Siblings and More • Innovative ways to conceive offspring: • 1) Couple in search of an oocyte donor advertises for an attractive, athletic woman • 2) Cancer patient stores her oocytes before therapy; becomes a mother two years later • 3) A paralyzed man has sperm removed and injected into his partner’s oocyte Savior Siblings and More • Lisa and Jack Nash sought to have a child for a different reason • They conceived and selected Adam to save his sister’s life • - She was suffering from Fanconi anemia • A month after his birth, physicians infused Adam’ umbilical cord stem cells into Molly Adam and Molly Nash Figure 21.1 Assisted Reproductive Technologies • ARTs are methods that replace the source of a male or female gamete, aid fertilization or provide a uterus • Developed to treat infertility but are becoming part of genetic screening • The US Government does not regulate ARTs • - However, the British Government does Infertility and Subfertility • Infertility is the inability to conceive a child after a year of frequent intercourse without contraceptives • Subfertility distinguishes couples who can conceive, but require longer time than usual • Affect one in six couples • A physical cause can be identified in 90% of cases: 30% in males, 60% in females Male Infertility • One in 25 men are infertile • Easier to detect, but often harder to treat than female infertility • Most cases of male infertility are genetic • Causes of infertility include: • - Low sperm count (oligospermia) • - A malfunctioning immune system • - A varicose vein in the scrotum • - Structural sperm defects Male Infertility Box Figure 1 • Most cases of male infertility are genetic • - Due to small deletions of Y chromosome that remove genes important for spermatogenesis • - Mutations in genes for androgen receptors or other hormones promoting sperm development • In cases of low sperm count, sperm can be stored frozen, then pooled • Lack of motility in sperm prevents movement in the female reproductive tract Female Infertility • Many women with subfertility or infertility have irregular menstrual cycles • - This makes it difficult to pinpoint when conception is most likely • Tracking ovulation cycles aids in determination of the most likely days for conception • Abnormalities in any part of the female reproductive system can cause infertility Figure 21.2 Female Infertility • Fertility drugs stimulate ovulation but may induce release of multiple oocytes • Blocked fallopian tubes can result in ectopic pregnancy (tubal pregnancy). • Excess tissue growth in uterine lining may make it inhospitable for an embryo • - Fibroids: benign tumors • - Endometriosis: buildup of uterine lining Female Infertility • Secretions in the vagina and cervix may be hostile to sperm • Infertility may also result if the oocyte fails to release sperm-attracting chemicals • Early pregnancy loss due to an abnormal chromosome number is more common in older female • - May appear as infertility because bleeding resembles a heavy menstrual flow Infertility Tests • The man is checked first, because it is easier, less costly and less painful to obtain sperm than oocytes • - Sperm are checked for number (sperm count) motility and morphology (shape) • A gynecologist can then check the female to see if reproductive organs are present and functioning • Psychological factors may also be at Assisted Reproductive Technologies (ARTs) • Many people with fertility problems use alternative ways to conceive • In the US, about 1% of the 4 million births each year are from ARTs • Several of the ARTs were developed in nonhuman animals Assisted Reproductive Technologies (ARTs) • Examples • - Intrauterine insemination • - Surrogate motherhood • - In vitro fertilization (IVF) • - Gamete intrafallopian transfer (GIFT) • - Zygote intrafallopian transfer (ZIFT) • - Oocyte banking and donation • - Preimplantation genetic diagnosis Intrauterine Insemination • Donated sperm is placed in a woman’s reproductive tract, typically at the cervix or in uterus • Success rate is 5-15% • 1790: first reported pregnancy from artificial insemination • 1953: methods for freezing and storing sperm were developed • Sperm catalogs list personal characteristics Surrogate Motherhood • In surrogate motherhood, a woman carries a pregnancy to term for another woman who cannot conceive and/or carry the pregnancy • Custody rights are given up at birth • A surrogate mother may or may not have contributed an oocyte • Complex legal and emotional issues must be considered In vitro Fertilization (IVF) • For in vitro fertilization, a sperm fertilizes an oocyte in a culture dish • Embryos are transferred to the oocyte donor’s uterus (or a surrogate’s uterus) for implantation • 1978: First IVF child born (Louise Joy Brown) • - Since then, 4 million IVF children • Intracytoplasmic sperm injection (ICSI) is more effective than IVF alone Intracytoplasmic Sperm Injection • For cases in which sperm cannot penetrate the oocyte, IVF can be accompanied by ICSI which injects sperm directly into the oocyte • ICSI allows conception in cases of low sperm count, abnormal sperm shape, sperm motility problems, • - And in cases where male has spinal cord injuries and cannot ejaculate Intracytoplasmic Sperm Injection Figure 21.4 Gamete Intrafallopian Transfer (GIFT) • GIFT is a method in which superovulated oocytes from a woman and sperm from her partner are placed together in her uterine (fallopian) tube • Fertilization occurs in the woman’s body • Allows conception in cases of fallopian tube blockage • 22% success rate and costs less than IVF Zygote Intrafallopian Transfer (ZIFT) • IVF ovum is introduced into the uterine tube and allowed to move to the uterus for implantation • Also about 22% successful • GIFT and ZIFT are done much less frequently than IVF • - They often will not work for women with scarred uterine tubes From Genetics To Genomics • Genetics is a young science, genomics is younger still • The term genome was coined in 1920, to refer to a complete set of chromosomes and its genes • - Now it refers to all the DNA in a haploid set of chromosomes • The term genomics was coined in 1986 • - Indicates the study of genomes Positional Cloning • A gene-by-gene approach that matches single genes to specific diseases • Begins with a phenotype, and gradually identifies a causative gene, localizing it to a part of a chromosome • In the 1980s and 1990s, yielded discoveries of genes that cause such diseases as Duchenne muscular dystrophy, cystic fibrosis and Huntington disease Huntington Disease Pedigree Box Figure 1 The Human Genome Project • The idea to sequence the human genome emerged in the 1980s with several goals • Officially started in 1990 • - $3 billion, 15-year project • - Under the direction of the DOE and NIH • Draft of the human genome in 2001 • Finished sequence in 2003 • Represents the work of thousands of researchers in an international collaboration Human Genome Project (ELSI) • Recognizing the impact of the human genome project on public policy • 3% of the government-sponsored budget was set aside for Ethical, Legal, and Social Issues • To prevent misuse of information and genotypic discrimination Sequencing Methods DNA Sequence Data Figure 22.5 Sequencing Methods • Newer approaches to DNA sequencing use a microfluidics environment • - A method called 454 sequencing, can sequence 20 million bases in 4.5 hours! • Even newer approaches use nanomaterials to distinguish how each of the four bases disrupts an electrical field Comparative Genomics • Hundreds of species have had their genomes sequenced • - First, viruses and bacteria • - Then, our closest relatives (rats and chimps), and our favorites (cats and dogs) • A Sampling of Animal Genomes Figure 22.8 Comparative Genomics May Help Us Answer Important Questions • Minimal set of genes for life • Distinctions between three domains of life • Genes for the simplest eukaryote • Basic blueprint for an animal • Genes for terrestrial living • Birds to mammals • Chimps to humans Personal Genome Sequencing • Comparing the genomes of healthy people to those with certain diseases will reveal how gene combinations affect health • - This permits recognition of controllable environmental factors • Sequencing personal genomes is under way • - The information can be used in several ways