Gene And Disease 基因与疾病

1. Gene And Disease基因与疾病 Deqiao Sheng PhD shengdq@ctgu.edu.cn Biochemistry Department

2. Basic concept and classification • Genes transmit inherited traits (including mutations that cause disease) from one generation to the next • Genetic factors play a major role in the development and severity of many, if not most, diseases. • Cancer • Alzheimer's • Diabetes • Infections • Damage to the genes by radiation, chemicals and the like may accumulate over a lifetime and contribute to the changes associated with aging.

3. What are genes? • A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a polypeptide or for an RNA chain that has a function in the organism. • Genes are specific lengths of DNA that determine the order of amino acids used to make protein. • Alternative forms of the same gene are called alleles.

4. Useful definitions • Locus: a unique chromosomal location defining the position of an individual gene or DNA sequence • Allele : one of several alternative forms of a gene existing at a locus (Homologous chromosome) • Mutation: sequence variation resulting in a phenotypic difference

5. Genotype • The genotype is the genetic makeup of a cell, an organism, or an individual (i.e. the specific allele makeup of the individual) usually with reference to a specific character under consideration. • Phenotype • A phenotype is the composite of an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, phenology, behavior, and products of behavior (such as a bird's nest).

6. An organism's genotype is a major (the largest by far for morphology) influencing factor in the development of its phenotype, but it is not the only one. • Even two organisms with identical genotypes normally differ in their phenotypes. One experiences this in everyday life with monozygous (i.e. identical) twins. Identical twins share the same genotype, since their genomes are identical; but they never have the same phenotype, although their phenotypes may be very similar.

7. Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and the interactions between the two!!!

8. What is a gene mutation and how do mutations occur? • A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome. • Gene mutations can occur for a variety of reasons, and have a range of effects, from benign to malignant. • Benign mutations in genetic material explain why people look very different, for example, while cancer is caused by malignant genetic mutations.

9. Hereditary or germline mutations occur when eggs or sperm develop mutations which are passed on to the baby. These mutations often occur because of errors in the generation of eggs and sperm, although they can also be errors which have been passed down over generations. • If a gene mutation occurs after fertilization, as might occur when some of the rapidly dividing cells in a developing fetus mutate, it is a new or de novo mutation. • Both types of mutation can lead to congenital disabilities, or they may be so minimal that they are not evident.

10. Hereditary Mutations Egg Sperm Mutation Occurs Fertilized Egg Mutation Reproductive Bone Pancreas Brain Body Cells of Offspring

11. Acquired Mutations Normal Bone Cell Mutation Occurs Altered Gene Altered Bone Cells Normal Bone Cells

12. Two classes of mutations are spontaneous mutations (molecular decay) and induced mutations caused by mutagens. • Spontaneous mutation • Depurination, Deamination , Slipped strand mispairing • Induced mutation (by mutagens): • Chemicals: Base analogs , DNA intercalating agents (e.g. ethidium bromide), DNA crosslinkers, Oxidative damage • Radiation :Ultraviolet radiation • pyrimidine dimer

13. Mutation can result in several different types of change in sequences; these can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely.

14. Classification of mutation types By effect on structure • Point mutations (Silent mutations/Missense mutations/Nonsense mutations) • Insertions • Deletions (remove one or more nucleotides or large chromosomal regionsfrom the DNA)

16. Insertion Deletion

18. By effect on function • Loss-of-function mutations • Gain-of-function mutations • Dominant negative mutations • Lethal mutations • back mutation or reversion

19. Cell membrane DNA Nucleus Chain of amino acids DNA bases mRNA Gene Protein Ribosome Altered DNA→Altered Protein

20. Genes and Disease • Categories of Human disease • Single-gene disorders (Monogenic disease) • Multifactorial disorders (Polygenic disease) • Chromosomal disorders • Mitochondrial disorders • Acquired genetic disease (infectious diseases)

21. Monogenic diseases • Caused by the inheritance of a single defective gene • Scientists currently estimate that over 10,000 of human diseases are known to be monogenic. • Pure genetic diseases are caused by a single error in a single gene in the human DNA. The nature of disease depends on the functions performed by the modified gene.

22. The single-gene or monogenic diseases can be classified into three main categories: • Dominant（显性） • Recessive （隐性） • X-linked （X-连锁）

23. All human beings have two sets or copies of each gene called “allele”; one copy on each side of the chromosome pair. • Recessive diseases are monogenic disorders that occur due to damages in both copies or allele. • Dominant diseases are monogenic disorders that involve damage to only one gene copy. • X linked diseases are monogenic disorders that are linked to defective genes on the X chromosome which is the sex chromosome. The X linked alleles can also be dominant or recessive. These alleles are expressed equally in men and women, more so in men as they carry only one copy of X chromosome (XY) whereas women carry two (XX).

24. Monogenic diseases • Hundreds of different monogenic diseases, caused by errors in hundreds of different genes, have been discovered. • Most of these disorders are very rare; however a few are relatively common. Well known monogenic diseases include cystic fibrosis, sickle cell anemia and Tay Sachs disease, which are recessive diseases, and myotonic dystrophy and Marfan syndrome, which are dominant.

26. Sickle-cell anaemia镰状红细胞贫血 • Sickle cell anemia is a disease of red blood cells. It is caused by a mutation in the hemoglobin gene. • A single base change results in a single amino acid substitution. This mutation causes the hemoglobin to change its conformation to a more elongated form under certain conditions, distorting the red blood cells and impairing their ability to carry oxygen.

27. Normal hemoglobins in the red cell consist of Hb A, Hb F, and Hb A2. The protein sequences are DNA coded on Chromosome 11 for the beta, delta and gamma chains. The alpha chains are coded on Chromosome 16. The beta variants such as Hb S, Hb C, and Hb D all occur from a mutation on Chromosome 11.

28. SCA is an autosomal recessive disease caused by a point mutation in the hemoglobin beta gene (HBB) found on chromosome 11p15.4. • Single base mutation in the 6th codon (CTC to CAC) of the beta-hemoglobin gene • Results in substitution of valine for glutamic acid in beta chain

30. Hemoglobin S is an inherited variant of normal adult hemoglobin (hemoglobin A). It results from a substitution of valine for glutamic acid in the sixth position of the β globin chain.

31. Normal Hemoglobin • Hemoglobin AA (adult) • Hemoglobin F (fetal) • Sickle Cell Hemoglobin • Hemoglobin AS (trait) • Hemoglobin SS (disease) • In sickle cell trait (Hgb AS) 35-45% of hemoglobin is affected

33. Pathophysiology • Sickled cells have shortened lifespan (16-20 days compared to 120) resulting in chronic anemia • Microvascular occlusion leads to impaired delivery of oxygen to tissues and chronic tissue damage • Sickled cells also cause endothelial damage to larger vessels resulting in thickened walls, stenosis, occlusion and thrombus formation

34. Fragile X syndrome • The Fragile X syndrome is caused by a "fragile" site at the end of the long arm of the X-chromosome. • It is a genetic disorder that manifests itself through a complex range of behavioral and cognitive phenotypes. It is the result of genetic mutation which varies considerably in severity among patients.

35. Fragile X syndrome is the most common cause of inherited mental retardation. Although it is a X-linked recessive trait with variable expression and incomplete penetrance, 30% of all carrier women are affected.

36. Multifactorial disorders • Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. • Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified.

37. Asthma(哮喘 ) autoimmune diseases cancers ciliopathies cleft palate diabetes heart disease hypertension inflammatory bowel disease mental retardation mood disorder obesity refractive error infertility

38. Cancer • Cancer is ultimately the result of cells that uncontrollably grow and do not die. Normal cells in the body follow an orderly path of growth, division, and death. Programmed cell death is called apoptosis, and when this process breaks down, cancer begins to form. Unlike regular cells, cancer cells do not experience programmatic death and instead continue to grow and divide. This leads to a mass of abnormal cells that grows out of control.

39. Cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008 • Lung, stomach, liver, colon and breast cancer cause the most cancer deaths each year. • About 30% of cancer deaths are due to the five leading behavioral and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, alcohol use.

40. Tobacco use is the most important risk factor for cancer causing 22% of global cancer deaths and 71% of global lung cancer deaths. • Cancer causing viral infections such as HBV/HCV and HPV are responsible for up to 20% of cancer deaths in low- and middle-income countries.

41. The main types of cancer are: • lung (1.37 million deaths) • stomach (736 000 deaths) • liver (695 000 deaths) • colorectal (608 000 deaths) • breast (458 000 deaths) • cervical cancer (275 000 deaths)

42. What causes cancer? • Cancer arises from one single cell. The transformation from a normal cell into a tumor cell is a multistage process, typically a progression from a pre-cancerous lesion to malignant tumors. These changes are the result of the interaction between a person's genetic factors and three categories of external agents, including:

43. physical carcinogens, such as ultraviolet and ionizing radiation; • chemical carcinogens, such as asbestos, components of tobacco smoke, aflatoxin (a food contaminant) and arsenic (a drinking water contaminant); and • biological carcinogens, such as infections from certain viruses, bacteria or parasites.

44. There are many different kinds of cancers. Cancer can develop in almost any organ or tissue, such as the lung, colon, breast, skin, bones, or nerve tissue. • There are many causes of cancers, including: • Benzene and other chemicals • Drinking excess alcohol • Environmental toxins, such as certain poisonous mushrooms and a type of poison that can grow on peanut plants (aflatoxins) • Excessive sunlight exposure • Genetic problems • Obesity • Radiation • Viruses

45. Ageing is another fundamental factor for the development of cancer. The incidence of cancer rises dramatically with age, most likely due to a build up of risks for specific cancers that increase with age.

46. Determining what causes cancer is complex. • Many things are known to increase the risk of cancer, including tobacco use, certain infections, radiation, lack of physical activity, obesity, and environmental pollutants. • These can directly damage genes or combine with existing genetic faults within cells to cause the disease. Approximately five to ten percent of cancers are entirely hereditary.

47. Cancers are primarily an environmental disease with 90-95% of cases attributed to environmental factors and 5-10% due to genetics. • Environmental, as used by cancer researchers, means any cause that is not inherited genetically, not merely pollution. Common environmental factors that contribute to cancer death include tobacco (25-30%), diet and obesity (30-35%), infections (15-20%), radiation (both ionizing and non-ionizing, up to 10%), stress, lack of physical activity, and environmental pollutants.

48. Studies have shown that the primary determinants of most cancers are lifestyle factors, such as tobacco, dietary and exercise habits, environment carcinogens and infectious agents, rather than inherited genetic factors. • In fact, inherited cancer syndromes caused by high penetrance genes transmitted In fact, the proportion of cancers caused by high penetrance genes is low, about less than 5% for breast cancer and less for most other cancer types except retinoblastoma in children.

49. Pathophysiology • Cancer is fundamentally a disease of failure of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, the genes which regulate cell growth and differentiation must be altered. • Cancer occurs because of mutations in the genes responsible for cell multiplication and repair.

50. The affected genes are divided into two broad categories. • Oncogenes are genes which promote cell growth and reproduction. • Tumor suppressor genes are genes which inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. • Typically, changes in many genes are required to transform a normal cell into a cancer cell.