1. Biochemistry Department
Gene And Disease 基因与疾病
Deqiao Sheng PhD
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
Gene mutations can be either inherited from a parent or acquired.
Hereditary mutations are carried in the DNA of the reproductive cells. When reproductive cells containing mutations combine to produce offspring, the mutation will be in all of the offspring’s body cells. The fact that every cell contains the gene change makes it possible to use cheek cells or a blood sample for gene testing.
Reproductive
Bone
Pancreas
Brain
Body Cells of Offspring

11. Acquired Mutations Normal Bone Cell Mutation Occurs Altered Gene
Acquired mutations are changes in DNA that develop throughout a person’s lifetime.
Although mistakes occur in DNA all the time, especially during cell division, a cell has the remarkable ability to fix them. But if DNA repair mechanisms fail, mutations can be passed along to future copies of the altered cell.
Altered Bone Cells
Normal Bone Cells

12. Induced mutation (by mutagens):
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 regions from 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. Altered DNA→Altered Protein
Cell membrane
DNA
Nucleus
Chain of amino acids
DNA bases
mRNA
Gene
Protein
When a gene contains a mutation, the protein encoded by that gene is likely to be abnormal.
Sometimes the protein will be able to function, but imperfectly. In other cases, it will be totally disabled. The outcome depends not only on how it alters a protein’s function but also on how vital that particular protein is to survival.
Altered DNA→Altered Protein
Ribosome

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.

25. Type or protein from mutant gene
Example
Clinical disorder
Enzyme
Phenylalanine hydroxylase
Adenosine deaminase
Phenylketonuria
Severe combined immune deficiency (SCID)
Enzyme inhibitor
Alpha-1-antitrypsin
Emphysema and liver disease
Membrane receptor
Low-density lipo-protein receptor
Familial hypercholesterolemia
Membrane ion channel
Cystic fibrosis transmembrane conductance regulator
Cystic Fibrosis
Structural protein
Hemoglobin
Fibrillin
Dystrophin
Sickle cell disease
Marfan’s syndrome
Muscular dystrophy
Cell growth inhibitor
NF-1
Neurofibromatosis
Tumor suppressor
Rb protein
Retinoblastoma
Clotting factor
Factor VIII
Hemophilia

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
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. Sickle Cell Hemoglobin
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
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 ( deaths)
liver ( deaths)
colorectal ( deaths)
breast ( deaths)
cervical cancer ( 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 causes of cancers, including:
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
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.

51. Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.

52. The mutation of critical genes, including supressor genes, oncogenes and genes involved in DNA repair, leads to genetic instability and to progressive loss of differentiation.

54. Global status report on noncommunicable diseases 2010 (WHO)
Cancer is second leading cause of death

55. Estimated annual number of new cases and deaths for the 10 most common cancers, by World Bank income groups and by sex, 2008

56. Cardiovascular disease
Major cardiovascular diseases (CVD) include coronary heart disease, cerebrovascular disease, heart failure, rheumatic heart disease and congenital heart disease. The major risk factors associated with cardiovascular diseases are cigarette smoking, unhealthy diet, physical inactivity, hypertension, diabetes and high blood cholesterol.

57. CVD may also result from a variety of genetic causes, including single-gene mutations, the interaction of multiple genes and environmental factors. Economic transition, urbanisation, industrialization and globalisation bring about lifestyle changes that promote heart disease. Life expectancy in developing countries is rising sharply and people are exposed to these risk factors for longer periods

58. Of the estimated 16.6 million deaths attributed to CVD worldwide, 80% is in developing countries. By 2010, CVD is estimated to be the leading cause of death in developing countries.

59. Cardiovascular disease is a class of diseases that involve the heart or blood vessels (arteries, capillaries and veins). Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease. The causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common.

60. Almost all cardiovascular disease in a population can be explained in terms of a limited number of risk factors: age, gender, high blood pressure, high serum cholesterol levels, tobacco smoking, excessive alcohol consumption, family history, obesity, lack of physical activity, psychosocial factors, diabetes mellitus, air pollution. While the individual contribution of each risk factor varies between different communities or ethnic groups the consistency of the overall contribution of these risk factors is remarkably strong.

61. Chromosomal Disorders
Numerical (aneuploidy)
Monosomies (loss of one copy of chromosome)
If autosome affected, usually incompatible with life
Sex chromosome monosomies are compatible with life
Trisomies (extra copy of chromosome)
Structural
Result form chromosome breakage followed by loss or rearrangement of genetic material

62. Chromosomal Disorders
Loss of chromosomal material produces more severe defects than does gain
Excess chromosomal material may result for complete chromosome (trisomy) or part of a chromosome
Imbalances of sex chromosomes are better tolerated than imbalances of autosomes

63. Chromosomal Disorders
Aneuploidy of Sex Chromosomes
Turner’s Syndrome (45, X0)
Poly X Female (45 XXX)
Kleinfelter’s Syndrome (47, XXY)
XYY Males
Trisomy of Autosomes
Trisomy 21 (Down Syndrome)
Trisomy 13 (Patau’s Syndrome)
Trisomy 18 (Edward’s Syndrome)

64. Down Syndrome
Down Syndrome is a type of mental retardation caused by extra genetic material in chromosome 21. This can be due to a process called nondisjunction, in which genetic materials fail to separate during a crucial part of the formation of gametes, resulting in an extra chromosome (called trisomy 21).

66. Common physical signs include:
Decreased muscle tone at birth
Excess skin at the nape of the neck
Flattened nose
Separated joints between the bones of the skull (sutures)
Single crease in the palm of the hand
Small ears
Small mouth
Upward slanting eyes
Wide, short hands with short fingers
White spots on the colored part of the eye (Brushfield spots)

67. Children may also have delayed mental and social development
Children may also have delayed mental and social development. Common problems may include:
Impulsive behavior
Poor judgment
Short attention span
Slow learning

68. Mitochondrial disorders
Mitochondrial disorders: are rare disorders caused by mutations in non-chromosomal DNA located within the mitochondria. (The mitochondria are subcellular organelles.) These disorders can be found to affect any part of the body including the brain and the muscles.
Mitochondria DNA (mtDNA)

69. Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell.
Mitochondria are found in every cell of the human body except red blood cells.
Mitochondria convert the energy of food molecules into the ATP that powers most cell functions.

70. Mitochondrial DNA can be regarded as the smallest chromosome
Mitochondrial DNA can be regarded as the smallest chromosome. Human mitochondrial DNA was the first significant part of the human genome to be sequenced. In most species, including humans, mtDNA is inherited solely from the mother.

71. Depending on which cells are affected, symptoms may include loss of motor control, muscle weakness and pain, gastro-intestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, seizures, visual/hearing problems, lactic acidosis, developmental delays and susceptibility to infection

72. Mitochondrial diseases are the result of either inherited or spontaneous mutations in mtDNA or nDNA which lead to altered functions of the proteins or RNA molecules that normally reside in mitochondria.
Diseases of the mitochondria appear to cause the most damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.

73. The unique features of mitochondrial genetics are essential for the understanding of the etiology and pathogenesis of mitochondrial disorders.
Normally, all mitochondria of a human subject contain genetically identical mtDNA copies (homoplasmy). However, the mtDNA has a mutation rate approximately 10–20 times higher than that of the nuclear DNA.