Gene And Disease基因与疾病

Deqiao Sheng PhD

shengdq@ctgu.edu.cnBiochemistry Department

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.

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.

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

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 o

bservable characteristics or traits: such as its morphology, development, biochemical or physiological properties, phenology, behavior, and products of behavior (such as a bird's nest).

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.

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

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.

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.

Hereditary Mutations

Fertilized Egg

Mutation Occurs

BrainPancreasBoneReproductive

Body Cells of Offspring

Mutation

SpermEgg

Acquired Mutations

Altered Bone Cells

Normal Bone Cell

Normal Bone Cells

Mutation Occurs

Altered Gene

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

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.

Classification of mutation types

By effect on structure– Point mutations (Silent mutations/Missense mut

ations/Nonsense mutations)

– Insertions

– Deletions (remove one or more nucleotides or large chromosomal regions from the DNA)

Insertion Deletion

By effect on function– Loss-of-function mutations

– Gain-of-function mutations

– Dominant negative mutations

– Lethal mutations

– back mutation or reversion

Altered DNA→Altered Protein

NucleusDNA

Protein

Chain of amino acids

Ribosome

Gene

DNA bases mRNA

Cell membrane

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)

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.

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

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).

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.

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

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.

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.

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

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.

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

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

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.

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.

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.

Asthma( 哮喘 ) autoimmune diseases cancers ciliopathies cleft palate diabetes heart disease hypertension

inflammatory bowel disease

mental retardation mood disorder obesity refractive error infertility

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.

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.

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.

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)

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:

–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.

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 mushr

ooms and a type of poison that can grow on peanut plants (aflatoxins)

– Excessive sunlight exposure– Genetic problems– Obesity– Radiation– Viruses

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.

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.

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.

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.

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.

The affected genes are divided into two broad categories. – Oncogenes are genes which promote cell growth and re

production. – Tumor suppressor genes are genes which inhibit cell div

ision 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.

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.

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.

Global status report on noncommunicable diseases 2010 (WHO)

Cancer is second leading cause of death

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

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.

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

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.

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.

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.

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 r

earrangement of genetic material

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

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)

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).

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 (suture

s)– 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 s

pots)

Children may also have delayed mental and social development. Common problems may include:– Impulsive behavior

– Poor judgment

– Short attention span

– Slow learning

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)

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.

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.

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

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.

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.