GENETICS AND GENOMICS
Genetics is the study of heredity, that is, those characteristics inherited by children from their parents.
-The functional unit of heredity is the gene and each gene is a certain portion of a Deoxyribonucleic acid (DNA) molecule but not necessarily a continuous stretch of DNA.
-Genes are carried on rod-shaped structures called Chromosomes, which consist of DNA molecules and their associated proteins that become visible as densely stained bodies during cell division.
-The transfer of genetic information between generations occurs through genes in the nuclei of eggs and sperm, via the process of meiosis.
-A gene nucleotide sequence tells a cell how to link a certain sequence of amino acids together to construct a specific protein molecule.
-All genes of one person are called the Genome and it is estimated a human has about 31, 000 to 35, 000 protein-encoding genes, which specify 100,000 to 200,000 different proteins.
-Somatic cells contain 23 pairs of chromosomes, or 46 total chromosomes and are said to be Diploid because they have two sets of chromosomes.
-Somatic cells are all the cells of the body except for the Gametes or Sex cells. Examples of somatic cells are epithelial cells, muscle cells, neurons, fibroblasts, lymphocytes and macrophages.
-The sperm and egg cells, which contain 23 individual chromosomes, are Haploid. They have half the amount of genetic material of other cell types, or one copy of the genome.
-Genomics are terms used to define the multiple, interacting genes in human body.
-Proteomics is a study that focuses on the spectrum of proteins that specific cell types produce.
-A proteomics approach to studying breast cancer, for example, compares the thousands of types of proteins in a healthy milk duct-lining cell to the proteins in the same type of cell that has become cancerous.
-The science of genetics has shown that genes provide our variability as well as illnesses, including eye, hair color and skin; height and body form; special talents; and hard-to-define characteristics such as personality traits.
-Although the environment can influence gene expression, people’s physical characteristics and abilities are largely determined by their genetic makeup.
-The environment includes the chemical, physical, social and biological factors surrounding an individual that influence his or her characteristics.
Modes of Inheritance:
The probability that a certain trait will occur in the offspring of two individuals can be determined by knowing how genes are distributed in meiosis and the combinations in which they can join at fertilization.
Chromosomes and Genes Come in Pairs: Human cell, resulting from conception, is a diploid, containing two copies of each of the 23 different chromosomes.
-A Karyotype is a chart of the chromosomes isolated from a cell at metaphase, arranged in order by size and structure.
-It reveals that most human cells, with the exception of germ cells, contain 23 pairs of similar-looking chromosomes (except for X and Y chromosomes).
-Two chromosomes, designated X and Y, determine sex are called Sex chromosomes.
-The other 22 pairs are called Autosomes.
-For convenience, the autosomes are numbered in pairs from 1 through 22, and sex chromosomes are denoted as X and Y chromosomes.
-Each chromosome carries many genes and the location of a particular gene on a chromosome is called its Locus.
-Homologous chromosomes have the same gene at the same locus, although they may carry different forms of that gene, called Alleles, which produce alternative forms of a particular trait.
-A person with two different alleles for a gene is Heterozygous for that gene, while an individual who has two identical alleles of a gene is said to be Homozygous for that gene.
-The alleles or genes that an individual possesses for a particular trait constitutes the Genotype and a person’s appearance or health condition is called the Phenotype.
-An allele is Wild Type if its associated phenotype is either normal function or the most common expression in a particular population. Wild type is denoted with a + sign.
-An allele is Mutant when a change in wild type occurs in which uncommon phenotype is produced. Disease-causing alleles are mutant.
Dominant and Recessive Inheritance: In heterozygotes, one allele determines the phenotype and such allele whose action masks that of another allele is said to be Dominant. When the allele whose expression is masked, Recessive allele occurs.
-Dominant alleles are usually indicated with a capital letter.
-A gene that causes a disease can be recessive or dominant and it may also be Autosomal (carried on a nonsex chromosome) or X-linked (carried on the X chromosome) Y-linked (carried on the Y chromosome).
-Whether a trait is dominant or recessive, autosomal or carried on a sex chromosome, is called its Mode of Inheritance.
-The mode of inheritance has important consequences in predicting the chance that an offspring will inherit an illness or trait. It has the following rules:
- a) In the heterozygous condition, an allele that is expressed when the other is not is dominant. The masked allele is recessive.
- b) Recessive and dominant genes may be autosomal or X-linked or Y-linked.
- c) An autosomal recessive condition affects both sexes and may skip generations. The homozygous dominant and heterozygous individuals have normal phenotypes. The heterozygous is a carrier and the affected individual inherits one mutant from each parent.
- d) An autosomal dominant condition affects both sexes and does not skip generations. A person inherits it from one parent, who is affected.
- e) Pedigrees and Punnett squares are used to depict modes of inheritance.
-A punnett square symbolizes the logic used to deduce the probabilities of a particular genotypes occurring in offspring.
-A pedigree is a diagram that depicts family relationships and genotypes and phenotypes when they are known.
-In an autosomal recessive illness, an affected person’s parents are usually carriers and they do not have the illness.
-In an autosomal dominant condition, an affected person typically has an affected parent.
-Most of the 300 or so known human inherited disorders are autosomal recessive. These conditions manifest symptoms very early, sometimes before birth.
-Autosomal dominant conditions often have an adult onset.
Different Dominance Relationships: Most genes exhibit complete dominance or recessiveness, but there are two other exception namely: a) Incomplete Dominance and b) Codominant.
1) In Incomplete dominance, the dominant gene does not completely mask the effect of the recessive gene. In this case the individual has two abnormal or disease causing alleles.
-An example of incomplete dominance is Familial Hypercholesterolemia (FH), in which a gene responsible for producing Low Density Lipoprotein (LDL) receptors on the liver cells that take up cholesterol from blood stream is abnormal.
-Individuals with two abnormal alleles die of heart attacks in childhood, those with only one abnormal allele (a Heterozygote) have half the normal number of cholesterol receptors and they also die as young adults.
-The people with two wild or normal alleles do not develop this type of hereditary heart disease, in short they do have normal life expectancies.
-Another type of incomplete dominance is Sickle cell disease, in which a gene responsible for producing hemoglobin in red blood cells is abnormal.
-The result is red blood cells that are stretched into elongated sickle shaped, and the cells tend to stick in capillaries, thereby blocking blood flow to tissues.
-In addition, the sickle-shaped cells tend to rupture more easily than normal red blood cells.
-A person with genotype SS has a normal hemoglobin, while a person with sickle cell disease has genotype ss and has abnormal hemoglobin.
2) In Codominant, two alleles can combine to produce an effect without either of them being dominant or recessive.
-An example is two of the three alleles of the I gene, which determines ABO blood type.
-People of type A have a molecule called antigen A on the surfaces of their red blood cells, and blood type B corresponds to red blood cells with antigen B.
-A person with type AB has red blood cells with both the A and B antigens and Type O means that neither of the antigens (AB) is present.
-The I gene encodes the enzymes that place the A and B antigens (Glycoproteins) on red blood cell surfaces.
-The three alleles are IA, IB and i. People with type A blood may be either genotype IAIA or IA I; type B may be IBIB or IB I; type AB to IAIB; and type O to ii.
Gene Expression:
The same gene or allele combination can produce different degrees of phenotype in different individuals because of influences such as nutrition, exposure to toxins, other illnesses and the activities of other genes.
A major goal of genomics will be to identify and understand these interactions.
Penetrance and Expressivity: Penetrance is the percentage of a population with a given geneotype that actually exhibits the predicted phenotype. If 80 of 100 people who have inherited the dominant Polydactyly allele have extra digits, the allele is 80% penetrant.
-A genotype is incompletely penetrant if not all individual inheritng it express the phenotype.
-A genotype is variably expressive if it is expressed to different degrees in different individual. This completely penetrant, which means that everyone who inherits the disease-causing allele will exhibit the trait.
-For example, both polydactyly and inherited breast cancer are incompletely penetrant, that is, not all people or women who inherit mutant gene for polydactyly or called BRCA1 respectively have extra fingers or toes or the cancer.
-A phenotype is Variably Expressive if the symptoms vary in intensity in different people.
Penetrance refers to the all-or-none expression of a genotype in an individual; expressivity refers to the severity of a phenotype.
Pleiotropy: Pleiotropy is a phenomenon in which one gene produces multiple phenotypic effects.
-For example, sickle-cell disease is caused by a recessive allele that changes one amino acid in hemoglobin. It causes RBCs to assume an abnormally elongated, pointed shape when oxygen levels are low, and it makes them sticky and fragile.
-As RBCs rupture, a person becomes anemic, and the spleen becomes enlarged. Because of the deficiency of RBCs, the blood carries insufficient oxygen to the tissues, resulting in multiple, far reaching effects on different parts of the body.
-Another example is Marfan syndrome, an autosomal dominant defect in an elastic connective tissue protein called Fibrillin.
-Since there is abundance of fibrillin in the lens of the eye, in the bones of the limbs, fingers and ribs and in the aorta explains the symptoms of lens dislocation, long limbs, spindly fingers and a caved-in chest.
-The most serious symptom is a life-threatening weakening in the aorta wall, which sometimes causes the vessel to suddenly burst.
Genetic Heterogeneity: Genetic heterogeneity refers to the phenotype that can be caused by alterations in more than one gene.
-For example, the nearly 200 forms of hereditary deafness are each due to impaired actions of a deferent gene.
-The same symptoms may result alterations in genes whose products are enzymes in the same biochemical pathway.
Complex Traits:
Most of the inherited disorders mentioned so far are Monogenic-that is, they are determined by a single gene, and their expression is usually not greatly influenced by the environment.
-Most of the characteristics and disorders reflect input from the environment as well as genes.
-On the other hand, a trait caused by the action of more than one gene is called Polygenic. For example, Height, skin color and eye color are polygenic trait.
-Polygenic traits typically are characterized by having a great amount of variability.
-Because of the many genes involved, it is difficult to predict how a polygenic trait will be passed from one generation to the next.
-Trait molded by one or more genes plus the environment are termed Complex Traits.
-For example, height, skin and eye colors and common illnesses such as heart disease, diabetes mellitus, hypertension and cancers are complex traits.
-A frequency distribution for a polygenic trait forms a bell curve.
Matters of Sex:
A male has one X and one Y chromosome and he is called Heterogametic sex, a female has two X chromosomes and she is called Homogametic sex.
Sex Determination: A male zygote forms when a Y-bearing sperm fertilizes an egg, while a female zygote forms when an X-bearing sperm fertilizes an egg.
-A gene on the Y chromosome, called SRY, switches on genes in the embryo that promote development of male characteristics and suppresses genes that promote development of female characteristics.
-Because a female lacks a Y chromosome, she also lacks an SRY gene.
Sex Chromosomes and Their Genes: The X chromosome has more than 1,000 genes and the Y chromosome has only a few dozen genes.
-The genes on the sex chromosomes are inherited differently than those on autosomes because the sexes differ in sex chromosomes constitution.
Y-linked genes are considered in through groups, based on their similarity to X-linked genes.
1) The first group consists of genes at the tips of the Y chromosome that have counterparts on the X chromosome.
-These genes encode a variety of proteins that function in both sexes, involve in or controlling such activities as Bone growth, signal transduction, synthesis of hormones and receptors and energy metabolism.
2) The second group of Y-linked genes are very similar to genes on the X chromosome, but they are not identical.
-These genes are expressed in nearly all tissues, including those found only in males.
3) The third group of genes includes those unique to the Y chromosome.
-Many of them control Male Fertility, such as SRY gene. Some genes encode proteins that participate in cell cycle control, regulate gene expression, enzymes and protein receptors.
Males are Hemizygous for X-linked traits; that is , they can have only one copy of an X-linked gene, because they have only one X chromosome.
Females can be heterozygous or homozygous for genes on the X chromosome, because they have two copies of it.
-A male always inherits his Y chromosome from his father and his X chromosome from his mother, while a female inherits one X chromosome from each parent.
-For X-linked recessive traits that seriously impair health, affected males may not feel well to have children.
-Dominant X-linked traits are rarely seen because affected males typically die before birth.
Gender Effects on Phenotype: Certain autosomal traits are expressed differently in males and females, due to differences between the sexes.
1) A Sex-limited trait affects a structure or function of the body that is presenting only males or only females and such a gene may be X-linked or autosomal.
-For example, Beard growth and Breast Size are sex-limited traits and in animal breeding, milk yield and horn development are important sex-limited traits.
2) In Sex-Influence inheritance, the traits or alleles are dominant in one sex but recessive in the other.
-For example, the baldness allele is dominant in males but recessive in females, which is why more men than women are bald.
-A heterozygous male is bald, but a heterozygous female is not and a bald woman would have two mutant alleles.
About 1% of human genes exhibit Genomic Imprinting, in which the expression of a disorder differs depending upon which parent transmits the disease-causing gene or chromosome.
-The phenotype may differ in degree of severity, in age of onset or even in the nature of the symptoms.
Chromosome Disorders:
Abnormalities in a person’s genetic makeup, that is, in his or her DNA, cause genetic or chromosome disorder.
-Extra, missing, or rearranged chromosomes or parts of them can cause syndromes, because they either cause an imbalance of genetic material or disrupt a vital gene.
-Rearrangement of chromosomes disrupts a vital gene and results in unbalanced gametes that contain too little or too much genetic material.
Polyploidy and Aneuploidy are words that take a closer look at specific types of chromosome disorders.
1) Polyploidy: It is an extra chromosome set.
-Polyploidy results from fertilization involving a Diploid Gamete instead of Haploid gamete and the fertilized egg is Triploid.
-Most human polyploids do not survive beyond a few days of birth and they cease to develop as embryos of fetuses.
-Polyploidy is common in flowering plants but rare in animals.
2) Aneuploidy: Cells with extra or missing chromosome are aneuploid.
-Aneuploidy results from Nondisjunction, in which a chromosome pair does not separate, either in meiosis I or meiosis II, producing a gamete with a missing or extra chromosome.
-If it is fertilized by an X-bearing sperm, the result is Trisomic and Monosomic zygote.
-A cell with an extra chromosome is trisomic and a cell with a missing chromosome is momosomic.
-Individuals with trisomies are more likely to survive to be born than those with monosomies.
-Sex chromosome aneuploids are less severely affected than are autosomal aneuploids.
-XO or Turner syndrome affects 1 in 2,000 newborn girls and often the only symptom is a lag in sexual development, with hormone supplements, life can be fairly normal, except for fertility.
-Males with an extra X chromosome have XXY or Klinefelter syndrome and many males encounter fertility problems.
-XXY males have sexual underdevelopment, which includes rudimentary testes and prostate glands and no pubic or facial hair, growth of breast tissue, long limbs and large hands and feet. It affects 1 in every 500 to 2,000 male births.
-Another sex chromosome aneuploid in which the male has an extra Y chromosome, called XYY or Jacobs syndrome, which affects 1 in 1,000.
-Associated characteristics are great height, acne, and speech and reading problems.
-Aneuploidy accounts for about 50% of Spontaneous Abortions and it can be detected prior to birth by Amniocentesis, the examination of cells in a sample of amniotic fluid or by Chorionic Vallus Sampling, the removal and examination of cells from the Chorion.
Prenatal Tests: Several types of tests performed on pregnant women can identify anatomical or physiological features of fetuses that can indicate or detect the abnormal chromosomes. They are:
1) Ultrasound can detect large-scale structural abnormalities and assess growth.
2) Maternal serum maker tests indirectly detect a small fetal liver, which can indicate a trisomy.
3) Amniocentesis samples and examines fetal chromosomes in amniotic fluid.
4) Chorionic villus sampling (CVS) obtains and examine chorionic villus cells, which descend from the fertilized egg and therefore are presumed to be genetically identical to fetal cells.
5)Fetal cell sorting obtains and analyzes rare fetal cells in the maternal circulation.
Gene Therapy:
Knowledge of the genes involved in a disorder may result in Gene Therapy or Genetic Engineering that repairs or replaces defective genes, resulting in cures of genetic disorders.
-Gene therapy operates at the gene level, but treatment of some inherited disorders at the protein level.
-For example, a person with hemophilia receives the missing protein clotting factor and someone with cystic fibrosis takes cow digestive enzymes to compensate for poor pancreatic function.
Two Approaches to Gene Therapy: There are two types of gene therapy: a) Heritable Gene Therapy (Germline Gene Therapy) and b) Nonheritable Gene Therapy (Somatic Gene Therapy).
1) Heritable gene therapy alters all genes in an individual and therefore must be done on a gamete or fertilized egg.
-It is not done in humans but it is useful in other species such as transgenic mice, cows and goats and transgenic crop plants.
2) Nonheritable gene therapy targets only affected cells and therefore cannot be transmitted to the next generation.
-It replaces or corrects defective genes in somatic cells, often those in which symptoms occur.
Tools and Targets of Gene Therapy: Researchers use several methods to introduce therapeutic genes into cells.
-The healing genes are sent into cells in Viruses, Liposomes, Blasted in or as naked DNA.
-Good target structures for gene therapy include the following:
- a) Bone Marrow: Bone marrow tissue the precursor of all mature blood cells. It provides a route to treat blood disorders and immune deficiencies.
-Certain stem cells in bone marrow can also travel to other sites, such as muscle, liver and brain and differentiate there into, respectively, muscle, liver or neural cells.
- b) Skin: Skin cells grow well in the laboratory and it can be grafted back onto the person.
-Skin grafts genetically modified to secrete therapeutic proteins, such as enzymes, clotting factors or growth hormones and may provide a new drug delivery route.
- c) Muscle: Muscle tissue is a good target for gene therapy for several reasons.
-It comprises about half of the body’s mass, is easily accessible and is near blood supply.
- d) Liver: Liver is a very important focus of gene therapy because it controls many bodily functions and because it can regenerate.
- e) Lungs: Respiratory tract is an excellent candidate for gene therapy because an aerosol can directly reach its lining cells, making it unnecessary to remove cells, alter and reimplant them.
-The lung epithelial cells take up inhaled genes and produce the proteins missing.
- f) Endothelium: It is the tissue, which forms capillaries and lines the interiors of other blood vessels. It can be altered to secrete a substance directly into the bloodstream.
- g) Nerve tissue: Gene therapy of neurons is not feasible because these cells do not divide.
- h) Gene Therapy Against Cancer: Viruses may provide a treatment for a type of Brain tumor called a Glioma, which affects neuroglial cells.
-Cancerous neuroglial cells divide very rapidly, usually causing death with a year, even with aggressive treatment.
Genomics and a New View of Anatomy and Physiology: Today , human genetics and genomics have shifted focus to normal variations as well as conditions molded by interactions among genes and environmental factors.
-With this new way of looking at ourselves, physiology is not only being dissected at the cellular level, but at the level of the chemical signals that enable cells to interact to form tissues, and tissues to form organs.