BIO 101_Genetics for Medical Studies.pdf

BIO 101_GENETICS FOR MEDICAL STUDIES Genetics: Genetics is the scientific study of genes and heredity—of how certain qualities or traits are passed from parents to offspring as a result of changes in DNA sequence. A gene is a segment of DNA that contains instructions for building one or more mole...

BIO 101_GENETICS FOR MEDICAL STUDIES Genetics: Genetics is the scientific study of genes and heredity—of how certain qualities or traits are passed from parents to offspring as a result of changes in DNA sequence. A gene is a segment of DNA that contains instructions for building one or more molecules that help the body work. The complete set of genetic material within an organism, encompassing both genes and regulatory elements governing gene activity, constitutes its genome. This genetic blueprint is present in virtually all cells of an organism. In the case of human, plant, and animal cells, the genome is contained within a structure known as the nucleus. Interestingly, the majority of the human genome remains consistent across all individuals, with only minor variations distinguishing one person from another. Heredity: In the simplest of words, heredity refers to the passing of traits or characteristics through genes from one generation (parent) to the other generation (offspring). The offspring, get their features and characteristics that is genetic information from their mother and father. The impact of heredity is particularly noticeable in sexual reproduction, where there is a significant variation in the traits that are passed on. Genetic variation occurs as a result of some errors in DNA replication (copying). Variation holds significant importance as it drives evolution and serves as the foundation of heredity. It results from a combination of factors, including gene mutations, interactions between genes and the environment, and diverse combinations of genetic material. It's worth noting that even during asexual reproduction, variation can occur, although it may not be as visibly pronounced as in sexual reproduction. Some Terms useful in Genetics and Hereditary Studies  Gene – The fundamental element of inheritance, comprising a sequence of DNA, the carrier of genetic information. Genes have the capacity to undergo mutations and can exist in two or more alternative variations.  Alleles – These are alternative versions of genes and influence the same characteristics or traits but in different forms. Alleles are situated at the same position on a chromosome.  Chromosomes – These are thread-like structures made up of nucleic acids (DNA) and proteins. They are mostly found in the nucleus of the cells. They carry the hereditary or genetic information in the form of genes.  Genotype – It is the complete heritable genetic identity of an organism. It is the set of alleles that are carried by the organism. It also includes non-expressed alleles.  Phenotype – It is the description of the actual physical characteristics of an organism or the expressed form of the genotype.  Dominant alleles – When an allele affects the phenotype of an organism, then it is a dominant allele. Capital letters represent dominant alleles. For example, “T” to express tallness.  Recessive alleles – An allele that affects the genotype in the absence of the dominant allele is called a recessive allele. Small letters represent recessive alleles. For example – “t” for tallness.  Homozygous – Each organism has two alleles for every gene (Each chromosome has one each). In homozygous, both the alleles are same. For Example, “TT” is the homozygous expression for tallness trait.   Heterozygous – If the two alleles are different from each other, then they are heterozygous in nature. For Example, “Tt” is the heterozygous expression for tallness trait. GENETIC BASICS OF SOME HUMAN DISEASES (CANCER, DIABETES) AND VARIABILITY (PHARMACOGENETICS) While human diseases can have numerous causes, family history frequently stands out as one of the most influential risk factors for common and complex conditions like cancer, cardiovascular disease (CVD), diabetes, autoimmune disorders, and mental health disorders. Each person inherits a full complement of genes from both parents, alongside a wide range of cultural and socioeconomic experiences from their family. Family history is considered a robust predictor of an individual's disease susceptibility since family members closely embody the unique genetic and environmental interactions that an individual encounters. It's evident that inherited genetic variations within families play a significant role in both the direct and indirect development of diseases. A genetic disease refers to any medical condition that results from an anomaly in an individual's genetic composition. This genetic anomaly can vary widely in scale, ranging from a minor alteration, such as a single base mutation in a single gene, to a more significant abnormality involving entire chromosomes or sets of chromosomes through additions or deletions. Certain individuals receive genetic disorders through inheritance from their parents, while other genetic diseases arise from acquired alterations or mutations in preexisting genes or gene groups. These genetic mutations may emerge sporadically or be triggered by environmental factors. Types of genetic disorders There are four different types of genetic disorders (inherited) and include: 1. Single gene inheritance 2. Multifactorial inheritance 3. Chromosome abnormalities 4. Mitochondrial inheritance 1. Single Gene Inheritance Disorders Single gene inheritance, often referred to as Mendelian or monogenetic inheritance, is characterized by alterations or mutations in the DNA sequence of an individual gene leading to this type of inheritance. There exist numerous recognized single-gene disorders, also termed monogenetic disorders, each associated with an anomaly in a single gene. Single-gene disorders have different patterns of genetic inheritance, including  autosomal dominant inheritance, in which only one copy of a defective gene (from either parent) is necessary to cause the condition. Examples of conditions involving autosomal dominant inheritance include the Marfan syndrome, Huntington's disease and Neurofibromatosis);  autosomal recessive inheritance, in which two copies of a defective gene (one from each parent) are necessary to cause the condition. Examples of conditions involving autosomal recessive inheritance include cystic fibrosis, sickle cell anemia (sickle cell disease), hemochromatosis, Tay-Sachs disease, alpha- and beta-thalassemias; and  X-linked inheritance, in which the faulty gene is situated on the X-chromosome, primarily affecting females. In X-linked inheritance, the gene can exhibit either dominant or  recessive characteristics. Some X-linked traits in humans include color blindness, muscular dystrophy, hemophilia, congenital deafness, spinal ataxia, ocular albinism, brown teeth, congenital cataract, retinitis pigmentosa, diabetes insipidus, etc. The X-linked inheritance for a particular gene in females may either be homozygous or heterozygous 2. Multifactorial Genetic Inheritance Disorders Multifactorial inheritance is also called complex or polygenic inheritance. Multifactorial inheritance disorders are caused by a combination of environmental factors and mutations in multiple genes. For example, different genes that influence breast cancer susceptibility have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22. Some common chronic diseases are multifactorial disorders. Examples of multifactorial inheritance include 1. Heart disease, 2. High blood pressure, 3. Alzheimer's disease, 4. Arthritis, 5. Diabetes, 6. Cancer, and 7. Obesity. Multifactorial inheritance also is associated with heritable traits such as fingerprint patterns, height, eye color, and skin color. 3. Chromosomal Abnormalities Chromosomes are distinct structures that made up of DNA and proteins, and reside within the nucleus of every cell. As they serve as the vehicles for genetic information, any disruption/ disturbance in the number or structure of chromosomes can lead to medical conditions. These chromosomal abnormalities usually arise from issues during the process of cell division. There are four main types of structural chromosomal aberrations, and they are; deletion, duplication, inversion, and translocation. Down syndrome (sometimes referred to as "Down's syndrome") or trisomy 21 is a common genetic disorder that occurs when a person has three copies of chromosome 21. There are several other chromosomal abnormalities which include: -Edward's syndrome or trisomy 18; -Patau syndrome or trisomy 13; -Cri du chat syndrome or 5p minus syndrome (partial deletion of short arm of chromosome 5); -Wolf-Hirschhorn syndrome or deletion 4p syndrome; -Jacobsen syndrome or 11q deletion disorder; -Klinefelter's syndrome or presence of additional X chromosome in males; -Turner syndrome or presence of only a single X chromosome in females; -XYY syndrome and XXX syndrome. 4. Mitochondrial Genetic Inheritance Disorders This type of genetic disorder is caused by mutations in the non-nuclear DNA of mitochondria. Mitochondria are small round or rod-like organelles that are involved in cellular respiration and found in the cytoplasm of plant and animal cells. Each mitochondrion may contain 5 to 10 circular pieces of DNA. Since egg cells, but not sperm cells, keep their mitochondria during fertilization, mitochondrial DNA is always inherited from the female parent. Examples of the mitochondrial disease include 1. Leber's hereditary optic atrophy (LHON), an eye disease; 2. Myoclonic epilepsy with ragged red fibers (MERRF); and 3. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a rare form of dementia. CANCER Defined: Cancer is a group of diseases characterized by the uncontrolled division of abnormal cells. It is a complex and multifaceted disease with a genetic basis. In the most basic terms, cancer refers to cells that grow out-of-control and invade other tissues. Cells may become cancerous due to the accumulation of defects, or mutations, in their DNA. Certain inherited genetic defects (for example, BRCA1 and BRCA2 mutations) and infections can increase the risk of cancer. Environmental factors (for example, air pollution) and poor lifestyle choices—such as smoking and heavy alcohol use—can also damage DNA and lead to cancer. Most of the time, cells are able to detect and repair DNA damage. If a cell is severely damaged and cannot repair itself, it usually undergoes so-called programmed cell death or apoptosis. Cancer occurs when damaged cells grow, divide, and spread abnormally instead of self-destructing as they should. Malignant Tumors Vs. Benign Tumors A tumor is an abnormal mass of cells. Tumors can either be benign (non-cancerous) or malignant (cancerous). Benign Tumors Benign tumors grow locally and do not spread. As a result, benign tumors are not considered cancer. They can still be dangerous, especially if they press against vital organs like the brain. Malignant Tumors Malignant tumors have the ability to spread and invade other tissues. This process, known as metastasis, is a key feature of cancer. There are many different types of malignancy based on where a cancer tumor originates. Cancer Metastasis Metastasis is the process whereby cancer cells break free from a malignant tumor and travel to and invade other tissues in the body. Cancer cells metastasize to other sites via the lymphatic system and the bloodstream. Cancer cells from the original or primary tumor can travel to other sites such as the lungs, bones, liver, brain, and other areas. These metastatic tumors are "secondary cancers" because they arise from the primary tumor. Metastatic cancer retains the name of the primary cancer. For example, bladder cancer that metastasizes to the liver is not liver cancer. It is called metastatic bladder cancer. Metastasis is significant because it helps determine the staging and treatment. Some types of metastatic cancer are curable, but many are not. Table showing the estimated numbers of new cases and deaths for common cancer types (National Cancer Institute 2022) Types of Cancer Cancer can occur anywhere in the body. Broadly, cancers are classified as either solid (for example breast, lung, or prostate cancers) or liquid (blood cancers). Cancer is further classified according to the tissue in which it arises. Carcinoma: Carcinomas are cancers that occur in epithelial tissues in the body. They comprise 80% to 90% of all cancers. Most breast, lung, colon, skin, and prostate cancers are carcinomas. This class includes the two most common skin cancers, basal cell carcinoma and squamous cell carcinoma. Also in this class is the glandular cancer adenocarcinoma. Sarcoma Cancer: Sarcomas occur in connective tissue like the bones, cartilage, fat, blood vessels, and muscles. This class of cancers includes the bone cancers osteosarcoma and Ewing sarcoma, Kaposi sarcoma (which causes skin lesions), and the muscle cancers rhabdomyosarcoma and leiomyosarcoma. Myeloma Cancer: Myelomas are cancers that occur in plasma cells in the bone marrow. This class of cancer includes multiple myeloma, also known as Kahler disease. Leukemia: Leukemias are a group of different blood cancers of the bone marrow. They cause large numbers of abnormal blood cells to enter the bloodstream. Lymphoma Cancer: Lymphomas are cancers of the immune system cells. These include the rare but serious Hodgkin lymphoma (Hodgkin’s lymphoma, also Hodgkin’s disease) and a large group of white blood cell cancers known collectively as non-Hodgkin lymphoma (non-Hodgkin’s lymphoma). Mixed Cancer: Mixed cancers arise from more than one type of tissue. The Genetic Basis of Cancer Cancer is a genetic disease in which malignant cells have undergone mutations and epigenetic changes but maintain the transformed phenotype even when cultured or when injected into immunologically tolerant experimental animals. However, most of the genetic events in tumors are somatic (i.e., not hereditary), brought about environmentally or randomly, and the identified inherited (often referred to as “genetic”) causes account for a small proportion of all cancers. Specifically, the genes with mutations that are relevant to the carcinogenic process, fall into two classes: tumor suppressor genes and oncogenes. The distinction between heritable and environmental causes may be easily made if a hereditary cancer syndrome or an environmental exposure, such as tobacco smoking or human papilloma virus, poses a high risk. Role of Mutations: Genetic mutations play a central role in the development of cancer. These mutations can be caused by various factors, including exposure to carcinogens, radiation, and genetic predisposition. In essence, cancer can be characterized as a disease that results from genetic mutations and epigenetic alterations, such as abnormalities in DNA methylation. Among these alterations, mutations are more prevalent and can manifest as missense mutations (changing amino acids), frameshift mutations (disrupting the reading frame), or nonsense mutations (leading to protein truncation). In some cases, mutations don't impact the amino acid sequence but rather affect regulatory regions like promoters or splice sites. Additionally, there are DNA sequence variations, known as polymorphisms, which may not directly and definitively relate to the observed traits but could still play a role in cancer susceptibility or development. Genes involved in cancer can be classified into two main categories: Proto-oncogenes and Tumor suppressor genes Proto-oncogenes: Genes that promote normal cell growth but can become oncogenes when mutated. Tumor suppressor genes: Genes that inhibit cell growth and prevent cancer. Mutations in these genes can lead to uncontrolled cell growth. Genetic Factors in Cancer Susceptibility Hereditary vs. Sporadic Cancers: Understanding the distinction between hereditary and sporadic cancers is crucial. Hereditary cancers: These result from inherited genetic mutations that predispose individuals to specific cancer types. Sporadic cancers: Arise from random mutations and are not strongly influenced by genetics. BRCA Genes and Breast Cancer: An example of hereditary cancer is breast cancer associated with mutations in BRCA1 and BRCA2 genes. These genes play a crucial role in repairing DNA damage and maintaining genomic stability. Mutations in BRCA1 and BRCA2 significantly increase the risk of breast and ovarian cancer. Mechanisms of Oncogenesis The Process of Oncogenesis: The development of cancer involves multiple stages, including: Initiation: The initial genetic mutation that disrupts normal cell function. Promotion: Further cell division and accumulation of mutations. Progression: The development of a full-blown tumor with invasive properties. Hallmarks of Cancer: There are several key characteristics of cancer cells, including uncontrolled growth, evasion of apoptosis, and angiogenesis (formation of new blood vessels to support tumor growth). Diabetes and Genetics "Diabetes and Genetics" refers to the intersection of the genetic factors that contribute to the development, progression, and risk of diabetes. This field of study investigates how an individual's genetic makeup can influence their susceptibility to diabetes, the type of diabetes they may develop, and their response to diabetes treatments. Understanding the genetic aspects of diabetes is crucial for developing more personalized and effective approaches to its prevention and management. Diabetes: Diabetes is a chronic medical condition that occurs when the body is unable to properly regulate the levels of sugar (glucose) in the blood. Glucose is a primary source of energy for the body's cells, and its concentration in the bloodstream is tightly controlled by the hormone insulin, which is produced by the pancreas. Disease condition may occurs either when the pancreas does not produce enough insulin (a hormone that regulates blood glucose) or when the body cannot effectively use the insulin it produces. There are two main types of diabetes: 1. Type 1 Diabetes: This is an autoimmune condition where the immune system attacks and destroys the insulin-producing cells in the pancreas for unknown reasons. As a result, people with Type 1 diabetes do not produce insulin and require lifelong insulin therapy. 2. Type 2 Diabetes: This is the more common form of diabetes. It occurs when the body's cells become resistant to the effects of insulin (insulin resistance), or when the pancreas does not produce enough insulin to meet the body's needs. Type 2 diabetes is often associated with lifestyle factors, such as poor diet, lack of physical activity, and obesity. Other formes of diabetes include Prediabetes, Gestational diabetes, Type 3c diabetes, Latent autoimmune diabetes in adults (LADA), Maturity-onset diabetes of the young (MODY), Neonatal diabetes, Brittle diabetes.  Genetic Basis of Diabetes Role of genetics in diabetes risk The genetic mutations that cause diabetes involve the proteins responsible for insulin production or the ability of the body to use insulin. Mutations cause the proteins to function improperly. Genetic testing can identify these mutations in certain cases, but the usefulness of the information they provide varies. The role of genetics in diabetes risk is significant, and it varies depending on the type of diabetes. 1. Type 1 Diabetes:  Genetic Susceptibility: Type 1 diabetes is believed to have a strong genetic component. Certain genes, primarily those within the human leukocyte antigen (HLA) complex, are associated with an increased risk of Type 1 diabetes. Individuals with specific HLA genotypes are more likely to develop this autoimmune form of diabetes.  Family History: Having a family member with Type 1 diabetes, particularly a first-degree relative (parent or sibling), increases an individual's risk.  Environmental Triggers: While genetics plays a crucial role in susceptibility, environmental factors like viral infections or dietary influences can also trigger the development of Type 1 diabetes in those with genetic predispositions. 2. Type 2 Diabetes:  Polygenic Disorder: Type 2 diabetes is a complex, polygenic disorder influenced by multiple genetic variants. Unlike Type 1 diabetes, where specific genes have a dominant impact, Type 2 diabetes risk involves the interplay of numerous genetic factors.  Family History: Having a family history of Type 2 diabetes increases one's risk. If a parent or sibling has Type 2 diabetes, the likelihood of developing the condition is higher.  Specific Genes: Several genes associated with glucose metabolism, insulin sensitivity, and insulin production contribute to an individual's risk. These include TCF7L2, PPARG, and KCNJ11, among others.  Epigenetic Factors: Epigenetic modifications, which can be influenced by environmental factors, can affect gene expression and play a role in Type 2 diabetes risk.