Spectrum of Disease and Genetic Factors

• Spectrum of disease refers to the range of manifestations a disease can exhibit, from its initial biological onset to its final outcomes
• It can also describe how exposure to a disease can lead to different outcomes, such as varying symptoms and severity, within a population

Human Diseases

• Human diseases result from a combination of genetic and environmental factors
• In certain conditions, genetic factors are dominant such as in Down syndrome
• Other times infections are caused predominately by environmental factors
• Most chronic non-communicable conditions like schizophrenia, diabetes, and congenital malformations involve an interaction of both genetic and environmental factors

Genetic Diseases

• Humans have an estimated of 20,000 to 25,000 genes
• Alterations in these genes or their combinations can lead to genetic diseases or disorders
• These are classified into chromosome disorders, single-gene disorders, multifactorial disorders, acquired somatic disorders, and mitochondrial disorders

Chromosome Disorders

• A cell with a multiple of 23 chromosomes is euploid

• Haploid gametes (n=23) and diploid somatic cells (2n=46) are euploid

• Chromosomal disorders are conditions caused by abnormalities in chromosome number or structure

• Chromosomal abnormalities in chromosome number are of two types:

  • Polyploidy
  • Aneuploidy

• Polyploidy is the presence of a complete extra set of chromosomes in a cell

• Triploidy (69 chromosomes) and tetraploidy (92 chromosomes) are examples observed in humans

• Aneuploidy is when a person has missing or additional individual chromosomes

• Autosomal aneuploidy involves abnormal numbers of autosomes (chromosomes 1-22) whereas sex chromosome aneuploidy affects X or Y chromosomes

• Trisomy (extra autosomal chromosome, 2n +1) includes:

  • Down Syndrome (Trisomy 21 - 47,XX,+21 or 47,XY,+21)
  • Edward Syndrome (Trisomy 18 - 47,XX,+18 or 47,XY,+18)
  • Patau Syndrome (Trisomy 13 - 47,XX,+13 or 47,XY,+13)

• Monosomy (missing autosomal chromosome, 2n-1) is lethal and results in early miscarriage

• Trisomy (extra sex chromosome, 2n +1) includes:

  • Klinefelter Syndrome (47, XXY)
  • Triple X Syndrome (47, XXX)
  • XYY Syndrome or Jacobs Syndrome (47, XYY)

• Monosomy (missing sex chromosomes, 2n -1) includes Turner Syndrome (45, X)

• Common sex chromosome aneuploidies include 48,XXYY and 48,XXXY while rare sex chromosome aneuploidies include 49,XXXXY syndrome or Fraccaro syndrome

• Autosomal aneuploidy is more severe and often fatal

• Sex chromosome aneuploidy has milder effects, often allowing individuals to survive

• Most autosomal monosomies are lethal whereas most sex chromosome aneuploidies can be viable

• Autosomal aneuploidy means that many are infertile, while sex chromosome aneuploidy can allow some individuals to retain fertility

• Both are usually due to de novo nondisjunction during meiosis

• Structural chromosomal abnormalities occur when structure of chromosome is altered when broken and incorrectly rejoined

• These changes can result in missing, extra, or rearranged genetic material, potentially leading to developmental disorders, congenital anomalies, or cancer

• Types of structural chromosomal abnormalities include:

  • Deletions where loss of a chromosomal segment leads to loss of essential genes
  • Duplications, where an extra copy of a chromosomal segment leads to extra genetic material
  • Translocations, where a segment from one chromosome is transferred to another
  • Inversions where a segment flips within the same chromosome, reversing but not leaving
  • Ring Chromosomes, where chromosomal ends fuse together, forming a ring structure
  • Isochromosomes, where a chromosome splits abnormally, creating two identical arms with loss of one arm and duplication of the other

Single Gene Disorders

• Single gene disorders (or monogenic disorders) are the condition is caused by mutations in a single gene leading to defective proteins or function losses

• These disorders follow Mendelian inheritance patterns (dominant, recessive, or X-linked) and can be inherited or arise due to new (de novo) mutations

• Types of single gene disorders are based on inheritance patterns

  • Autosomal dominant disorders:
    • Only one mutated copy of the gene (from one parent) causes the disorder
    • Affected individuals have a 50% chance of passing it to offspring
    • Examples include Huntington's Disease (HTT-Progressive neurodegeneration) and Marfan Syndrome (FBN1-Connective tissue disorder w/ long limbs & heart problems)
  • Autosomal recessive disorders:
    • Both copies of the gene must be mutated (one from each parent) for the disease to manifest
    • Carriers (heterozygous individuals) are unaffected but can pass mutation to offspring
    • Examples include Cystic Fibrosis (CFTR-Thick mucus production, respiratory and digestive issues), Sickle Cell Disease (HBB-Abnormal hemoglobin, leading to sickle-shaped red blood cells), and Phenylketonuria (PKU) (PAH-Inability to metabolize phenylalanine, leading to intellectual disability if untreated)
  • X-Linked Disorders:
    • Mutations occur on the X chromosome
    • Males (XY) show are affected due to only having one X chromosome, while females (XX) can be carriers with mild or no symptoms
    • Haemoglobinopathies are inherited genetic conditions affecting the molecules in blood by genetic change
    • Include Haemoglobin variants/Thalassaemias

Multifactorial Disease

• These are common diseases like diabetes, cancer, cardiovascular diseases, coronary artery disease, mental health issues, and neurodegenerative disorders

• These result from the interaction of polygenic and environmental inheritance

• These do not follow Mendelian inheritance

• Cumulative interactions of multiple genes and the environment

• In atherosclerosis, lipid levels, LDL oxidation, macrophage/platelet/macrophage adhesion, endothelia damage, lymphocyte recruiment, intramural proliferation, and formation of atheromatous plaques are factors

• In diabetes Mellitus:

  • Elevated blood glucose, and long term effects of premature atherosclerosis, retinopathy, neuropathy, and nephropathy are factors
  • Both types are polygenic influenced by the environment
  • Includes polygenic disorders, HLA and INS genes, mutations affect insulin production
  • Viral infections and childhood diet in T1DM are autoimmune

• In cancer:

  • It causes mutations in genes that code for: proteins in signaling pathways for cell proliferation, cytoskeletal components, regulators of the mitotic cycle, programmed cell death machinery, and proteins involved in detection and repair of DNA mutations
  • Gain of function mutations or loss of function result, genes with novel properties result
  • Proto-oncogenes mutated cause cell change

Acquired Somatic Genetic Disorders

• Somatic genetic disorders are acquired genetic mutations in non-germline cells during a person’s lifetime

• Mutations are not inherited from parents and are not capable of being passed to offspring

• These are acquired due to:

  • Environmental exposures
  • Replication errors
  • Ageing

• This plays a significant role in cancer and degenerative disorders

• Characteristics:

  • Non-heritable. Mutations are not passed to future generations.
  • Acquired during life. Mutations accumulate over time due to environmental factors or spontaneous errors.
  • Mosaicism possible. If mutations occur early in development, a person may have a mix of normal and mutated cells (somatic mosaicism).
  • Localized effect. Mutations are confined to specific tissues or organs and do not affect the entire body.

• Causes of mutations in acquired somatic cells

  • UV radiation
  • Carcinogens
  • Chemicals and toxins
  • Replication errors
  • Viral infections
  • Ageing & telomere shortening

Treatment of Genetic Disorders

• Gene therapy can work in several ways:
  • Replacing mutated genes or removing faulty proteins that caused disease
  • Inactivating problematic mutated genes
  • Introduce a new gene so the body can create a lacking protein

The Human Genome Project

• HGP was an international research aimed at the mapping and sequencing of ENTIRE human genome

• Launched in 1990 and completed in 2003 and provided foundation for understanding genetic dseases, evolution, and human biology

• Sequence the entire human genome (~3 billion DNA base pairs)

• Identify and map all human genes (~20,000–25,000 genes)

• Analyse genetic variations and their role in diseases

• Finds include:

  • Only ~1.5% of the genome codes for proteins. The rest includes regulatory elements, non-coding RNA, and repetitive sequences.
  • Humans have ~20,000–25,000 protein-coding genes, less than the expected ~100,000 genes.
  • About 23.2% codes for expression, replication, maintenance with 21.1% contributing to cellular signal transduction and 17.5% for different functions with 38.2% categorized as other
  • DNA is identical among all humans despite variation contributing to differences in traits and possible susceptibility

• Enabled by finding genes responsible for genetic disorders and development of targeted therapies (faulty genes corrected or replaced with functional copies)

• Precision Medicine improves genetic disorder medical assistance that uses all of an individual's information for personalized aid

System Biology

• Systems biology is a field to understand larger aspects that influence organism cells biology in natural and synthetic forms
• It encompasses a complex biological knowledge in regulatory networks of life