Genetics in Health and Disease

Importance of Genetics

• Understanding genetics helps explain individual differences in health and disease among humans.
• Human genomes comprise approximately 3 billion base pairs, contributing to phenotypic variations.
• Variations in genes can lead to diseases and can be used for disease risk predictions.

DNA Structure and Function

• DNA consists of nucleotides made up of a nitrogenous base, a pentose sugar, and a phosphate group.
• Purines include adenine and guanine, while pyrimidines include cytosine and thymine.
• DNA forms a double helix, with two strands connected by hydrogen bonds between paired bases (A with T, C with G), creating a stable structure.

Central Dogma of Molecular Biology

• Genetic information flows from DNA to mRNA through transcription, and from mRNA to protein through translation.
• Genetic variation plays a crucial role in understanding the origins of diseases.

DNA Replication

• DNA replication involves unwinding DNA from histones and using initiator proteins to signal helicase to unzip the strands.
• Primers created by DNA primase allow DNA polymerase to synthesize new strands in a 5' to 3' direction.
• The process generates leading and lagging strands, forming a replication fork.

DNA Repair Mechanisms

• DNA polymerase can correct mutations during replication via 3’ endonuclease activity, cutting phosphodiester bonds to replace incorrect nucleotides.
• Nucleotide excision repair involves removal of damaged bases, with nuclease cutting the DNA strand and DNA polymerase repairing the gap, sealed by ligase.

Mutations

• Mutations may arise from environmental factors (UV light, radiation, chemicals) or spontaneous errors in processes like DNA replication or transcription.
• Point mutations affect a single base pair and can be classified as silent, missense, or nonsense.
• Mutations can also involve insertions, deletions, or translocations of DNA segments.

DNA Repair Genes and Cancer

• Mutations in DNA repair genes, such as BRCA1 and BRCA2, can lead to an increased risk of cancers (e.g., pancreatic, colon).
• DNA repair genes maintain genome stability by correcting breaks caused by environmental damage or errors in cell division.

Future Lectures

• Upcoming topics include DNA basics and replication, meiosis, chromosomal inheritance, and traits related to inheritance.

Introduction to Meiosis

• Sexual reproduction involves the fusion of two haploid cells, generating a unique diploid zygote.
• Meiosis produces haploid gametes, which is crucial for genetic variation.
• Errors during meiosis can lead to chromosomal diseases.

Objectives of Study

• Understand mechanisms of genetic variation in haploid gametes.
• Identify diseases caused by meiotic errors.
• Explain non-disjunction and its impact on chromosome disorders.
• Compare aneuploidy-associated disorders.
• Discuss structural errors in chromosomes like inversions and translocations.

Purpose of Meiosis

• Converts diploid cells to haploid gametes (sperm and eggs) needed for reproduction.
• Abnormal chromosome numbers often relate to various diseases.
• Results in genetically diverse offspring.

Process of Meiosis

• Two rounds of nuclear division: meiosis I and meiosis II.
• Daughter cells are haploid after chromosomal replication and segregation.
• Homologous chromosomes undergo alignment and separation during division.

Genetic Variation Mechanisms

• Prophase I: homologous chromosomes pair and exchange information (crossing over).
• Random assortment of chromosomes in prometaphase leads to unique genetic combinations.

Cytogenetics and Karyotyping

• Cytogenetics studies chromosome structure and function.
• Karyotypes visualize chromosomes, numbered 1-22 for autosomes and XX or XY for sex chromosomes.
• Homologous chromosomes appear identical; there is a systematic labeling.

Chromosome Number Disorders

• Caused by complete chromosome loss or duplication due to non-disjunction.
• Parental age increases the risk of nondisjunction events.

Understanding Aneuploidy

• Aneuploidy leads to abnormal chromosome counts (monosomy or trisomy).
• Monosomy is typically lethal while some trisomies can lead to viable births (e.g., trisomy 21 - Down syndrome).
• Extra gene dosage can disrupt development and bodily functions.

Sex Chromosome Non-Disjunction

• Abnormal sex chromosome numbers can lead to viable but altered phenotypes, such as Triplo-X syndrome, Klinefelter syndrome (XXY), and Turner syndrome (XO).
• X inactivation allows females to function with two X chromosomes, although some genes can still be expressed from the inactive X.

Duplications and Deletions

• Cri-du-chat syndrome arises from a deletion on chromosome 5p, leading to distinct physical and developmental issues.

Chromosomal Structural Rearrangements - Inversions

• Inversions occur due to misalignment during meiosis, potentially leading to gene dosage changes.
• Effects are typically mild unless critical gene sequences are disrupted.

Disorders Associated with Inversions

• Chromosome 9 inversion disorder may be linked to various congenital abnormalities and developmental issues, though its clinical significance remains uncertain.

Chromosomal Structural Rearrangements - Translocations

• Translocations involve the exchange of chromosomal segments and can affect gene function.
• Often associated with cancers and disorders like schizophrenia.

Disorders Related to Translocations

• Williams-Beuren syndrome, linked to a specific chromosomal translocation, results in distinctive facial features and intellectual challenges, along with a friendly demeanor.

Chromosomes and Genes

• Genes exist on homologous chromosomes; each chromosomes has identical genes, one from each parent.
• Alleles refer to different versions of the same gene; most genes have more than two alleles.

Genotypes and Phenotypes

• Genotypes consist of allele combinations that determine traits.
• Phenotypes are the observable characteristics formed by allele interactions.

Dominant and Recessive Alleles

• Dominant alleles (A) override recessive alleles (a).
• Examples of dominant traits include achondroplasia and Huntington's disease.
• Recessive traits include conditions like albinism and cystic fibrosis, requiring two copies of a recessive allele to manifest.

Pedigrees and Inheritance

• Individuals need two copies of a recessive gene to express a recessive trait/disease.
• A pedigree chart displays inheritance patterns and helps identify carriers of diseases such as alkaptonuria.

X-Linked Traits

• Sex chromosomes (X and Y) are non-homologous; males are hemizygous for X-linked traits, possessing only one allele.
• Common X-linked disorders include red-green color blindness and certain types of hemophilia; both traits are recessive and more prevalent in males.
• Fathers do not pass X-linked traits to sons; females must inherit two copies to express the trait, while one copy classifies them as carriers.

Recessive Lethal Alleles

• Essential genes must be functional for survival, but deleterious recessive alleles can circulate if a functioning copy is present.
• If both parents are heterozygous, 25% of offspring may be homozygous recessive and potentially experience lethal effects if the gene is essential.

Dominant Lethal Alleles

• Dominant lethal inheritance patterns can result in lethality even in heterozygous forms, but are rare.
• Conditions like Huntington's disease exhibit this pattern; symptoms typically present after age 40, allowing for gene transmission prior to onset.

Molecular Pathology

• Molecular pathology connects genotypes to phenotypes by studying disease at a molecular level.
• Importance lies in understanding how genetic variations lead to specific diseases.
• Traditional methods involved slow, painstaking searches for mutations within chromosomes; current methods include whole exome sequencing to identify all protein-coding variations.

Mutations

• Mutations are classified as loss of function (LOF) or gain of function (GOF).
• LOF mutations result in a gene losing its normal function, which can be total or partial, often leading to absent or non-functional gene products.
• GOF mutations allow a gene to adopt a new function or incorrectly respond to signals, potentially causing diseases.

Loss of Function (LOF) Mutations

• Caused by deletions (gene or promoter), chromosomal rearrangements, or missense mutations, impacting protein production.
• Common examples include pyruvate kinase deficiency caused by LOF mutations.
• Gene deletions can result in a total or partial loss of protein products, disrupting normal function.

Gain of Function (GOF) Mutations

• Rarer than LOF mutations and occur through mechanisms like chromosomal rearrangements or missense mutations.
• Associated with diseases such as alpha-1-antitrypsin deficiency.
• Can lead to a failure in gene regulation, causing proteins to be expressed incorrectly.

Toxic and Aggregate Proteins

• Proteins require proper shape to maintain function; misfolded proteins can lead to toxic aggregates.
• Alzheimer's disease correlates with mutations causing abnormal protein folding, resulting in amyloid plaques.
• Misfolded proteins are significant contributors to neurodegenerative diseases.

Oncogenes and Tumor Suppressor Genes

• Oncogenes are mutated proto-oncogenes that, when altered, drive cell proliferation and cancer development.
• Common mutations include amplification of ERBB2 (HER2) and mutations in EGFR associated with lung cancer.
• Tumor suppressor genes, like p53, act as negative regulators of the cell cycle, and mutations in these genes permit uncontrolled cell growth, contributing to approximately 50% of human cancers.

Cell Cycle Control

• The cell cycle consists of two main phases: interphase (G1, S, G2) and mitosis.
• Internal checkpoints are necessary to ensure accurate DNA replication and repair before cell division.
• Disrupted checkpoints can lead to genomic instability and cancer progression.

Summary

• Molecular pathology highlights the genetic basis of diseases through mutational analysis.
• Understanding LOF and GOF mutations is crucial for diagnosing and treating genetic disorders and cancers.
• Key genes involved in cell cycle regulation are potential targets for cancer therapy and research into effective treatments.

Molecular Pathology

• Focuses on the connection between genotypes (genetic information) and phenotypes (observable characteristics) at a molecular level.
• Advances from older methods of identifying mutations in clinical settings now utilize whole exome sequencing to find all variants in protein-coding regions.

Loss of Function (LOF) vs. Gain of Function (GOF)

• Loss of Function Mutations:

  • Result in complete or partial loss of gene activity, leading to no gene product.
  • Caused by gene deletions, chromosomal rearrangements, and missense changes, commonly seen in diseases like pyruvate kinase deficiency.

• Gain of Function Mutations:

  • Lead to new gene activities or responses to incorrect signals.
  • Caused by mechanisms such as extra gene copies, chromosomal rearrangements, and missense mutations, with examples like Alpha-1-antitrypsin (AAT) mutations.

Importance of Protein Structure

• Disruption in protein structure from mutations can significantly affect protein functionality, impacting cellular processes and health.

Cancer and the Cell Cycle

• Uncontrolled cell growth is a fundamental characteristic of all cancers.
• Understanding cancer necessitates knowledge of the cell cycle, which consists of regulated phases including G1 (preparation for DNA synthesis), S (DNA replication), G2 (preparation for mitosis), and mitosis itself.

Cell Cycle Regulation

• Internal checkpoints and regulators ensure accurate genetic replication and stability of daughter cells.
• Failures in repair mechanisms can lead to erroneous cell division, promoting cancer development.

Mechanisms Leading to Cancer

• Growth Advantage: Mutated cells may proliferate faster, leading to tumorigenesis.
• Genome Destabilization: Increased mutation rates can further exacerbate instability, resulting in structural abnormalities.

Passenger vs. Driver Mutations

• Driver mutations contribute to cancer progression, providing growth advantages, while passenger mutations are incidental and do not affect growth rates.

Proto-Oncogenes and Tumor Suppressor Genes

• Proto-Oncogenes: Normal genes aiding in cell cycle progression that become oncogenes when mutated, accelerating cell division.
• Tumor Suppressor Genes: Typically function to suppress cell cycle progression; mutations can lead to uncontrolled proliferation and cancer.

Role of p53

• Known as the "guardian of the genome," p53 is a critical transcription factor in cell cycle regulation.
• p53 activation through phosphorylation starts the repair process of DNA damages and can activate the expression of genes such as:
  • P21 (CDKN1A): Halts the cell cycle to allow DNA repair.
  • PUMA and NOXA: Promotes apoptosis if DNA is irreparable, helping prevent the propagation of damaged cells.

Summary

• Molecular pathology serves as a bridge between genetic mutations and their phenotypic expressions, imperative for diagnosing diseases.
• Understanding the nuances of LOF and GOF mutations is essential in the recognition and treatment of genetic disorders and cancers.