Building Blocks, ppt 1, Genetic and Organic Syndromes

Instructor and Professional Background

• Imran Musaji, PhD, CCC-SLP
  • Current Role: Assistant Professor.
  • Educational Background:
    • PhD, CCC-SLP (Certificate of Clinical Competence in Speech-Language Pathology).
    • MS in Human Biology.
    • MA in Communication Sciences and Disorders.

Course Resources and Communication

• Textbook Alternative: Master Clinician Network
  • The standard physical textbook is not required; instead, the Master Clinician Network serves as the primary resource.
• Email Protocol
  • All emails must be sent through Blackboard.
  • Benefits of using Blackboard for communication:
    • Automatically tags the email for easier identification by faculty.
    • Ensures the correct address is used, as the university address book may contain multiple or outdated addresses.
    • Prevents technical errors or "bad email spirits" that could affect academic progress.

The Importance of Genetics in Speech-Language Pathology

• ASHA Position Statement (2005)
  • It is increasingly critical for audiologists and speech-language pathologists (SLPs) to understand the principles of genetics, genetic testing, and genetic counseling.
• Core Research in the Field
  • Developmental Language Disorder (DLD): Recent reviews (e.g., Mountford et al., 2022) explore the genetic and molecular basis of DLD.
  • Childhood Apraxia of Speech (CAS):
    • CAS is a severe speech disorder characterized by motor planning and programming deficits.
    • Genetic factors contribute substantially to CAS aetiology.
    • Monogenic (single-gene) pathogenic variants are identified in approximately one-third of cases.
    • To date, roughly 20 single genes have been implicated in CAS.
    • Research involving trio genome sequencing (probands and parents) is used to identify molecular causation and novel pathways co-expressed during brain development.

Clinical Applications and Precision Medicine

• Precision Medicine Overview
  • Emerging approach to disease management that considers an individual's genetic and environmental profile.
  • Avenues for improved outcomes include prevention and personalized treatments.
• Case Study: Classic Galactosemia (CG)
  • CG is an inborn error of metabolism typically diagnosed via newborn screening.
  • Children with CG are at high risk for severe speech and language disorders, usually emerging by age 2 or 3.
  • Babble Boot Camp:
    • A proactive intervention program (Peter Lab at ASU) designed to leverage genotype-phenotype associations.
    • Targets infants with CG starting at 2 months old through 24 months.
    • Uses parent training to implement routines before the expected delay occurs.
    • Research study (NIH-funded) involves random assignment to different treatment windows: Speech therapy from 15–24 months vs. 2–24 months.

History and Evolution of Genetic Science

• 1980s–1990s: Development
  • Initial creation of DNA manipulation and sequencing technology.
  • Over-enthusiasm surrounding the potential of gene therapy.
• 1999–2000s: The Period of Realism and Despair
  • Death of a patient in an early clinical trial in 1999 led to heavy scrutiny.
  • Leukemia emerged as a side effect in several patients treated for Severe Combined Immunodeficiency (SCID).
• 2010s–Present: Re-emergence
  • Completion of the Human Genome Project (HGP).
  • Improvements in viral vectors and immune reaction management.
  • Discovery of new mechanisms of action.
  • Rise of CRISPR technology and predictions for its application in DNA editing.

Genetic Factors in Biological Sex and Gender

• Biological Sex Foundations
  • Determined by chromosomes, genes, hormones, and internal/external sex organs.
  • Typical Female Development: Typically marked by $46XX$ chromosomes and the absence of the $SRY$ gene.
  • Typical Male Development: Typically marked by $46XY$ chromosomes and the presence of the $SRY$ gene.
• Intersex Conditions and Chromosomal Variations
  • Turner Syndrome ($45X$): Individuals have female external structures but may have impaired ovarian development and low estrogen.
  • Klinefelter Syndrome ($47XXY$): Individuals have male external structures but may experience low testosterone, small testes, infertility, and breast development.
  • Androgen Insensitivity Syndrome (AIS): Caused by an $AR$ gene mutation. External structures may be female while internal structures are male ($46XY$ karyotype).
    • Complete AIS: Female external structures with undescended testes.
    • Partial AIS: Ambiguous genitals.
  • 5-alpha reductase deficiency: Caused by $SRD5A2$ gene mutation. $46XY$ individuals may have female or ambiguous external anatomy at birth, but a testosterone surge at puberty results in the development of male characteristics.
  • Congenital Adrenal Hyperplasia: Caused by $CYP21A2$ gene mutation. Results in elevated male hormones in $46XX$ individuals, potentially leading to fused labia or an enlarged clitoris.
• Gender Spectrum vs. Sexuality
  • Transgender: Identifying with a gender different from the sex assigned at birth.
  • Cisgender: Identifying with the gender corresponding to the sex assigned at birth.
  • Nonbinary: Identifying as neither completely male nor completely female; may be gender-fluid.
  • Sexuality: Relates to sexual orientation and attraction, which is separate from sex and gender identity.

The Central Dogma and Nucleic Acids

• The Central Dogma of Molecular Biology
  • A fundamental principle stating: "DNA makes RNA, which makes protein."
• Nucleic Acid Components
  • Long chains of molecules consisting of three primary parts:
    1. Sugar molecule: Forms the backbone. Named based on the type of sugar ($5'$ and $3'$ carbon positions define the backbone orientation).
    2. Phosphate group.
    3. Nitrogenous base: Pairs to connect two strands.
• Sugar Differences
  • Ribose: The sugar found in RNA.
  • 2-deoxyribose: The sugar found in DNA, which contains one fewer oxygen atom than ribose.
• Base Pairs in DNA
  • Adenine ($A$) pairs with Thymine ($T$).
  • Cytosine ($C$) pairs with Guanine ($G$).
• Base Pairs in RNA
  • Adenine ($A$) pairs with Uracil ($U$).
  • Cytosine ($C$) pairs with Guanine ($G$).

RNA Types and Functions

• Messenger RNA (mRNA)
  • Acts as a copy of a section of DNA.
  • Can leave the cell nucleus to transport genetic instructions to sites of protein synthesis (ribosomes).
• Transfer RNA (tRNA)
  • Also known as transport RNA.
  • Carries specific amino acids to the ribosome.
  • Matches its anticodon to the specific codon on the mRNA during protein synthesis.
• MicroRNA (miRNA)
  • Involved in regulating gene expression.
  • Interferes with matching mRNAs, which can reduce the amount of protein a gene produces.

DNA Packaging and Chromosome Structure

• The Storage Problem
  • A complete DNA strand contains approximately $249 \times 10^{6}$ nucleotides.
  • Stretched out, a single DNA strand is about 2 inches ($5.08\text{ cm}$) long.
  • An average cell is only $0.01\text{ cm}$ long.
• Packaging Mechanism
  1. DNA binds with histones (core of eight histone molecules).
  2. Forms nucleosomes (appearing as "beads on a string").
  3. Nucleosomes pack into a coil.
  4. Coils twist into larger coils, forming chromatin fibers.
  5. Fibers fold into loops to form the specialized package called a chromosome.
• Chromosome Anatomy
  • p arm: The short arm of the chromosome.
  • q arm: The long arm of the chromosome.
  • Centromere: The constriction point where the two arms meet.
  • Telomere: The protective end cap of the chromosome.
• Human Chromosome Count
  • Humans have 23 pairs (total of 46).
  • One set is inherited from each parent.
  • Autosomes: The first 22 pairs.
  • Sex Chromosomes: Pair #23 ($X$ or $Y$).
  • Ploidy: Terminology distinguishes between a single set ($1N$) and a double set ($2N$).

Genetic Mapping and Alleles

• Locus
  • The specific physical location (address) of a gene on a chromosome.
  • Example: The $CFTR$ gene associated with Cystic Fibrosis is located at $7q31.2$ (Chromosome 7, q arm, region 31.2).
• Allele
  • Variants of a gene. A gene may have slight variations in its DNA sequence among individuals; each variation is an allele.

Amino Acids and the Genetic Code

• Decoding Building Blocks
  • The body uses 20 specific amino acids for genetic coding, although over 500 exist in nature.
• Codon
  • A sequence of three nitrogenous bases that codes for one specific amino acid.
  • Example: mRNA is read as a series of codons to build a chain.

Protein Synthesis and Structure

• Steps of Protein Production
  1. Transcription (Step 1):
     • DNA uncoils at the specific gene site.
     • RNA polymerase initiates transcription at the promoter region.
     • mRNA is produced using one DNA strand as a template.
  2. mRNA Processing (Step 2):
     • Involves the removal of introns and splicing of exons.
     • Finished mRNA is transported out of the nucleus to a ribosome.
  3. Translation (Step 3):
     • mRNA attaches to a ribosome.
     • tRNA anticodons match with mRNA codons.
     • An amino acid chain is formed. Loading the amino acid to tRNA is the most energy-intensive part of the process, requiring ATP.
     • The protein chain is folded and processed, often aided by chaperonins (heat shock proteins).
• Levels of Protein Complexity
  • Primary Structure: The linear sequence of amino acids in the chain.
  • Secondary Structure: Local folding (e.g., alpha helices or pleated sheets) linked by hydrogen bonds.
  • Tertiary Structure: The overall 3D shape resulting from attractions between various secondary structures.
  • Quaternary Structure: A protein consisting of more than one amino acid chain.

The Genome and Human Genome Project

• Genome Definition
  • The complete set of chromosomes and all associated DNA that makes up the code for an organism.
• Human Genome Project (HGP)
  • Completed approximately 15 years ago.
  • Provided a map for modern applications in medicine, law enforcement, psychology, environment, and agriculture.

Epigenetics and Imprinting

• Epigenetics Definition
  • Changes in traits or gene expression that are not caused by changes in the DNA sequence itself (e.g., methylation, histone acetylation).
• Imprinting
  • A process where genes from one parent are silenced or repressed.
  • Prader-Willi Syndrome: Inheriting a mutated allele from the father while the mother’s allele is naturally silenced. Characteristics include intellectual disability and hyperphagia (excessive eating).
  • Angelman Syndrome: Inheriting a mutated allele from the mother while the father’s allele is naturally silenced. Characteristics include excessive laughter, happy demeanor, seizures, and intellectual disability.
• Histone Acetylation
  • A mechanism that makes DNA "easier to read," whereas some other epigenetic modifications make DNA "harder to read."

Questions & Discussion

• What are variants of a gene called?
  • These variants are known as alleles.
• What are the base pairs in DNA and RNA?
  • DNA: $C$ pairs with $G$; $T$ pairs with $A$.
  • RNA: $C$ pairs with $G$; $U$ pairs with $A$.
• Can you identify the formal address for specific genes on Chromosome 7?
  • $IFN\beta2$ (Interferon): $7p21.3$
  • $PSP$ (Phosphoserine phosphatase): $7p15.2$
  • $EGFR$ (Epidermal growth factor receptor): $7p12.2$
  • $EPO$ (Erythropoietin): $7q21.1$
  • $CF$ (Cystic Fibrosis): $7q31.2$
  • $TCRB$ (T cell antigen receptor): $7q35.0$
• Identify a genetic disorder associated with imprinting.
  • Options include Prader-Willi Syndrome (related to the paternal allele) and Angelman Syndrome (related to the maternal allele).

Assignments and Future Topics

• Current Assignments
  • Complete the review tutorial (5 short sections with video and reading).
  • Complete assigned readings and videos.
  • Complete the Blackboard quiz (randomized questions; highest grade after three attempts counts).
• Upcoming Topics
  • DNA Synthesis: Replication.
  • RNA Production: Transcription.
  • Protein Synthesis: Translation.