Biology 1030: Human Anatomy and Physiology 1 - Genetics

Central Dogma: From DNA to Protein

A. Information Flow Overview

• DNA contains the blueprints for proteins in sequences of nucleotides, which are called "genes."

• A copy of the gene, known as messenger RNA (mRNA), is produced using the DNA blueprint.

• This mRNA then moves out to the cytoplasm.

• In the cytoplasm, ribosomes utilize the information within the mRNA and available amino acids to synthesize a protein.

• Review point: Ribosomes attached to the rough Endoplasmic Reticulum (rER) typically produce proteins destined for secretion or membrane insertion, while free-floating ribosomes in the cytoplasm produce proteins that function within the cytoplasm.

B. Transcription: mRNA Production

• This process involves the production of messenger RNA (mRNA) using a DNA template.

• It occurs within the nucleus.

• Only one strand of the DNA polymer serves as a template, and only one gene is transcribed at a time, not the entire DNA strand.

• Transcription for each gene happens separately, only when appropriate cellular signals are present.

• The enzyme RNA polymerase builds the mRNA polymer by using the DNA as a template and incorporating available RNA nucleotides.

• Once formed, the mRNA exits the nucleus through a nuclear pore.

C. Translation: Protein Synthesis

• mRNA carries the specific instructions to create a particular protein.

• Translation is the process where the language of nucleic acids is converted into the language of proteins, occurring at ribosomes in the cytoplasm.

• The Genetic Code: This acts as the dictionary between the two languages (nucleic acid and protein).

  • Triplet codon: A nucleic acid "word" consisting of three RNA nucleotides that encodes for one specific amino acid.

  • Redundant code: There are 64 possible combinations of three nucleic acids (codons) available to code for only 20 different amino acids.

    • This redundancy means that several similar codons can encode for the same amino acid.

    • Result: This allows some mutations to be "silent," meaning they change the DNA/mRNA sequence but do not alter the resulting amino acid sequence or protein function.

  • Special codons:

    • Start codon: The codon that initiates protein synthesis (e.g., AUG, which also codes for Methionine).

    • Stop codons: Codons that signal the termination of protein synthesis (e.g., UAA, UGA, UAG).

Protein Modification and Localization

• The location and specific process of protein modification are dependent on the type and ultimate function of the protein.

1. First Example: Tubulin (Cytoplasmic Protein)

• Tubulin is a cytoplasmic protein, part of the cytoskeleton.

• Translation of tubulin occurs on a free-floating ribosome within the cytoplasm.

• Any necessary modifications occur in the cytoplasm.

• The tubulin monomer then joins any growing microtubule in the cytoplasm.

2. Second Example: DNA Polymerase (Nuclear Protein)

• Translation of DNA polymerase occurs on a free-floating ribosome in the cytoplasm.

• After synthesis, DNA polymerase enters the nucleus through a nuclear pore.

• DNA polymerase performs its function inside the nucleus, specifically during the S phase of the cell cycle (DNA replication).

3. Third Example: Channel Protein (Membrane/Secreted Protein)

• Translation of a channel protein occurs on a ribosome bound to the rough Endoplasmic Reticulum (rER).

• The protein then moves from the rER to the Golgi apparatus.

• Alterations of proteins in the Golgi apparatus:

  • Proteins can be trimmed in size, meaning some amino acids are removed.

  • Carbohydrates can be added to the proteins (glycosylation).

• Packaging of proteins from the Golgi apparatus:

  • Proteins are sorted and then sent to their final destination, such as the plasma membrane, encapsulated within the membrane of a vesicle.

Genetics: Genes, Alleles, and Mutations

A. Gene

• A gene is a section of DNA that encodes a protein, defined by a specific sequence of nucleotides.

• It determines a particular trait.

• Genes are inherited through generations.

B. Allele

• An allele is an alternative version of a gene, differing by one or more nucleotides from other versions.

• Each allele determines a variation of a specific trait.

• Alleles originate through past germline mutations that were passed down via egg or sperm cells.

C. Mutations

• Mutations are the fundamental source of new alleles.

• Cell types and mutations:

  • Somatic cells: Mutations in somatic cells are not passed down to offspring. They can occur due to mistakes during DNA replication or exposure to mutagens like radiation, UV light, or chemicals.

  • Germ-line cells: Mutations occurring in germ-line cells (sperm or egg cells) can be passed down to subsequent generations.

• Types of Mutations:

  • Missense mutation ("miss the sense"):

    • A mutation that changes the amino acid sequence in a protein. The new allele encodes for a similar, but functionally different, protein.

    • Figure 2 illustrates a missense mutation where a change from GAG to GUG in mRNA results in Val instead of Glu.

  • Nonsense mutation:

    • A mutation that introduces an early STOP codon into the mRNA sequence.

    • The new allele either doesn't produce an mRNA or produces a severely shorter and non-functional protein.

    • Figure 3 demonstrates a nonsense mutation where a TAC to ATT change in DNA leads to a UAA STOP codon in mRNA, truncating the protein.

  • Silent mutation:

    • A mutation that changes the DNA and mRNA sequence, but, due to the redundancy of the genetic code, the resulting amino acid sequence remains unchanged.

    • Figure 4 shows a silent mutation where GAA to GAG in DNA still codes for Leu and Thr and Arg in the protein, illustrating no change in the protein sequence.

Genotype and Phenotype Interactions

D. Genotype and Phenotype Interactions

• Genotype: Refers to the specific set of alleles present in an individual.

• Phenotype: Refers to the observable traits produced by those alleles, which are determined by the inheritance pattern.

• For each gene, an individual inherits two alleles: one from the egg and one from the sperm.

  • Homozygous: An individual is homozygous if the two alleles for a particular gene are identical (e.g., BB or bb).

  • Heterozygous: An individual is heterozygous if the two alleles for a particular gene are different (e.g., Bb).

3. Inheritance Patterns (Introduction)

a. Multiple Alleles

• More than two alternative alleles exist for a given gene within a population (though an individual still only has two).

• Example: ABO blood type system, which has three alleles: I^A, I^B, and i.

4. Complete Dominance (Dominant/Recessive Alleles)

• The dominant allele will determine the trait if it is present (in both homozygous dominant and heterozygous genotypes).

• The recessive allele will determine the trait only if the dominant allele is not also present (i.e., in homozygous recessive genotypes).

• This type of inheritance is usually associated with an inherited nonsense mutation, which often leads to a non-functional or absent protein for the recessive allele.

• Examples:

  • Eye color (simplified model, e.g., brown is dominant to blue: Bb or BB = brown, bb = blue).

  • Cystic fibrosis (FF or Ff = normal, ff = cystic fibrosis).

  • ABO blood type: Alleles I^A and I^B are completely dominant over the i allele (e.g., I^A i results in A blood type, I^B i results in B blood type, while ii results in O blood type).

5. Codominance

• Both alleles that a person has are distinctly expressed and show their effects simultaneously.

• The resulting phenotype exhibits the characteristics of both alleles.

• This pattern is always associated with an inherited missense mutation, where both alleles produce functional, but different, proteins.

• Example: ABO blood type system. Individuals with the I^A I^B genotype express both A and B antigens on their red blood cells, resulting in AB blood type.

6. Incomplete Dominance

• Heterozygous organisms display a phenotype that is intermediate between the phenotypes of the two homozygous alleles.

• The phenotype can appear to be a "blend" of the two parental traits.

• There is a one-to-one correspondence between genotype and phenotype.

b. Example: Sickle Cell Anemia (A complex example related to incomplete dominance/codominance)

• Description of the disease:

  • Common among populations originating from equatorial Africa and their descendants.

  • Caused by a mutation in the gene for hemoglobin, resulting in the production of hemoglobin S protein (Hb$^S$ allele) instead of normal hemoglobin A (Hb$^A$ allele).

  • Homozygous recessive genotype (Hb$^S$Hb$^S$): Phenotype is Sickle Cell Anemia. Individuals experience reduced blood flow and pain, especially in low oxygen conditions, due to sickle-shaped red blood cells.

• Sickle Cell Trait:

  • Exhibited by heterozygous individuals (Hb$^A$Hb$^S$).

  • They typically do not have full-blown anemia but may experience some symptoms under conditions of very low oxygen.

  • In these individuals, the presence of Hb$^A$ prevents the Hb$^S$ from fully crystallizing and causing severe sickling of red blood cells.

  • Remarkably, the sickle cell trait appears to provide protection against malaria within these populations.

7. Polygenic Inheritance (distinct from multiple alleles)

• Some traits depend upon the simultaneous inheritance and expression of more than one gene.

• The majority of complex traits exhibit polygenic inheritance, often with multiple possible alleles for each contributing gene.

Heredity: Meiosis and Chromosome Changes

III. Inheritance Patterns (Continued)

A. Karyotype

• A karyotype is an image depicting the complete set of chromosomes within a cell, typically arranged in homologous pairs.

• Homologous chromosome pairs are numbered from 1 to 22 (autosomes), followed by the sex chromosomes.

• Each chromosome pair exhibits a certain characteristic staining pattern, which helps in identification.

• Figure 5 provides an example of a karyotype.

B. Meiosis: Passing Down Genetic Information

• Meiosis is a specialized process of cell division that results in four daughter cells, each containing only one set of chromosomes (i.e., they are haploid).

• Meiosis occurs exclusively in germline cells and is responsible for producing gametes (egg and sperm).

• During the divisions of meiosis, homologous chromosomes pair up.

• Each gamete ultimately receives only one chromosome from each homologous pair.

3. During Meiosis…

a. Crossing Over

• This is the exchange of genetic material between homologous chromosomes.

• Homologous chromosomes pair together to form tetrads and then physically swap segments of their alleles.

• Crossing over further randomizes the set of alleles that are passed down to gametes, increasing genetic diversity.

• Figure 7 visually demonstrates the process of crossing over.

b. Chromatid Separation

• During anaphase of meiosis, the chromatids split, and each resulting gamete randomly receives different sets of alleles, contributing to varied genetic combinations in offspring.

C. Inheritance Calculations

• Inheritance calculations can be made using a Punnett square.

1. Punnett Square

• A Punnett square is a diagram used to predict the genotypes of a particular cross or breeding experiment.

2. Example 1:

• Parents are Male: BB and Female: bb.

• Punnett Square:

  	B	B
  b	Bb	Bb
  b	Bb	Bb

• Result: All offspring will have the genotype Bb.

Importance of Individual Chromosomes

D. Importance of Individual Chromosomes (Karyotype Review)

• Autosomes: These are the first 22 pairs of chromosomes in a human karyotype, shared by both males and females.

• Sex chromosomes: This is the last pair of chromosomes (the 23^{rd} pair), consisting of the X and Y chromosomes, which determine an individual's biological sex.

2. Changes in Chromosome Number

• Most alterations in chromosome number (e.g., addition or loss of a chromosome) are incompatible with life, often causing the embryo to die.

• However, there are some well-known exceptions where individuals can survive with such changes, though often with specific phenotypes.

• Nondisjunction (Figure 9): This is the primary cause of changes in chromosome number. It occurs when homologous chromosomes fail to separate during meiosis I or sister chromatids fail to separate during meiosis II, leading to gametes with either n+1 or n-1 chromosomes. Fertilization then results in a zygote with 2n+1 (trisomy) or 2n-1 (monosomy) chromosomes.

a. Down Syndrome (47 chromosomes)

• Also known as Trisomy 21. This means there are three copies of chromosome 21 instead of the usual two.

• Phenotype: Individuals typically exhibit characteristic facial features, intellectual disability of varying degrees, and often congenital heart defects, among other health issues.

• The risk of having a child with Down syndrome increases with the age of the mother.

• Figure 8 depicts a karyotype illustrating Trisomy 21.

b. Klinefelter Syndrome (49 chromosomes - typically arises from XXY genotype resulting in 47 chromosomes)

• Affected individuals are XXY males.

• Phenotype: Typically characterized by tall stature, reduced fertility, small testes, and sometimes learning difficulties or delayed speech.

c. Turner Syndrome (less than 46 chromosomes - specifically XO, resulting in 45 chromosomes)

• Affected individuals are XO females (meaning they have only one X chromosome and no second sex chromosome).

• Phenotype: Distinctive features include short stature, webbed neck, heart defects, and ovarian dysfunction leading to infertility.

3. Sex-Linked Genes

• These genes are located on the sex chromosomes, primarily due to the significant size and genetic differences between the X and Y chromosomes.

• X chromosome:

  • It is considerably larger than the Y chromosome and contains hundreds of genes vital for many functions.

  • Females typically have two X chromosomes (XX genotype).

Punnett Square Examples (Continued)

3. Example 2:

• Parents are Male: Bb and Female: Bb.

• Punnett Square:

  	B	b
  B	BB	Bb
  b	Bb	bb

• Result: Genotypic ratio of 1/4 BB : 1/2 Bb : 1/4 bb.

4. Example 3:

• Parents are Male: I^A I^B and Female: ii.

• Punnett Square:

  	I^A	I^B
  i	I^A i	I^B i
  i	I^A i	I^B i

• Result: All offspring will be heterozygous. Genotypic ratio of 1/2 I^A i : 1/2 I^B i. Phenotypically, 50\% will have A blood type and 50\% will have B blood type.