Gene Expression, Epigenetics and the Placenta

• There are several key aspects related to gene expression, epigenetics, gene mutation and chromosomes that are worth taking note of.

Gene Expression and Epigenetics

• Gene expression uses information from a gene to synthesize a functional gene product.
• Gene expression varies with time, tissue type, and environmental conditions. Epigenetics studies how environmental factors and behaviors change gene expression.

Gene Expression in the Placenta

• The placenta is an intricate collection of cell populations.
• Single-cell transcriptomics can reveal functions that might help prevent pregnancy losses or stillbirths.
• Human placental genes fall into five groups encoding proteins and perform the following functions:
• Dampen the mother's immune response.
• Invade the uterine lining.
• Build the blood supply.
• Release hormones to maintain pregnancy.
• Represent the genes from the woman.

Globin Chain Switching

• Hemoglobin is a blood protein with different polypeptide chains.
• Different globin polypeptide chains are used to make hemoglobin as a human develops.
• Hemoglobin forms depend on blood oxygen level changes.

Building Tissues and Organs

• Genes are turned on and off during development as stem cells self-renew and yield more specialized daughter cells.
• Transcriptomics and proteomics can give a more complete view of gene expression.

Shared Gene Expression Connects Diseases

• A diseasome is a map linking diseases based on shared gene expression.
• It identifies consistently over- or underexpressed genes in multiple diseases.
• Connections between seemingly unrelated conditions are also revealed.

Control of Gene Expression

• Chromatin remodeling involves Histone proteins interacting with chemical groups, thus exposing or shielding DNA.
• MicroRNAs are small RNAs that bind to mRNAs, preventing protein translation.
• Microproteins are tiny proteins that influence the functioning of larger proteins.

Maximizing genetic information

• Alternative splicing enables different versions of a protein by adding or deleting parts.
• A DNA sequence within a gene's intron on the template strand may encode protein on the coding strand.
• Prostate-specific antigen (PSA): a protein involved in liquefying semen. It serves as a biomarker for prostate cancer.
• The PSA gene has 5 exons and 4 introns, and alternative splicing produces seven isoforms.

More ways to maximize genetic information

• Proteins can be modified after translation.
• A precursor protein can be cut into two.
• An intron of the neurofibromin gene harbors instructions for three other genes on the coding strand.

Most of the Human Genome Does Not Encode Protein

• Only about 1.5% of human DNA encodes protein.
• The rest includes viral sequences, noncoding RNAs, introns, promoters, other control sequences, and repeated sequences.

Viral DNA

• Genomes include DNA sequences that represent viruses.
• Viruses are nonliving particles with nucleic acid (DNA or RNA) encased in protein.
• Retroviruses copy genetic material into DNA and insert into a host chromosome.

Noncoding RNAs

• The human genome produces both coding (mRNAs) and noncoding RNAs (ncRNAs).
• tRNAs and rRNAs are well-studied noncoding RNAs, with about 500 types of tRNA genes and 243 types of rRNA genes in the human genome.

Repeats

• Human genomes feature highly repetitive sequences.
• Transposons (transposable elements) comprise 40–45% of the genome. Transposons can move around the genome, which may contribute to genetic instability.
• Different repeats (telomeres, etc) contribute to genome complexity.

Conclusion

• Gene expression is dynamic and influenced by time, tissue, and environment.
• Understanding gene expression is crucial for understanding development, disease and evolution.
• Further research will continue to reveal gene expression's complexities and its impact on human health.
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The Nature of Gene Variants

• A mutation is any change in a DNA sequence.
• Mutate refers to the process of altering a DNA sequence.
• Mutant refers to a phenotype or an allele.
• Polymorphism is a variant present in >1% of a population.

Germline vs. Somatic Mutations

• Germline mutations occur during DNA replication before meiosis, which affects all individual cells and is heritable.
• Somatic mutations occur during DNA replication before mitosis, which affects only some cells, is not heritable, and leads to somatic mosaicism.
• Some diseases are observed in mosaic individuals.
• Complete mutation presence in all cells is incompatible with life.
• Mosaic condition arises from a early embryo cell mutation.
  • Ex Proteus syndrome

Sickle Cell Disease

• A single DNA base change in the beta-globin gene (CTC to CAC) replaces glutamic acid with valine.

Beta Thalassemia

• Beta Thalassemia results from too few beta globin chains because of mutations in the beta globin gene.

Collagen Disorders

• Mutations in collagen genes can lead to medical conditions in connective tissues.
• Collagen structure altered due to slight alternations.

Allelic Diseases

• Allelic diseases are different clinical phenotypes caused by mutations in the same gene.
• Mutations in the CFTR gene can cause cystic fibrosis with a range of symptoms, from impaired breathing and digestion to male infertility or frequent bronchitis.

Causes of Mutation

• Mutations occur spontaneously or are caused by chemical or radiation exposure.
• Mutagen: An agent that causes mutation.

Spontaneous Mutation

• Spontaneous Mutation arises from errors in DNA replication or chemical damage.

Induced Mutations

• Exposure can be intentional, accidental, or natural.
  • Ex: Radiation (X-rays, gamma rays), chemicals (alkylating agents, acridines).

Types of Mutations

• Mutations are classified by whether they remove, alter, or add a function, or by how they structurally alter DNA.
• The same single-gene disease can result from different types of mutations.
  • Ex Familial Hypercholesterolemia

Point Mutations

• Changes in a single DNA base - Transition being purine to purine or pyrimidine to pyrimidine, and transversion being purine to pyrimidine or vice versa.

Splice-Site Mutations

• Alters a site where introns are normally removed from mRNA causing either protein lengthening from intron retention or protein shortening by exon skipping.

Frameshift Mutations

• Frameshift mutations arise from adding or deleting bases if a gene is not a multiple of 3, which disrupts the reading frame, deleting or inserting DNA.
  • Tandem duplication where a part of a gene's sequence is repeated.

Pseudogenes and Transposons

• Pseudogenes (like protein coding genes) aren't translated to proteins. They come form gene duplication when there's meiosis misalignment.
• Transposons ("jumping genes") can alter gene function through disrupting sites and frame shifts it their insertion isn't a multiple of three balances

Expanding Repeats

• Expanding repeat - Gene grows where a small DNA sequence is copied and added.
  • Leads to anticipation (symptoms worsen over generations.)

Copy Number Variants (CNVs)

• CNVs are genetic variations where a specific DNA sequence varies in the number of copies among individuals.
• CNVs change duplicates, triplicates, or delete entire genes that affect gene function.
• CNVs contribute to genetic differences among individuals, and are particularly common in people with behavioral disorders; Ex ADHD, ASD, and Schizophrenia

Importance of position

• The location of a mutation affects the phenotype.
• Different mutations at the same site can have different effects.
• Conditional Mutation - Expressed only under environmental triggers.

Factors that Lessen the Effects of Mutation

• Synonymous Codons - The genetic code protects against mutation because synonymous codons specify the same amino acid.
• Stem Cell Protection - Oldest DNA stands segregate with the stem cell

DNA Repair mechanisms

• DNA polymerase checks the DNA sequence.
• Excision Repair - Incorrect nucleotides are removed and replaced.
• Nucleotide Excision Repair - Replaces up to 30 nucleotides. Base Excision Repair - Replaces 1-5 nucleotides.
• Mismatch repairs: Checks newly replicated DNA for misalignments.

Uniparental Disomy (UPD)

• Both chromosome copies inherited from only one parent.
  • Can be caused by nondisjunction in both gametes or trisomy followed by chromosome loss.
  • It can cause disease if it creates a homozygous recessive state or affects an imprinted gene.

Atypical Chromosomes

• The capability to repair DNA is crucial for health maintenance. Individuals with doubled repair gene mutations may experience disorders.

Hetrozygotes (those with one muted repair gene) can have hightened sensitivity to environmental damage

• Ex: Dwarfness

Hereditary nonpolyposis colon cancer (HNPCC)

• It has an associated DNA repair detect in mismatch repair which leads to a higher cancer risk of colorectal cancer.
• It affects 1/200 people which genetic testing is recommended those newly diagnosed with it colon cancer

Achyaxia Teleangiectasia (AT)

• A an autosomal receic disorder caused by defect in a kinase involved in the cell cycle checkpoint causing higher risk,axia , Teleangiectasia, delayed maturation and othe symptoms.

Conclusion

• DNA mutation changes sequences can lead to variance effects ranging from no noticeable change (diseases), occurring spontaneously or mutages.

A karyotype:

• It classifies DNA mutations based on type (point,insertion,deletion,expaning repeats) and location influencing their Impact on phenotype.
• DNA repairs mechanism exist correct damage but defects can lead to increased risk for cancer cells.

Portrait of a Chromosome

• Chromosome: Genetic information threadlike structure. These chromosomes are in the cells nucleus.
• The human genome has 20,000+ protein-encoding genes, with are amongst the spread 24 chromosome types.
• Chromosome-level illnesses come by troubling individual genes & regulation.
• Different chromosome types is done thru size/shape with staining and dyes
• Euchromation - Has a ton of protein with encoding sequences, appears light
• Heterchromation - has highly repetitive DNA sequences, appears dark

Essential parts of a chromosome are:

• Telomeres that are structured to have chromosome (6 TTAGGG) tips, and its shorten a person mitotic cell (mitosis that divides cells)
• Replication forks that begin to form
• Chromosome with metacentric if a centromere divides it in 2, and approx. equal length
• Each centromere includes DNA and protein as  spindle fibers attach when the cell is divided

Detecting Chromosomes

•  Chromosomes imaged from the nucleus, red blood not included.
• Chromosomes are checked in relatives known to have atypical chromosome.
• Chromosomes help track & see the chromosomes when the cancer is in progress

Subtemomeres

• Telomere repeats of protein rich areas and some encoding genes, that start transiting

Conclusion

Atypical chromosome numbers are shown in both numerical and structural chromosome that can have bad health effects. Technological studies with fetal DNA are keys to the start of chromosome abnormalities.