6.1 The concept of the gene and its evolution

The concept of the gene has evolved significantly since Mendel's time. From discrete units of heredity to complex entities, our understanding has expanded with scientific advancements. Genes are now seen as more than just DNA sequences coding for proteins.

Modern genomics has revealed the intricacies of gene function and regulation. Alternative splicing, non-coding RNAs, and distant regulatory elements challenge traditional gene definitions. These discoveries highlight the dynamic nature of genetic information and its expression.

Evolution of the Gene Concept

Mendel's Experiments and the Foundation of Genetics

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• Gregor Mendel conducted experiments on pea plants in the mid-19th century
• Established fundamental principles of heredity
  • Concepts of dominant and recessive traits
  • Law of segregation (alleles separate during gamete formation)
• Wilhelm Johansen coined the term "gene" in 1909 to describe the discrete units of heredity identified by Mendel

Linking Genes to Proteins and the Structure of DNA

• George Beadle and Edward Tatum proposed the one gene-one enzyme hypothesis in the 1940s
  • Suggested that genes act by directing the synthesis of specific enzymes
  • Supported by experiments in the bread mold Neurospora crassa
• James Watson and Francis Crick discovered the double helix structure of DNA in 1953
  • Provided the physical basis for understanding genes as sequences of nucleotides
  • Complementary base pairing (A-T, G-C) enables DNA replication and information storage
• Recombinant DNA technology developed in the 1970s
  • Allowed scientists to isolate, manipulate, and study individual genes
  • Ushered in the era of molecular genetics (gene cloning, sequencing, and manipulation)
• The Human Genome Project, completed in 2003, marked a milestone in understanding the complete set of human genes and their organization within the genome

Central Dogma of Molecular Biology

Information Flow and the Genetic Code

• Francis Crick proposed the central dogma in 1958
  • Genetic information flows from DNA to RNA to proteins
  • Proteins are the functional products of genes
• Transcription involves the synthesis of messenger RNA (mRNA) from a DNA template
• Translation refers to the synthesis of proteins using the genetic code carried by mRNA
• The genetic code is a set of rules that specifies the correspondence between codons (triplets of nucleotides) in mRNA and amino acids in proteins
  • 64 possible codons, with 61 coding for amino acids and 3 serving as stop codons
  • Redundancy in the genetic code (multiple codons can code for the same amino acid)

Expanding and Challenging the Central Dogma

• The central dogma has been expanded to include additional processes
  • Reverse transcription (RNA to DNA) is essential for the life cycles of retroviruses (HIV)
  • RNA replication is crucial for some RNA viruses (influenza)
• The discovery of non-coding RNAs has revealed that not all genetic information is translated into proteins
  • MicroRNAs (miRNAs) regulate gene expression by binding to mRNA and inhibiting translation
  • Long non-coding RNAs (lncRNAs) play roles in gene regulation and chromatin organization
• Epigenetic modifications can alter gene expression without changing the underlying DNA sequence
  • DNA methylation (addition of methyl groups to cytosine bases) can silence gene expression
  • Histone modifications (acetylation, methylation) can affect chromatin structure and gene accessibility

Defining Genes in the Genome

Challenges to the Classical Gene Concept

• Alternative splicing allows a single gene to produce multiple protein isoforms
  • Exons can be included or excluded in the final mRNA, leading to different protein products
  • Estimates suggest that over 90% of human genes undergo alternative splicing
• Overlapping genes blur the boundaries between genes
  • The same DNA sequence can be read in different reading frames to produce distinct proteins
  • Examples include the INK4a/ARF locus in humans, which encodes two tumor suppressor proteins
• Pseudogenes are non-functional gene-like sequences that have lost their protein-coding ability due to mutations
  • Can be difficult to distinguish from functional genes based on sequence alone
  • May have regulatory roles or be transcribed into non-coding RNAs

Expanding the Definition of a Gene

• Enhancers, silencers, and other regulatory elements can be located far from the genes they control
  • These distant regulatory regions are important for fine-tuning gene expression
  • Enhancers can be located hundreds of kilobases away from their target genes
• Pervasive transcription suggests that a large portion of the genome is transcribed into RNA but not necessarily translated into proteins
  • Non-coding RNAs play important roles in gene regulation and cellular functions
  • The ENCODE project revealed that over 80% of the human genome is transcribed at some point
• Gene fusions can create new functional genes by combining parts of two or more genes
  • Can occur through chromosomal rearrangements or read-through transcription
  • The BCR-ABL fusion gene is a hallmark of chronic myeloid leukemia

Genomic Technologies and Gene Function

Sequencing and Comparative Genomics

• High-throughput DNA sequencing technologies have enabled rapid and cost-effective sequencing of entire genomes
  • Illumina sequencing uses reversible terminator chemistry and bridge amplification
  • Pacific Biosciences and Oxford Nanopore technologies allow for long-read sequencing
• Comparative genomics involves comparing the genomes of different organisms
  • Reveals evolutionary conservation of genes and their functions across species
  • Helps identify lineage-specific genes and genomic adaptations
• Transcriptomics studies the complete set of RNA transcripts produced by a cell or tissue
  • RNA-seq uses high-throughput sequencing to quantify gene expression levels
  • Provides insights into alternative splicing and the dynamic nature of gene expression

Genetic Variation and Functional Genomics

• Genome-wide association studies (GWAS) identify genetic variants associated with complex traits and diseases
  • Compare the genomes of individuals with and without a particular trait or disease
  • Single nucleotide polymorphisms (SNPs) are commonly used as genetic markers
• Genome editing technologies, such as CRISPR-Cas9, allow for precise manipulation of genes
  • Guide RNAs direct the Cas9 endonuclease to create targeted double-strand breaks in DNA
  • Enables the study of gene function through knockout, knockin, and mutagenesis experiments
• Single-cell genomics analyzes the genomes and transcriptomes of individual cells
  • Reveals heterogeneity in gene expression within tissues and the importance of rare cell types
  • Helps identify cell lineages and developmental trajectories
• Integration of genomic data with other omics data (proteomics, metabolomics) provides a comprehensive understanding of cellular functions and organismal phenotypes
  • Systems biology approaches aim to model the complex interactions between genes, proteins, and metabolites
  • Network analysis can reveal key regulatory hubs and pathways involved in specific biological processes