Gene

• 1. Introduction

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  The word gene carries two different meanings inside biology, and the gap between them has tangled scientists for decades. One meaning, the Mendelian gene, is the basic unit of heredity. The other, the molecular gene, is a sequence of nucleotides in DNA that is transcribed to produce RNA. A length of 1500 base pairs once seemed like a reasonable guess for a typical gene back in 1965. That estimate would not survive contact with reality. How did a single word come to hold two definitions at once? Why does even a strict definition admit, in the words of one textbook, that there is no definition that is entirely satisfactory? And how did a man counting peas in a Moravian garden set all of this in motion before the term gene even existed?

• 2. Two Meanings, One Word

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  Richard Dawkins, in The Selfish Gene, argued that the Mendelian gene is the unit of evolution. This is the classical gene of genetics, referring to any heritable trait, and it lives in a separate world from the molecular gene used across biochemistry and molecular biology. The molecular gene is described in terms of DNA sequence, and many of its definitions are misleading or incorrect.

  Very early work suggested that one gene makes one protein, originally phrased as one gene, one enzyme. That tidy idea broke down. Genes that produce repressor RNAs were proposed in the 1950s, and by the 1960s textbooks already included noncoding genes for functional RNA molecules like ribosomal RNA and tRNA alongside protein-coding genes.

  Kostas Kampourakis, in his book Making Sense of Genes, adds a crucial requirement to the molecular definition: function. He considers genes as DNA sequences encoding information for functional products, whether proteins or RNA molecules. Stretches of DNA that produce non-functional transcripts do not qualify. Transcribed pseudogenes and junk RNA produced as noise from transcription errors fail the test.

  Despite both kinds of gene being known for more than 50 years, some textbooks and publications still define a gene only as a DNA sequence that specifies a protein. A 2021 article in American Scientist took this restricted line, insisting that a true gene must be both transcribed and translated. Critics have pushed back against this so-called standard definition, calling for an expanded one, even though the broader view has been recognised for more than half a century.

• 3. From Peas To Pangenes

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  Gregor Mendel never used the word gene. From 1857 to 1864, in Brno in the Austrian Empire, today's Czech Republic, he studied inheritance patterns in 8000 common edible pea plants, tracking distinct traits from parent to offspring. He described his results mathematically as 2 to the power of n combinations, where n is the number of differing characteristics. He explained the outcome in terms of discrete inherited units giving rise to physical characteristics.

  Before Mendel, the dominant theory was blending inheritance, the idea that each parent contributed fluids that mixed to produce the offspring. Charles Darwin built a rival theory he called pangenesis, from the Greek for all and birth. He used the word gemmule for the hypothetical particles that would mix during reproduction.

  Mendel's work went largely unnoticed after its first publication in 1866. It was rediscovered in the late 19th century by Hugo de Vries, Carl Correns, and Erich von Tschermak. In 1889, de Vries published Intracellular Pangenesis and named his hereditary units pangenes, after Darwin's 1868 pangenesis theory.

  William Bateson coined the word genetics in 1906, from a Greek root meaning generative. Three years later, in 1909, Wilhelm Johannsen introduced the term gene, from the Greek gonos, meaning offspring and procreation. Johannsen had already drawn the distinction between genotype and phenotype, the genetic makeup of an organism against its observable traits. Eduard Strasburger, among others, still clung to the word pangene for the fundamental unit of heredity.

• 4. Reading The Double Helix

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  Rosalind Franklin and Maurice Wilkins studied the structure of DNA using X-ray crystallography. Their work led James D. Watson and Francis Crick to publish a model of the double-stranded DNA molecule, whose paired nucleotide bases suggested a mechanism for genetic replication. DNA itself had been shown to be the molecular repository of genetic information by experiments in the 1940s to 1950s.

  DNA consists of a chain made from four nucleotide subunits, each built from a five-carbon sugar called 2-deoxyribose, a phosphate group, and one of four bases: adenine, cytosine, guanine, and thymine. Adenine pairs with thymine through two hydrogen bonds, while cytosine and guanine form three. The two strands must therefore be complementary, and they run in opposite directions. One end carries an exposed hydroxyl group, the 3' end; the other carries an exposed phosphate, the 5' end.

  In the early 1950s the prevailing view held that genes in a chromosome acted like beads on a string. Seymour Benzer's experiments with mutants in the rII region of bacteriophage T4, from 1955 to 1959, showed instead that individual genes have a simple linear structure, likely equivalent to a linear section of DNA.

  The lab of Max Birnstiel was first to isolate single genes in 1965, the ribosomal RNA genes from Xenopus laevis. In 1972, Walter Fiers and his team first determined the sequence of a gene, that of the bacteriophage MS2 coat protein. Frederick Sanger's chain-termination DNA sequencing, developed in 1977, turned sequencing into a routine laboratory tool. An automated version of Sanger's method was used in early phases of the Human Genome Project.

• 5. The Architecture Of A Gene

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  The actual protein coding sequence is often only a small part of a protein-coding gene. The structure includes introns and untranslated regions of the mature mRNA, and even noncoding genes can carry introns removed during processing.

  Every gene is bound to regulatory sequences required for its expression. A promoter sequence comes first, recognized by transcription factors that recruit RNA polymerase to begin transcription, often at a consensus sequence like the TATA box. Strong promoters drive high rates of transcription; weak ones initiate it less often. Eukaryotic promoter regions are far more complex and harder to identify than those of prokaryotes.

  Enhancers can sit many kilobases upstream or downstream of a gene. They bind an activator protein and cause the DNA to loop, bringing the regulatory sequence close to the RNA polymerase binding site. Silencers do the opposite, binding repressor proteins that make the DNA less available. The mature messenger RNA carries untranslated regions at both ends, with binding sites for ribosomes and start and stop codons. The ends of transcripts are defined by cleavage and polyadenylation sites, where a string of about 200 adenosine monophosphates is added to protect the mRNA from degradation.

  Many prokaryotic genes are organized into operons, several protein-coding sequences transcribed together as a polycistronic mRNA. The term cistron here means gene. A repressor can bind the operator region at the start of the operon to block transcription, as in the Lac operon. Some eukaryotic genes are stranger still: introns can be larger than exons and even hold other genes nested inside them, and overlapping genes can share the same DNA on opposite strands or in different reading frames.

• 6. Genomes And Chromosomes

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  A chromosome consists of a single, very long DNA helix carrying thousands of genes. The spot where a particular gene sits is its locus, and each locus holds one allele, though members of a population may carry different alleles there. Eukaryotic genes are stored on large linear chromosomes, packed in the nucleus with storage proteins called histones to form nucleosomes, the bundled form known as chromatin.

  Eukaryotic chromosomes carry more than genes. Replication origins start the copying of DNA. Telomeres cap the ends with repetitive sequences and prevent degradation, shortening each time the genome is replicated and implicated in aging. The centromere binds spindle fibres that separate sister chromatids during cell division.

  Prokaryotes, the bacteria and archaea, typically store their genomes on a single circular chromosome. They sometimes add small circles of DNA called plasmids, which carry only a few genes and pass between individuals. Antibiotic resistance genes usually ride on plasmids and can move even between different species through horizontal gene transfer.

  Protein-coding DNA makes up barely 2% of the human genome, and complex organisms carry a majority of DNA without identified function, long called junk DNA. Yet about 80% of the bases in the genome may be expressed, so that label may be a misnomer. Genome size and gene count vary widely: rice holds more than 46,000 protein-coding genes, and the Earth's proteome is estimated at 5 million sequences.

• 7. Counting The Human Genome

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  Frameshift mutations in the rIIB gene of bacteriophage T4 demonstrated in 1961 that three sequential bases of DNA code for each amino acid. There are 64 possible codons but only 20 standard amino acids, so the code is redundant, with multiple codons specifying the same amino acid. This correspondence is universal among all species.

  The number of human genes has shifted as definitions and detection methods improved. Early predictions in the 1960s and 1970s, based on mutation load and counts of mRNAs, tended toward about 30,000 protein-coding genes. During the 1990s, guesses climbed as high as 100,000. The initial draft sequences of the human genome confirmed the earlier figure of about 30,000, but that estimate has since fallen to about 19,000 through the ongoing GENCODE annotation project. The latest estimates from Ensembl suggest 26,000 noncoding genes.

  Only a small portion of an organism's genes are essential for survival. In bacteria, an estimated 250 to 400 genes are essential for Escherichia coli and Bacillus subtilis, less than 10% of their genes, with half being orthologs largely involved in protein synthesis. The budding yeast Saccharomyces cerevisiae has roughly 1000 essential genes, about 20%, while mice and humans are estimated at around 2000, about 10%. The synthetic organism Syn 3 has a minimal genome of 473 essential and quasi-essential genes, yet 149 of them have unknown function.

  Gene names are set by the HUGO Gene Nomenclature Committee, which assigns each known human gene a unique approved name and symbol. Symbols are kept consistent with other members of a gene family and with homologs in other species, particularly the mouse, given its role as a common model organism.

• 8. Editing The Code

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  Since the 1970s, techniques have been developed to add, remove, and edit genes in an organism, the practice known as genetic engineering. Newer genome engineering methods use engineered nuclease enzymes to create targeted DNA repair in a chromosome, disrupting or editing a gene when the break is repaired. The related term synthetic biology describes extensive genetic engineering of an organism.

  Genetic engineering is now a routine research tool. Genes are easily added to bacteria, and lineages of knockout mice with a specific gene's function disrupted are used to investigate what that gene does. Many organisms have been modified for agriculture, industrial biotechnology, and medicine.

  In multicellular organisms, the embryo is typically engineered and grows into the adult genetically modified organism. The genomes of cells in an adult can also be edited through gene therapy to treat genetic diseases, carrying the molecular gene from the laboratory bench into the clinic.