Genetics

• 1. Introduction

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  Genetics is the study of genes, genetic variation, and heredity in organisms. In the 19th century, a Moravian Augustinian friar named Gregor Mendel sat among rows of pea plants in Brno and noticed something stubborn. Some plants produced purple flowers and others white, but never a shade in between. From that simple observation, Mendel proposed that organisms inherit traits through discrete "units of inheritance." That phrase, still used today, was an early and somewhat ambiguous name for what we now call a gene. How does a unit of inheritance turn into a corkscrew-shaped molecule read three letters at a time? Why does a Siamese cat have dark ears and a pale body? And how did a word coined in 1905 come to organize an entire branch of biology? These are the questions this documentary will follow.

• 2. Before Mendel

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  Imre Festetics, a Hungarian noble who lived in Koszeg, was the first person to use the word "genetic" in a hereditarian sense, and he is considered the first geneticist. In his 1819 work The genetic laws of nature, he described several rules of biological inheritance. His second law matches the one Mendel would later publish, and his third law set out basic principles of mutation, making him a forerunner of Hugo de Vries. Festetics argued that the changes seen across generations of farm animals, plants, and humans follow scientific laws. He deduced that organisms inherit their characteristics rather than acquire them, recognized recessive traits, and saw that features from past generations could reappear later.

  Charles Darwin's 1859 On the Origin of Species implied a rival idea called blending inheritance, the notion that offspring receive a smooth blend of their parents' traits. Mendel's results showed traits that did not blend after hybridization, pointing instead to combinations of distinct genes. A competing belief held that individuals inherit traits their parents had strengthened, an idea commonly associated with Jean-Baptiste Lamarck and now known to be wrong. The experiences of individuals do not change the genes they pass to their children. Darwin also proposed pangenesis, which Francis Galton reformulated as both particulate and inherited, leaving the field crowded with theories waiting to be tested.

• 3. From Pea Plants To A Name

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  In 1865, Mendel presented his paper "Versuche uber Pflanzenhybriden," or "Experiments on Plant Hybridization," to the Naturforschender Verein in Brno. There he traced the inheritance of certain traits in pea plants and described the patterns mathematically. His work suggested that heredity was particulate, not acquired, and that many inheritance patterns could be explained through simple rules and ratios. The significance went largely unrecognized until 1900, after his death, when Hugo de Vries and other scientists rediscovered his research.

  William Bateson, a champion of Mendel's work, coined the word genetics in 1905. The adjective genetic predates the noun and was first used in a biological sense in 1860, deriving from the Greek genesis, meaning origin. Bateson was both a mentor and a beneficiary, aided significantly by Becky Saunders, Nora Darwin Barlow, and Muriel Wheldale Onslow of Newnham College at Cambridge. He popularized the term in his inaugural address to the Third International Conference on Plant Hybridization in London in 1906.

  Nettie Stevens began studying the mealworm in 1900. Over the next 11 years she found that females carried only the X chromosome while males carried both X and Y, concluding that sex is a chromosomal factor determined by the male. In 1911, Thomas Hunt Morgan argued that genes sit on chromosomes, drawing on a sex-linked white eye mutation in fruit flies. Two years later his student Alfred Sturtevant used genetic linkage to show that genes are arranged linearly along the chromosome.

• 4. Finding The Molecule

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  In 1928, Frederick Griffith discovered transformation, the strange fact that dead bacteria could pass genetic material to living bacteria and change them. Sixteen years later, in 1944, the Avery-MacLeod-McCarty experiment identified DNA as the molecule responsible. Hammerling had established the nucleus as the repository of genetic information in eukaryotes in 1943, working on the single-celled alga Acetabularia. The Hershey-Chase experiment in 1952 confirmed that DNA, not protein, is the genetic material of the viruses that infect bacteria.

  James Watson and Francis Crick determined the structure of DNA in 1953, building on the X-ray crystallography of Rosalind Franklin and Maurice Wilkins, which indicated a helical, corkscrew shape. Their double-helix model placed two strands of DNA with nucleotides pointing inward, each matching a complementary partner on the opposite strand, like rungs on a twisted ladder. The arrangement showed that genetic information lives in the sequence of nucleotides. It also suggested replication: separate the strands, and each can template a new partner. This gives DNA its semi-conservative nature, where one strand of new DNA comes from an original parent strand.

  The years that followed brought an explosion of research. Tomoko Ohta amended the neutral theory of molecular evolution in 1973 by publishing the nearly neutral theory, stressing the role of natural selection and environment in how fast genetic evolution occurs. In 1977, Frederick Sanger introduced chain-termination DNA sequencing, letting scientists read a molecule's nucleotide sequence. In 1983, Kary Banks Mullis developed the polymerase chain reaction to isolate and amplify a specific section of DNA. The Human Genome Project, the Department of Energy, the NIH, and the private effort at Celera Genomics together sequenced the human genome in 2003.

• 5. The Rules Of Inheritance

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  Mendel showed that flowers on a single pea plant were either purple or white, never an intermediate, revealing that inheritance passes through discrete units called genes. The discrete versions of the same gene are called alleles. The pea is a diploid species, so each plant carries two copies of each gene, one from each parent, a pattern shared by humans and many other species. An organism with two copies of the same allele is homozygous at that locus, while one with two different alleles is heterozygous. Its full set of alleles is its genotype, and its observable traits make up its phenotype. When a dominant allele's qualities mask a recessive one, the recessive qualities recede and go unobserved, though some alleles show incomplete dominance with an intermediate phenotype or codominance expressing both at once.

  When two organisms reproduce sexually, their offspring randomly inherit one of each parent's two alleles. This is Mendel's first law, the Law of Segregation. Mendel found that crossing heterozygous organisms gives the dominant trait at odds of 3:1. Geneticists calculate such probabilities using theoretical and empirical probabilities, the product rule, and the sum rule. To track all of this they rely on diagrams and symbols, marking the usual non-mutant allele with a "+" and labeling parents the "P" generation, their offspring the "F1" generation, and the next cross the "F2" generation. The Punnett square predicts cross-breeding outcomes, and pedigree charts map a trait through a family tree.

  Genes generally assort independently, so inheriting an allele for pea color is unrelated to inheriting one for flower color, a pattern called Mendel's law of independent assortment. Genes also interact. In the Blue-eyed Mary, Omphalodes verna, one gene sets flower color as blue or magenta, but a second gene decides whether the flower has any color at all. Two copies of the white allele produce white flowers regardless of the first gene, an interaction called epistasis. Continuous traits like human height arise from many genes shaped by environment, captured by a measure called heritability. Human height has a heritability of 89 percent in the United States, but only 62 percent in Nigeria, where access to nutrition and health care varies more widely.

• 6. Inside The Double Helix

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  Deoxyribonucleic acid is built from deoxyribose sugar, a phosphate group, and one of four bases: adenine, cytosine, guanine, and thymine. Phosphates bond with sugars to form long backbones, and bases pair across them, thymine with adenine and cytosine with guanine, like rungs on a ladder. Together a base, phosphate, and sugar form a nucleotide, and chains of nucleotides coil into a double helix and wrap around proteins called histones. DNA wound around histones forms chromosomes, while some viruses use RNA as their genetic material instead.

  Genes lie linearly along these base-pair sequences. Bacteria usually carry a single circular genophore, while eukaryotes such as plants and animals hold their DNA in multiple linear chromosomes. The largest human chromosome runs about 247 million base pairs long. In eukaryotes the DNA is packaged into chromatin made of nucleosomes, segments wound around cores of histone proteins, and the combined sequence of all chromosomes is the genome. Ruth Sager helped discover nonchromosomal genes that sit outside the nucleus, often in chloroplasts in plants or in mitochondria, and these can still pass to offspring through either partner.

  Most animals and many plants are diploid, with two copies of every gene located at identical loci on homologous chromosomes. Many species carry sex chromosomes, and in humans the Y chromosome holds the gene that triggers male development, even as it has lost most of its content and genes while the X chromosome remains gene-rich. Mary Frances Lyon discovered X-chromosome inactivation during reproduction, which prevents passing on twice as many genes. Her discovery opened the way to understanding X-linked diseases.

• 7. Copying And Reshuffling Genes

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  Mitosis copies a cell's full genome so that each daughter cell inherits one copy, and it is the basis for asexual reproduction. Offspring genetically identical to their parents are called clones. Eukaryotes often use sexual reproduction instead, alternating between haploid forms with single genome copies and diploid forms with double copies. Haploid cells fuse into a diploid cell with paired chromosomes, and diploid organisms form haploids by dividing without replicating their DNA, so daughter cells randomly inherit one of each chromosome pair. In most animals and many plants the haploid form is reduced to single-cell gametes such as sperm or eggs.

  Bacteria gather genetic information without the haploid-diploid cycle. Through conjugation, a bacterium transfers a small circular piece of DNA to another, and through transformation it takes up raw DNA fragments from the environment. Both produce horizontal gene transfer, moving genetic fragments between organisms that would otherwise be unrelated. Natural bacterial transformation acts as a sexual process for moving DNA between cells of the same species, and its main adaptive function appears to be repairing DNA damage in the recipient.

  Genes on the same chromosome would in theory never recombine, yet they do through chromosomal crossover, where chromosomes exchange stretches of DNA during meiosis. Harriet Creighton and Barbara McClintock performed the first cytological demonstration of crossing over in 1931, working with corn. The probability of crossover between two points depends on the distance between them. Genes far apart are inherited as if uncorrelated, while genes close together show genetic linkage and tend to be inherited together. Combining these linkage amounts produces a linear linkage map of the genes' arrangement along the chromosome.

• 8. When Genes Meet The World

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  Genes express their effects by producing proteins, beginning when an RNA molecule is built to match a gene's DNA sequence in a process called transcription. That messenger RNA then guides translation, where each codon of three nucleotides maps to one of twenty amino acids or a signal to stop. This correspondence is the genetic code, and the information flows one way only. Francis Crick named this the central dogma of molecular biology. A single nucleotide difference can change an amino acid, as in sickle-cell anemia, where one base difference in the coding region for the beta-globin section of hemoglobin reshapes red blood cells into sickles that clog or degrade in blood vessels. Some DNA is transcribed into non-coding RNA, such as ribosomal RNA, transfer RNA, and microRNA, which serve cell functions without becoming protein.

  The Siamese cat shows how environment shapes the final phenotype. Its genes code for dark hair, but the pigment-producing proteins are temperature-sensitive and denature in warmer areas, so dark hair appears only at the cooler extremities like the legs, ears, tail, and face. Phenylketonuria offers a sharper example. The mutation disrupts the body's ability to break down the amino acid phenylalanine, causing a toxic build-up that leads to progressive intellectual disability and seizures, yet a strict diet avoiding that amino acid keeps a person healthy. To separate nature from nurture, scientists compare identical twins from one zygote with fraternal twins, who differ as much as ordinary siblings. One famous case studied the Genain quadruplets, identical quadruplets all diagnosed with schizophrenia.

  Not every gene is active at once. Transcription factors bind DNA to promote or block transcription, as in Escherichia coli, where tryptophan molecules bind a repressor that then shuts off the genes for making tryptophan, a negative feedback loop. Within eukaryotes, epigenetic features sit on top of the DNA sequence and pass from one cell generation to the next, letting identical genomes produce very different cell types. Rare exceptions like paramutation even show multigenerational inheritance, a striking departure from DNA as the sole basis of heredity.

  Errors during DNA replication, called mutations, occur at very low rates, roughly one error in every 10 to 100 million bases, thanks to the proofreading of DNA polymerases. Mutagenic chemicals interfere with base-pairing, UV radiation damages DNA structure, and reactive oxygen species from aerobic respiration are a particularly important source of damage. Misalignment during meiosis can also create large structural changes such as duplications, inversions, deletions, and chromosomal translocations. Studies in the fly Drosophila melanogaster suggest that when a mutation changes a protein, about 70 percent of these mutations are harmful, with the rest neutral or weakly beneficial.

  Population genetics studies how genetic differences are distributed and how those distributions shift over time. Allele frequencies change mainly through natural selection, alongside mutation, genetic drift, genetic hitchhiking, artificial selection, and migration. Over many generations genomes can change enough to produce evolution, and adaptation lets a species become better suited to its environment. Speciation forms new species, often after geographical separation cuts off gene exchange. Comparing the homology of different genomes lets scientists estimate evolutionary distance and divergence times, building evolutionary trees of common descent.

  Cancer is a genetic disease driven by an internal process of natural selection within the body. As cells divide, mutations occasionally arise that are not inherited by offspring but can make cells grow and divide more often. To become cancerous, a cell must accumulate mutations in three to seven genes, after which it can divide without growth factors, ignore inhibitory signals, and grow indefinitely. Such a cell may escape the epithelium, cross the endothelium of a blood vessel, and colonize a new organ as a deadly metastasis. The most frequent mutations are a loss of function in the p53 tumor suppressor or its pathway, and gain-of-function mutations in the Ras proteins and other oncogenes.

  Restriction enzymes cut DNA at specific sequences to produce predictable fragments, which gel electrophoresis then sorts by length. Ligation enzymes join fragments from different sources into recombinant DNA, the kind associated with genetically modified organisms, often carried on plasmids, the short circular DNA molecules used in molecular cloning. The polymerase chain reaction amplifies targeted DNA exponentially from extremely small amounts, which also makes it a way to detect specific sequences. Chain-termination sequencing, developed in 1977 by a team led by Frederick Sanger, is still routinely used, and genome assembly stitches together many fragments computationally.

  A few model organisms anchor most genetics research because existing work attracts new researchers and short generation times ease genetic manipulation. The widely used set includes Escherichia coli, the plant Arabidopsis thaliana, baker's yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, the zebrafish Danio rerio, and the house mouse Mus musculus. Medical genetics uses linkage and pedigree charts to locate disease genes, while genome wide association studies scan whole populations for multigenic traits. The field of pharmacogenetics studies how genotype affects drug responses, and next-generation sequencing has driven hopes of resequencing a human genome for a thousand dollars.

  The power to read and cut DNA eventually raised the question of editing human heredity itself. On the 19th of March 2015, a group of leading biologists urged a worldwide ban on the clinical use of methods such as CRISPR and zinc finger to edit the human genome in a heritable way. In April 2015, Chinese researchers reported basic research editing the DNA of non-viable human embryos using CRISPR, turning a once-theoretical debate into an immediate one.