The fruit fly packs its whole genome into just four pairs of chromosomes, few enough that each one can be recognised by sight. That simplicity made the fly the place where scientists first proved that genes sit in a fixed order along chromosomes, and turned that idea into maps. Some fly cells also copy their chromosomes again and again without dividing, producing giant striped versions that can be read almost like a physical map. Mapping also showed that the fly breaks some rules other animals follow, most strikingly at the tips of its chromosomes.
What a Fruit Fly’s Chromosomes Look Like
A female fly carries two X chromosomes, while a male carries one X and one Y. Besides these sex chromosomes there are two large ones, numbered 2 and 3, each with two long arms either side of its centre. The fourth chromosome is a tiny dot that carries only around a hundred genes. The non-repetitive part of the genome, where most genes lie, adds up to about 130 million DNA letters.1PubMed Central. Sub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells That makes the fly’s genome roughly one twenty-fifth the size of a human’s.
Having so few chromosomes is what made the fly so useful. A trait can quickly be linked to one of them, and each has a distinct shape under the microscope. Flies also breed in about ten days, so many generations fit into a few months.
Each chromosome mixes two kinds of DNA. Open, gene-rich stretches are called euchromatin, and tightly packed stretches are called heterochromatin. The tightly packed DNA clusters around the centres of chromosomes and is full of repeated sequences.2Science. Sequence finishing and mapping of Drosophila melanogaster heterochromatin Those regions hold mostly short repeats and few genes, and the few genes there are mostly switched off. Repeats are hard to read because the pieces look so alike. Even so, about 20 million DNA letters of it could be mapped and read.3Science. Sequence finishing and mapping of Drosophila melanogaster heterochromatin The Y chromosome is made almost entirely of this silent, tightly packed DNA, though it carries a handful of genes needed for male fertility.4PubMed Central. The Epigenome of Evolving Drosophila Neo-Sex Chromosomes: Dosage Compensation and Heterochromatin Formation
In most animals, matching chromosomes from mother and father line up only when eggs or sperm are being made. In flies and their relatives, matching chromosomes sit side by side as a normal part of ordinary cells.5PubMed Central. Homologous Chromosome Pairing in Drosophila melanogaster Proceeds through Multiple Independent Initiations
The Giant Chromosomes That Made Mapping Possible
Normally a cell copies its DNA once and then divides. Some fly cells instead copy their DNA over and over without dividing.6PubMed Central. Polyteny: still a giant player in chromosome research The copies stay tightly lined up and form one oversized chromosome, called a polytene chromosome.7PubMed Central. Polyteny: still a giant player in chromosome research You find these giants in the salivary glands of fly larvae.
Because hundreds of copies lie side by side, the giant chromosomes show a fixed pattern of dark and light bands. Each chromosome arm can be divided into numbered regions, which gives every gene an address, like a street map. One catch: the tightly packed regions are copied less often, so they look shrunken in the giants. Some of them only became visible when scientists used mutant flies that copy them fully.8PubMed Central. The structure of an endogenous Drosophila centromere reveals the prevalence of tandemly repeated sequences able to form i-motifs
The bands become a map because the same pattern appears in every larva of the species. A missing or flipped stretch shows up as a change in that pattern, and matching such changes to traits links genes to particular bands.
Seeing them takes little equipment. A squashed salivary gland on a slide spreads the chromosomes out, and an ordinary classroom light microscope is enough to view them.
How Scientists Pin Genes to Chromosomes
The oldest method relies on crossing over. When eggs and sperm form, matching chromosomes swap pieces. Genes far apart get separated by these swaps more often than genes close together. So how often two traits are inherited together gives their distance, and that was the basis of the first gene map, made in flies in 1913.
Deletions offer a sharper tool. A fly missing one stretch of a chromosome reveals whether a recessive mutation lies in that stretch. Engineered deletions now cover virtually the entire fly genome.9PubMed Central. Toward a complete Drosophila deficiency kit A gene is placed between the edges of two overlapping deletions, not by one deletion alone.10PubMed Central. The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome So the number of deletion edges, not the size of the deletions, sets how precise the map is.11PubMed Central. The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome A mutation can then be narrowed to a very small region with a few simple crosses.12PubMed Central. The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome
Balancer chromosomes solve a different problem: keeping mutations in stock. A balancer is a specially rearranged chromosome, with many flipped segments, that stops swapping with its partner.13PubMed Central. Rare recombination events generate sequence diversity among balancer chromosomes in Drosophila melanogaster Swaps that do happen produce chromosomes that can’t separate properly or that carry lethal missing or doubled pieces.14PubMed Central. Third Chromosome Balancer Inversions Disrupt Protein-Coding Genes and Influence Distal Recombination Events in Drosophila melanogaster Balancers also carry mutations that kill or sterilise flies with two copies.15PubMed Central. The joy of balancers So a harmful mutation can be kept in a lab stock for generations without being lost.16PubMed Central. The joy of balancers The flipped segments can break genes where the breaks fall, though.17PubMed Central. Third Chromosome Balancer Inversions Disrupt Protein-Coding Genes and Influence Distal Recombination Events in Drosophila melanogaster Balancers carry visible markers, so researchers can spot which flies have them, and they are among the most used tools in fly labs.
Chromosome Ends Made of Jumping Genes
Chromosome tips shorten a little each time DNA is copied, so cells need a way to rebuild them. Most animals, including humans, use an enzyme called telomerase to add short repeats to the tips.18PubMed Central. Transcriptional coupling of telomeric retrotransposons with the cell cycle A jumping gene is a stretch of DNA that can copy itself into new places. Fruit flies instead rely on three transposons (jumping genes) named HeT-A, TART and TAHRE.19PubMed Central. Transcriptional coupling of telomeric retrotransposons with the cell cycle These insert themselves specifically onto chromosome ends, forming long arrays that make up for lost DNA.20PubMed Central. Evolution of diverse mechanisms for protecting chromosome ends by Drosophila TART telomere retrotransposons HeT-A and TART do most of the work, with TAHRE added only occasionally.21PubMed Central. Drosophila: Retrotransposons Making up Telomeres
Most are parasites of the genome, but the fly tamed three of them for a useful job. Human tips are short repeats of six letters added by an enzyme, while fly tips are long pieces of whole jumping genes.
The centres are unusual too. The centre of each chromosome is marked by a special packing protein.22PubMed Central. Turnover of retroelements and satellite DNA drives centromere reorganization over short evolutionary timescales in Drosophila It sits on islands of jumping genes flanked by large blocks of short repeated sequences.23PubMed Central. Functional Significance of Satellite DNAs: Insights From Drosophila One such repeat sits only at the centre of chromosome 3.24PubMed Central. The structure of an endogenous Drosophila centromere reveals the prevalence of tandemly repeated sequences able to form i-motifs In closely related fly species, centres switch between jumping genes and repeats over short evolutionary times.25PubMed Central. Turnover of retroelements and satellite DNA drives centromere reorganization over short evolutionary timescales in Drosophila
Most jumping genes are harmful because they can land inside genes. Flies use small RNA molecules called piRNAs as an immune system against them in egg- and sperm-making tissue.26PubMed Central. Specialized piRNA Pathways Act in Germline and Somatic Tissues of the Drosophila Ovary The piRNAs match jumping-gene sequences and guide proteins that silence them while leaving the fly’s own genes alone.27PubMed Central. The piRNA Pathway Guards the Germline Genome Against Transposable Elements When this system fails, jumping genes overrun the genome and the fly becomes sterile.28PubMed Central. The piRNA Pathway Guards the Germline Genome Against Transposable Elements
How Packing Switches Genes On and Off
When a gene is moved next to tightly packed DNA, the packing can spread over it and switch it off at random in some cells.29PubMed Central. Position-Effect Variegation, Heterochromatin Formation, and Gene Silencing in Drosophila A fly with a rearranged red-eye gene of this kind has eyes mottled red and white.30PubMed Central. Position-Effect Variegation, Heterochromatin Formation, and Gene Silencing in Drosophila One protein puts chemical tags on the packing proteins, and another binds those tags and does the silencing.31PubMed Central. Live analysis of position-effect variegation in Drosophila reveals different modes of action for HP1a and Su(var)3-9 Mutations in either protein weaken the silencing, making the eyes redder.32PubMed Central. Live analysis of position-effect variegation in Drosophila reveals different modes of action for HP1a and Su(var)3-9
Mottled eyes became a famous tool because the colour is easy to score by eye. Researchers searched for mutations that made the eyes redder or whiter, and each such mutation pointed to a protein in the packing system.
Mapping where 53 packing proteins sit showed the genome splits into five main types of packing.33PubMed Central. Systematic protein location mapping reveals five principal chromatin types in Drosophila cells Some of these domains stretch over more than 100,000 DNA letters.34PubMed Central. Systematic protein location mapping reveals five principal chromatin types in Drosophila cells Sorting by chemical tags instead gives nine combined types.35PubMed Central. Comprehensive analysis of the chromatin landscape in Drosophila So the exact count depends on what is measured, but a few broad types cover the whole genome.
How Chromosomes Fold in Three Dimensions
DNA folds into self-contained loops called topologically associating domains, or TADs.36PubMed Central. TADs are 3D structural units of higher-order chromosome organization in Drosophila The fly genome has about 4,100 of these folding domains, from 3,000 to 460,000 DNA letters long and typically about 13,000.37PubMed Central. Sub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells Together they cover more than 92% of the non-repetitive genome.38PubMed Central. Sub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells Domains often match the packing types, with each holding a particular mix of chemical tags.39PubMed Central. TADs are 3D structural units of higher-order chromosome organization in Drosophila Genes within one domain interact more with each other, and the borders help keep switches from affecting genes in the next domain.
Proteins called insulators sit at many domain borders, some binding DNA and others linking distant sites together.40PubMed Central. Chromatin Insulator Factors Involved in Long-Range DNA Interactions and Their Role in the Folding of the Drosophila Genome Yet in early embryos lacking any one of three main insulator proteins, about 90% of domains still form, with weaker borders.41PubMed Central. CTCF, BEAF-32, and CP190 are not required for the establishment of TADs in early Drosophila embryos but have locus-specific roles Silenced developmental genes can touch each other across long distances, but mostly in pairs and rarely.42PubMed. Multiplexed chromatin imaging reveals predominantly pairwise long-range coordination between Drosophila Polycomb genes And about 30 to 40% of domains are shared with a fly species separated by about 49 million years.43PubMed Central. Topologically associating domains and their role in the evolution of genome structure and function in Drosophila Insulators are not essential for domains, though they still matter at particular spots.
How the X and Y Chromosomes Differ
Males have one X but females have two, so males would otherwise make half as much from X genes. In males, a protein group marks active X genes with a chemical tag that loosens packing and raises activity.44PubMed Central. Drosophila MSL complex globally acetylates H4 Lys16 on the male X chromosome for dosage compensation Almost all active genes on the male X carry high levels of this tag.45PubMed Central. Drosophila MSL complex globally acetylates H4 Lys16 on the male X chromosome for dosage compensation The male X is therefore unusually open and busy, the opposite of the silent Y.46PubMed Central. The Epigenome of Evolving Drosophila Neo-Sex Chromosomes: Dosage Compensation and Heterochromatin Formation Female mammals handle the same imbalance the other way, switching off one of their two X chromosomes.
Sex chromosomes began as an ordinary chromosome pair. In one fly species, a recently formed Y is turning from an ordinary chromosome into an inert one, while its X partner develops partial doubling-up.47PubMed Central. Sex chromosome evolution: molecular aspects of Y-chromosome degeneration in Drosophila Build-up of repeated DNA triggers the packing that silences the young Y.48PubMed Central. The Epigenome of Evolving Drosophila Neo-Sex Chromosomes: Dosage Compensation and Heterochromatin Formation
How Chromosomes Compare Across Fly Species
Comparing gene maps between species showed that the genes on each chromosome arm stay together.49PubMed Central. Muller “Elements” in Drosophila: How the Search for the Genetic Basis for Speciation Led to the Birth of Comparative Genomics The arms were named Muller elements A to F, a labelling still used today.50PubMed Central. Muller “Elements” in Drosophila: How the Search for the Genetic Basis for Speciation Led to the Birth of Comparative Genomics About 95% of genes stay on the same element across fly species.51PubMed Central. Chromosomal Rearrangement Inferred From Comparisons of 12 Drosophila Genomes Their order along the arm is mostly shuffled by flipped segments within an arm.52PubMed Central. Chromosomal Rearrangement Inferred From Comparisons of 12 Drosophila Genomes
The labels help when reading other flies’ chromosomes. Element A is the X in the fruit fly, and the tiny dot chromosome is element F. Elements can fuse, so one species’ single chromosome may hold two of them. A gene found in one species can be looked for on the matching element in another.
A flipped segment reverses gene order but keeps the genes on the arm. In the giant chromosomes of hybrids, flips show up as loops. They are the same kind of change used to build balancers, and they suppress swapping, which keeps gene groups together in wild populations.