Human chromosome 2 is two fused ape chromosomes

If humans and the other great apes descended from a common ancestor, then the difference in chromosome number between humans (46) and chimpanzees, gorillas, and orangutans (all 48) demands an explanation.^{1, 2} Either one chromosome was lost during human evolution—which would mean losing hundreds of genes and would almost certainly be lethal—or two ancestral chromosomes fused into one. In the early 1980s, chromosome banding studies revealed that human chromosome 2 matches two separate chimpanzee chromosomes band for band, strongly suggesting a fusion event.¹ Over the following decades, molecular biology confirmed this prediction in remarkable detail, uncovering the exact fusion site, the remnant telomeric sequences, and the deactivated second centromere. The story of human chromosome 2 is a textbook case of a prediction made by evolutionary theory and subsequently verified by independent evidence from genomics.^{2, 3}

The chromosome count problem

Chromosomes are the structures within the cell nucleus that carry an organism's DNA. Humans have 23 pairs of chromosomes (46 total), a fact established definitively in 1956 by Joe Hin Tjio and Albert Levan.⁴ The other great apes—chimpanzees (Pan troglodytes), bonobos (Pan paniscus), gorillas (Gorilla gorilla), and orangutans (Pongo pygmaeus)—all have 24 pairs (48 total).^{1, 5} This pattern extends to other Old World primates as well; many have 48 chromosomes, indicating that 48 is the ancestral condition for the great ape lineage.⁵

If humans share a common ancestor with the other great apes, as the overwhelming evidence from anatomy, fossils, and molecular biology indicates, then the reduction from 48 to 46 chromosomes must have occurred at some point in the human lineage after it diverged from the lineage leading to chimpanzees and bonobos, our closest living relatives.^{1, 6} The most parsimonious explanation is that two ancestral chromosomes fused end-to-end (a telomere-to-telomere fusion) to produce a single larger chromosome, reducing the total count by one pair.^{2, 3}

Diploid chromosome counts across the great apes^{1, 5}

Chromosome banding evidence

The first strong evidence for a fusion came from cytogenetics—the study of chromosome structure under the microscope. When chromosomes are stained with certain dyes (such as Giemsa stain), they display characteristic patterns of light and dark bands. These banding patterns are consistent within a species and can be compared across species to identify homologous chromosomes.^{1, 5}

In 1982, Jorge Yunis and Om Prakash published a landmark comparative study in Science that used high-resolution chromosome banding to compare the karyotypes (complete sets of chromosomes) of humans, chimpanzees, gorillas, and orangutans. They found that the banding pattern of human chromosome 2 is essentially a perfect match to two separate chimpanzee chromosomes placed end to end—what are now designated chimpanzee chromosomes 2A (corresponding to the long arm and part of the short arm of human chromosome 2) and 2B (corresponding to the remainder of the short arm).¹ The same correspondence was observed with the homologous chromosomes of gorillas and orangutans, indicating that the fusion occurred specifically in the human lineage after the split from the other great apes.^{1, 5}

This banding evidence was powerful but circumstantial. It showed that the patterns matched, but it could not reveal the molecular mechanism of the fusion or identify the exact point where the two ancestral chromosomes joined. That would require the tools of molecular biology.²

Discovery of the fusion site

Chromosomes have a characteristic structure. At each end sits a telomere—a cap of repetitive DNA sequences (in vertebrates, the hexanucleotide repeat TTAGGG, repeated thousands of times) that protects the chromosome from degradation and prevents it from fusing with other chromosomes.^{2, 3} If two chromosomes fused end-to-end, the telomeric sequences from both chromosomes should be detectable at the fusion point, oriented head-to-head (that is, one array of TTAGGG repeats pointing in one direction and the other array pointing in the opposite direction).²

In 1991, Jacobus W. IJdo and colleagues at Yale University School of Medicine reported the discovery of exactly this signature. Working with cosmid clones from the long arm of human chromosome 2 (band 2q13), they identified two allelic genomic cosmids (c8.1 and c29B) that each contained two inverted arrays of the vertebrate telomeric repeat arranged in a head-to-head orientation: 5'-(TTAGGG)_n-(CCCTAA)_m-3'.² The sequences flanking these telomeric arrays were characteristic of present-day human subtelomeric regions (the regions immediately adjacent to telomeres at chromosome tips), further confirming that this locus was the relic of an ancient telomere-to-telomere fusion.²

IJdo and colleagues concluded that their findings marked "the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2."² The fusion site was localized to chromosome band 2q13, precisely where the banding pattern analysis had predicted the junction of the two ancestral chromosomes would be.^{1, 2} This was a striking confirmation: the molecular data independently validated what cytogenetics had suggested a decade earlier.

The vestigial centromere

Every functional chromosome has exactly one centromere—a specialized region of repetitive DNA (called alphoid or alpha-satellite DNA in primates) where the spindle fibers attach during cell division to pull the chromosome to one end of the dividing cell.⁷ A chromosome with two functional centromeres (a dicentric chromosome) is unstable because the two centromeres can be pulled toward opposite poles during cell division, tearing the chromosome apart. If two chromosomes fused to form human chromosome 2, the resulting dicentric chromosome would have needed to inactivate one of its two centromeres to become stable.^{7, 8}

In 1992, Rocchi Avarello and colleagues at the University of Pavia demonstrated that this is exactly what happened. Using fluorescence in situ hybridization (FISH) with alphoid DNA probes, they detected a signal not only at the functional centromere of chromosome 2 (located at 2p11, corresponding to the centromere of ancestral chromosome 2A) but also at a second site on the long arm at approximately 2q21.3–q22.1—the position that corresponds to the centromere of ancestral chromosome 2B.⁷ This vestigial centromere is nonfunctional; it no longer binds kinetochore proteins or participates in cell division. But its alphoid DNA sequences remain detectable as a molecular fossil of the ancestral chromosome's centromere.⁷

A 2017 study by Chiatante and colleagues examined the evolutionary fate of this ancestral centromere in detail using molecular cytogenetics and comparative sequence analysis. They found that the inactivated centromere had undergone substantial degeneration over the roughly five to six million years since the fusion event, losing most of its alpha-satellite DNA. Their analysis strongly favored a model in which centromere inactivation occurred through a single-step excision process rather than gradual erosion, providing new insights into how dicentric chromosomes are stabilized after fusion events.⁸

Genomic sequencing confirms the fusion

The completion of the Human Genome Project and subsequent detailed sequencing of individual chromosomes allowed researchers to examine the fusion region at single-nucleotide resolution. In 2002, Yuxin Fan and colleagues at Case Western Reserve University published a comprehensive genomic analysis of the fusion site and its surrounding regions in Genome Research. They identified approximately 614 kilobases of sequence surrounding the fusion point at 2q13–2q14.1 and found that many portions of this region are duplicated elsewhere in the human genome, primarily at subtelomeric and pericentromeric locations—exactly the pattern expected if the fusion brought together sequences originally found at chromosome tips.^{3, 9}

In 2005, Hillier and colleagues published the essentially complete sequence of human chromosome 2 in Nature, comprising approximately 237 million base pairs representing more than 99.6% of the euchromatic sequence. Their analysis confirmed the presence of the head-to-head telomeric repeat arrays at the fusion site and the degenerate alphoid sequences at the vestigial centromere, placing both features in precise genomic context.¹⁰

That same year, the Chimpanzee Sequencing and Analysis Consortium published the initial draft of the chimpanzee genome. Genome-wide comparison confirmed that human chromosome 2 corresponds precisely to chimpanzee chromosomes 2A and 2B, with the sequences aligning in the predicted orientation. The consortium identified approximately 150,000 base pairs of sequence at the fusion site that are unique to the human chromosome and not present on either chimpanzee chromosome, representing subtelomeric material that was captured during the fusion event.⁶

Comparative FISH mapping by Kasai and colleagues further refined the picture by mapping 38 cosmid clones from the human chromosome 2q12–q14 region to the corresponding chimpanzee chromosomes. They found no difference in the relative order of the clones between human and chimpanzee, indicating that the genomic organization of this region has been highly conserved since the fusion and that the event was a clean end-to-end joining without significant rearrangement of the flanking sequences.¹¹

Summary of the converging evidence

The case for the fusion of two ancestral ape chromosomes to form human chromosome 2 rests on multiple independent lines of evidence, each of which was predicted by the hypothesis of common ancestry and each of which has been confirmed by observation.^{1, 2, 3, 6}

Strength of independent lines of evidence for the chromosome 2 fusion^{1, 2, 7, 6}

First, chromosome banding patterns demonstrated that human chromosome 2 matches chimpanzee chromosomes 2A and 2B band for band, a correspondence that extends to gorilla and orangutan homologs.¹ Second, the discovery of head-to-head arrays of telomeric repeat sequences (TTAGGG) at the interior of the chromosome, at band 2q13, revealed the molecular scar of the ancient telomere-to-telomere fusion.² Third, the detection of vestigial alphoid (centromeric) DNA at 2q21.3–q22.1 demonstrated the remnant of the second ancestral centromere, now nonfunctional.⁷ Fourth, complete genome sequencing confirmed that the DNA sequences of human chromosome 2 align precisely to two separate chimpanzee chromosomes in the predicted orientation, with subtelomeric duplications at the fusion site characteristic of chromosome ends.^{3, 6, 10}

The fusion in archaic humans

The chromosome 2 fusion is not unique to modern Homo sapiens. When Matthias Meyer and colleagues at the Max Planck Institute for Evolutionary Anthropology sequenced a high-coverage genome from a Denisovan individual in 2012, they specifically searched for evidence of the fusion by looking for DNA fragments containing the characteristic head-to-head telomeric repeats. They identified twelve such fragments in the Denisovan genome, confirming that Denisovans, like modern humans, had 46 chromosomes with a fused chromosome 2. By contrast, DNA from several chimpanzees and bonobos yielded no such fragments.¹²

The Neanderthal genome, sequenced by the same group, also shows the chromosome 2 fusion.^{12, 13} Since Denisovans and Neanderthals represent archaic human lineages that diverged from modern humans hundreds of thousands of years ago, the shared presence of the fusion demonstrates that it occurred before the divergence of these lineages—that is, the fusion is at least several hundred thousand years old and was present in the common ancestor of all known members of the genus Homo.¹²

A 2022 study by Poszewiecka and colleagues used patterns of biased nucleotide substitution around the fusion site to estimate when the fusion occurred, arriving at an estimate of approximately 0.9 million years ago (with a 95% confidence interval of 0.4 to 1.5 million years ago).¹⁴ This places the fusion event deep in the Pleistocene, well before the emergence of anatomically modern humans approximately 300,000 years ago, and is consistent with the fusion being shared across all known human and archaic hominin genomes.¹⁴

A prediction of evolution confirmed

The chromosome 2 fusion is often cited as one of the most compelling confirmations of common ancestry between humans and the other great apes because it followed the classic pattern of scientific prediction and verification.^{1, 2, 6} The reasoning proceeded as follows. If humans descended from a common ancestor shared with chimpanzees and the other great apes, and if that ancestor had 48 chromosomes (as all living great apes do), then the reduction to 46 chromosomes in humans required either the loss of a chromosome or a fusion event. Loss of an entire chromosome would eliminate hundreds of essential genes, making it almost certainly lethal. Therefore, evolution predicted that one human chromosome should contain the fused remnants of two ancestral ape chromosomes.^{1, 2}

This prediction was testable and specific. It demanded that one human chromosome should match two ape chromosomes in banding pattern. It demanded that telomeric sequences should be found in the interior of that chromosome. It demanded that a vestigial second centromere should be detectable. Each of these predictions was confirmed independently over a span of two decades, from the banding studies of Yunis and Prakash in 1982, to IJdo's discovery of the fusion site in 1991, to Avarello's detection of the vestigial centromere in 1992, to the complete genomic confirmation in the 2000s.^{1, 2, 7, 6}

No alternative hypothesis has been proposed that accounts for all of these features simultaneously. The interstitial telomeric repeats, the vestigial centromere, the precise banding correspondence, the genomic sequence alignment, and the shared presence of the fusion in all known human and archaic hominin genomes together form a coherent body of evidence that points unambiguously to a fusion event in the human lineage. Human chromosome 2 is, in the words of the Chimpanzee Sequencing and Analysis Consortium, a "landmark" of human evolutionary history visible at the molecular level.⁶