During the late 1950s and early 1960s, human chromosomes were assigned sizes, and the two smallest pairs were very close. Much happened between 1960 and publication of the first full chromosome sequence in December 1999. Cytogeneticists developed ever more specific stains and DNA probes to highlight and distinguish the chromosomes, revealing the guideposts that would help anchor linkage data to build the first gene maps. Some of these techniques estimated the gene density that genome sequencing today addresses directly. R banding, for example, reveals CpG islands, the repeats of C and G that herald the start of many a protein-encoding gene.
Many R bands means, roughly speaking, many genes.
The rise of positional cloning in the 1980s gradually allowed investigators to fill in chromosome maps, an effort that Science magazine visually tracked in each October's genome issue. But it was the cover of Nature that dramatically heralded the coming of the first human chromosome sequence, number 22. The cover depicts two hands reaching toward each other against a celestial backdrop of a DNA chip. The 33.5 million bases, representing 97 percent of the long arm of chromosome 22, with 11 gaps, introduced 545 protein-encoding genes and 134 pseudogenes, which are sequences very similar to those of active genes but unexpressed, like genetic graveyards. When we talk about chromosomes 21 and 22, we refer mostly to long arms.