Chromosome 2 and chromosome 4 are approximately 237 million base pairs and 186 million base pairs long. Scientists confirmed the existence of a total of 1,346 protein-coding genes on chromosome 2 and 796 protein-coding genes on chromosome 4.

Included on chromosomes 2 and 4 are genes previously linked to Huntington’s disease, polycystic kidney disease, a form of muscular dystrophy, and Wolf-Hirschhorn syndrome, a condition that causes severe birth defects and mental retardation.

With this publication, the GSC completes its contributions to initial human genome sequencing and early inventory of potentially interesting genetic features in the 23 human chromosomes. Researchers at the GSC were primarily responsible for chromosomes 2, 4, 7 and Y, producing the initial analyses of more than 20 percent of the human genome.

Other institutions that contributed to the sequencing and analysis of chromosomes 2 and 4 include the University of Washington School of Medicine, the European Molecular Biology Laboratory, Pennsylvania State University, Stanford Human Genome Center and Lawrence Livermore National Laboratory.

Scientists identified some of the human genome’s largest gene deserts on chromosomes 2 and 4. These are large regions of DNA that contain very little in the way of protein-building instructions.

“For example, there are two regions of chromosome 2 that are each almost 10 million base pairs long each surrounding a single gene called protocadherin,” Hillier says.

Researchers have found evidence that the protein made by the protocadherin gene is active in the heart and the brain. The protein made by the gene is thought to function in cell-to-cell recognition and adhesion but hasn’t been definitively characterized yet. The function of the deserts around the gene is elusive.

“The deserts contain short, specific non-coding segments segments that may well be sites of gene regulation such as transcription factor binding sites–areas on the DNA where molecules can bind to change the activity of the protocadherin gene or other genes,” says Hillier. “As we compared these areas to other genomes, we were intrigued to find both these short segments and this gene desert structure has been maintained in mammals and birds.”

The presence of the deserts in other genomes suggests they may have important regulatory functions that researchers have yet to identify, according to Hillier.

Also included on chromosome 2 is the longest protein coding sequence yet identified, a gene called titin that spans 280,000 base pairs and produces a muscle protein that is more than 33,000 amino acids long. Protein length varies widely, but typically averages about 500 amino acids.

Scientists identified several “hypervariable” regions, regions where the sequence of base pairs show significant variation among individuals.

“Our most highly variable region had 75 differences in a 5,000 base pair segment,” Hillier notes. “Normally there will be one or two differences every thousand base pairs, and we had set three differences per five thousand base pairs as our initial threshold for searching for these regions.”

Hillier and her colleagues sequenced several of these regions in a panel of 24 ethnically diverse people, and confirmed that these blocks of extreme variation occur regularly rather than randomly and appear to arise from two distinct underlying patterns. They then checked the regions in the chimp genome.

“In general, they were also highly variable in chimps,” Hillier says. “It’s going to take a lot more work to figure out what’s going on in these regions, but some of these occur near known genes and studying them will greatly facilitate the study of human genetic variation and, at least in some cases, its correlation with disease.”

Hillier notes that chimp genome sequence data was very helpful for their analysis of human chromosomes 2 and 4. Hillier, Wilson and others are leading the analysis of the chimp genome, which they expect to publish soon.

For example, a comparison of the human genome to the chimp genome and other previously produced genomes revealed a gene that only appears to be functional in the human and chimp genomes. Scientists have tentative evidence the gene may be used to make a protein in the brain and the testes. If researchers can confirm that the novel gene is used to make a protein, scientists will be eager to determine its potentially unique or important role in human and chimp physiology.

“Now that we have so many different genomes, we’re really in a position to start to understand them so much better,” Hillier says. “It really was the dark ages back in the 1990s when we had so little genomic sequence.”

From a WUSM press release.