Study of Largest & Last Chromosome of Human Genome Published

Researchers publishing in Nature have sequenced the last chromosome in the human genome—human chromosome 1. The sequence has been used to identify more than 1000 new genes and is expected to help researchers find novel diagnostics and treatments for many diseases. In the past year alone, genes involved in a dozen diseases, including cancer and neurological disease, have been identified using the freely available chromosome 1 sequence and DNA resources.

If it were typed out, chromosome 1's huge repository of genetic information would cover 60,000 pages. It is home to more than 3000 genes and more than 350 known diseases, including conditions as varied as cancer development, Parkinson's and Alzheimer's disease, high cholesterol and porphyria.

"The sequence we have generated, like that produced by our collaborators throughout the Human Genome Project, has driven biomedical discovery," said Dr Simon Gregory, Assistant Professor from Duke University, who led the project while at the Wellcome Trust Sanger Institute. "This moment, the publication of the sequence from the last and largest human chromosome, completes the story of the HGP and marks the growing wave of biological and medical research founded on the human genome sequence.

"Chromosome 1 contains fascinating stories of chromosome biology, of our evolution, and our health, and it's inspiring to have played a part in a program that will have so much power to understand the essence of human biology."

Human chromosomes are numbered from the largest (chromosome 1) to the smallest (chromosomes 22 and 21). Each is composed of many millions of genetic letters or bases, called A, C, T and G. The first genetic letter of chromosome 1 sequence, and hence the beginning of our genome, is "C".

The sequence of human chromosome 1 is 223,569,564 bases of genetic code—around 8% of our genome—and contains about twice as many genes as the average chromosome. "The size of chromosome 1 means its landscape spans extremes in gene content, with stretches of millions of bases of gene-rich oases and gene-poor deserts," continued Gregory, "as well as regions of the chromosome that are copied during early and late phases of cell division."

But the sequence must be mined to be of benefit. For example, differences in the sequence between individuals will help develop an understanding of diseases associated with this chromosome. Almost 4500 single-letter changes in the genetic code (called SNPs) were identified that could lead to changes in protein activity. In addition, 90 SNPs were found that would result in a shortened—and possibly inactive—protein. Although some 15 SNPs are associated with already known protection from malaria and predisposition to porphyria, the function of these newly located SNPs is yet to be discovered.

The finished sequence of chromosome 1 enabled the team to bring together chromosome-wide information associated with genetic variation from projects such as the HapMap—a leading international study of human genetic variation. Our chromosome pairs "recombine" with each other, so that regions inherited from our two parents are shuffled when passed on to our children.

Shuffling the deck tends not to disrupt genes. Most of the recombination found on chromosome 1 occurs at a few hotspots and more than 80% of hotspots are in only 15% of the sequence. Fine scale analyses have shown that recombination tends to be near to genes but outside the actual gene structures themselves.

Careful analysis also showed how our genome has undergone recent evolutionary selection. The team looked at correlations between the HapMap data and the annotated chromosome 1 sequence to investigate the variation between three human population groups with ancestry in Europe, Africa or Asia.

Genome sequence varies from person to person. New insights are being gained all the time. Researchers have found that genetic differences may be prevalent in one population but rare in, or absent from, another. Some of these like the gain or loss of large regions, have been recognized only in the past few years as a result of the Human Genome Project. For example, variations in the region around the GSTM1 gene can alter our susceptibility to cancer-causing chemicals or toxins and influence the toxicity or efficacy of certain drugs.

Chromosome 1 is particularly susceptible to rearrangement and it is thought that disruption to genes within these rearrangements play a role in several cancers and in mental retardation. The high-quality sequence has already helped researchers around the world to home in on genes that affect a range of cancers.

Rearrangements, deletions and duplications can tell us about our evolution and our diseases. More than 5% of the chromosome is duplicated and can provide material for the evolution of new functions. In one example, the partial duplication of a gene called NOTCH2 has resulted in a novel protein that is known to be functional in humans and has been implicated in disease. Meanwhile, deletion of regions of chromosome 1p is found in 1/5,000 to 1/10,000 live births and may contribute to mental retardation syndromes.