The sequencing of the human genome represents a major milestone that will have profound consequences for the practice of medicine. Many new disease genes will be identified, and this information may someday be used to predict a patient's risk of developing a specific disease or response to a particular drug. The following six News and Views articles discuss how The Human Genome Project will revolutionize the diagnosis and treatment of diseases including diabetes, asthma, cancer, autoimmunity and cardiac disease, as well as the potential for developing 'personalized therapies'. They also serve to remind us that although we have our 'genetic blueprint' in hand, a large amount of work remains before we fully understand how to best use it.
Type II diabetes has reached global epidemic proportions, and the availability of the human genome sequence will help elucidate the genetic basis of this complex disease. But finding the true diabetogenes will not be easy.
Type II (non-insulin dependent) diabetes is a complex group of disorders characterized by two apparently distinct pathophysiologic defects—insulin resistance (a decrease in insulin action at the level of muscle, fat and liver), and a failure of the pancreatic -cells to compensate for this resistance by appropriately increasing insulin secretion. There is strong evidence for an important role of genetics in both of these components1; however identifying the genes responsible for the development of type II diabetes has proven problematic. Will the sequencing and analysis of the human genome2 help unravel the genetics of this multifactorial disorder?
Thus far, most of the success in defining type II diabetes genes (diabetogenes) has been achieved by studying relatively rare forms of the disease (Fig. 1). Maturity-onset diabetes of the young (MODY) is an autosomal dominant disease that only accounts for approximately 2% of all diabetic patients. To date, six forms of MODY have been defined, each involving a gene important for -cell function. These genes encode hepatic nuclear factor-4 (HNF-4, associated with MODY 1), glucokinase (associated with MODY 2), HNF-1 (associated with MODY 3), insulin promoter factor-1 (IPF-1, associated with MODY 4), HNF-1 (associated with MODY 5) and NEUROD1/2 (associated with MODY 6)3,
4,
5,
6. Although insulin resistance appears to be the earliest defect in most patients with type II diabetes1, insulin receptor mutations are very rare and are usually observed in patients with severe insulin resistance syndromes7. About 0.1−1% of type II diabetes is maternally inherited, associated with deafness and due to defects in the mitochondrial genome. Interestingly, the most common mitochondrial variant (A3243G in tRNAleu) also causes MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)8. Some forms of lipoatrophic diabetes appear to be caused by mutations in nuclear lamins A/C (ref. 9), whereas Wolfram's syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is caused by a mutation in an uncharacterized protein with 10 transmembrane segments10.
Figure 1. Location of potential type II diabetes genes.
Several loci have been identified through linkage studies (black). Other loci include genes for monogenic forms of diabetes (red), candidate genes that have shown some evidence of association (blue) and candidate genes with known amino acid polymorphisms (green). An arrow indicates the mitochondrial mutation that is associated with the syndromes of diabetes insipidus, diabetes mellitus, and optic atrophy and deafness, which also causes MELAS syndrome.
Attempts to identify the diabetogenes responsible for the most common forms of type II diabetes have depended on genome-wide linkage studies or studies of candidate genes. The pre-sequencing phase of the Human Genome Project provided genetic and physical maps11, allowing whole-genome screens to identify chromosomal regions that are linked (cosegregate), with type II diabetes in families (Fig. 1). A locus on 2q37, termed NIDDM1, is linked to diabetes in some Mexican-Americans and corresponds to a single nucleotide polymorphism (SNP) in an intron of the gene for the calcium-dependent protease calpain 10 (ref. 12). This locus appears to act together with a gene on chromosome 15 to increase diabetes susceptibility13. Loci on 20q12-13 and 1q21-24 have been linked to diabetes in several Caucasian populations, but the specific diabetogenes in these regions remain to be determined14,
15,
16,
17,
18,
19,
20.
More than 60 potential candidate genes involved in insulin action, insulin secretion and adipose metabolism (since both obesity and lipoatrophy are linked to diabetes) have also been examined in the search for type II diabetes susceptibility genes. Although variants have been identified in many of these, only a few have been shown to associate with diabetes or impaired protein function (Fig. 1). Amino acid variants in insulin receptor substrate-1 (IRS-1) have been shown to decrease insulin signaling21, and variants in the peroxisome proliferator-activated receptor and the -cell transcription factor IPF1 have been associated with an increased risk of diabetes22,
23,
24. However, for most individuals, the genes that underlie type II diabetes susceptibility remain unknown.
Clearly, the detailed human genome sequence information now available2 will lead to the identification of more candidate genes for type II diabetes and will expedite our efforts to pinpoint specific genes responsible for chromosomal linkage peaks. But finding the true diabetogenes will not be easy. Despite several major family and population studies, the intervals linked with type II diabetes are large and may contain hundreds, or even thousands, of genes. Prioritizing the analysis of these genes based on known function may be misleading, as illustrated by the surprising role of lamins as diabetogenes in some forms of lipoatrophic diabetes9.
Thus, fine mapping is important, and the draft genome sequence offers us an important tool for this task: a map of 1.4 million single nucleotide polymorphisms (SNPs)(ref. 25). By genotyping hundreds of SNPs, one should be able to narrow the locus to a diabetes-associated haplotype. However, this strategy may prove difficult if there is allelic heterogeneity (different variants at the same locus contributing to diabetes in different people), as observed in MODY (ref. 4). The prospects of using the SNP map to find diabetogenes in genome-wide scans are also complicated by the enormous variance of linkage disequilibrium throughout the genome, along with the uncertainty of the linkage disequilibrium between SNPs and the actual polymorphisms that contribute to diabetes26. Furthermore, a large number of SNP markers would be needed to cover the whole genome (up to 500,000 according to one simulation)27.
Another important way in which the genome sequence is likely to facilitate the search for type II diabetes genes is by suggesting new components of insulin secretion and insulin action. Although much progress has been made over in the last decade in dissecting these cellular pathways, there are still many unsolved areas, and mining the human genome should help us fill these gaps. For example, by searching the draft sequence for homology to genes involved in membrane compartment organization, Bock et al.28 have identified 31 previously unknown Rab proteins. This family of low-molecular-weight GTPases comprises essential components of the vesicle-trafficking machinery and may be key elements in the translocation of glucose transporters from intracellular compartments to the plasma membrane in response to insulin, as well as insulin secretion.
At least 18 paralogues (distantly related or unrelated proteins which perform the same function in different cellular lineages) of drug targets were also identified in the genome, including a paralogue of the insulin-like growth factor-1 receptor2. The same 'mining' approach can be applied to other protein classes, such as SH2 domain-containing proteins, to find other unknown paralogues of known mediators of insulin action or secretion. Once these new candidates are defined, the SNP database should be a useful tool for identifying variants at these loci that can be tested for association with diabetes. One discouraging finding in this regard, however, is that the functional classification of the proteins derived from the human genome suggests that more genes encode proteins involved in metabolism, transcription/translation and intracellular signaling, than virtually all other categories of function together2. Thus, the number of candidate diabetogenes is likely to be very large.
Finally, there are three major caveats for the utility of the genome sequence in our search for diabetogenes that cannot be neglected: 1) type II diabetes is genetically heterogenous; 2) common forms of type II diabetes are almost certainly polygenic; and 3) strong gene/gene and gene/environment interactions play important roles in development of type II diabetes . Thus, mutations or polymorphisms that cause only modest deficits in gene/protein function may become clinically significant when coupled with other genetic or acquired defects. the resulting imperfect correlation between genotype and phenotype makes the task of finding the diabetogenes a formidable one.
In the U.S., there has been a 39% increase in prevalence of type II diabetes between 1990 and 1999, reflecting the strong environmental input into disease expression29. Likewise, animal and cellular models have indicated that haplo-insufficiency of two genes, each of which is clinically silent, can result in disease expression due to strong epistatic (synergistic) gene/gene interactions30.
For the Human Genome Project to keep its promise of helping to define the genes for complex disorders such as type II diabetes, we must understand these gene/gene and gene/environment interactions and develop methods to study the cellular impact of genetic variation in a systematic way. Most importantly, we need good physiologic phenotyping to identify more homogeneous disease subgroups for genetic analysis. These are exciting times in the field of genetics—however much needs to be done if we are to find the major genes underlying the current epidemic of diabetes.
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-cells to compensate for this resistance by appropriately increasing insulin secretion. There is strong evidence for an important role of genetics in both of these components
(HNF-4
) gene in diabetic Caucasians: identification of a Pro12Ala PPAR 
