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Human Molecular Genetics 2004 13(Review Issue 2):R303-R313; doi:10.1093/hmg/ddh231
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Human Molecular Genetics, Vol. 13, Review Issue 2 © Oxford University Press 2004; all rights reserved

Human chromosome 7 circa 2004: a model for structural and functional studies of the human genome

Stephen W. Scherer1,2,* and Eric D. Green3

1Program in Genetics and Genomic Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada, 2Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5G 1X8, Canada and 3National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Building 50, Room 522, Bethesda, MD 20892, USA

Received July 5, 2004; Revised July 8, 2004; Accepted July 16, 2004


   ABSTRACT
TOP
 ABSTRACT
SEQUENCING AND GENE ANNOTATION...
 GENOTYPE-PHENOTYPE AND...
 COMPARATIVE GENOMICS AND...
 UNSOLVED BIOLOGICAL PROBLEMS
 CONCLUSIONS
 REFERENCES
 
Human chromosome 7 is arguably amongst the most comprehensively characterized segments of the human genome. By microscopic examination, it belongs to the medium-sized group C submetacentric class, and historical studies involving chromosome-length measurements estimated that it accounts for ~5.3% of the human genome (or 160 Mb). Early successes in molecular genetics led to the identification of some of its biomedically important genes, including the T-cell receptor and homeobox families as well as the erythropoietin and cystic fibrosis genes. The Human Genome Project brought chromosome 7-specific and genome-wide initiatives, generating a wealth of genomic resources that have revealed the presence of over 350 disease-associated genes. Two distinct assemblies of the chromosome 7 sequence have been generated—one based largely on mapped large-insert clones and the other based on an integrated whole-genome shotgun sequencing strategy. These two sequences are mainly identical (<1% difference), and both estimate the unit length of chromosome 7 to be just over 158 Mb, remarkably similar to the originally predicted size. Systematic annotation efforts have anchored to the sequence, amongst many features, over 900 known genes and some 1000 other gene structures, as well as over 650 chromosomal breakpoints identified in patients with characterized phenotypic differences. Chromosome 7 has also been shown to contain the highest content of intra-autosomal segmental duplications in the human genome. The orthologous regions of roughly 22 Mb of chromosome 7 are currently being sequenced in multiple other vertebrate species. Examining these comparative sequence data, in conjunction with the other accumulating genomic information about these regions and the rest of the chromosome, should provide a model for the next generation of structural and functional analyses of the human genome.

Relative to its size, chromosome 7 has received a disproportionate amount of attention prior to and throughout the Human Genome Project (HGP)—and beyond. This largely resulted from a confluence of historical factors, mostly tracing back to the study of a number of interesting genes and diseases mapping to the chromosome (summarized in 1, 2). In the 1980s, the T-cell receptor gene families (TCRB and TCRG), the erythropoietin gene (EPO), the multidrug resistance genes (PGY1 and PGY3) and the homeobox A gene family (HOXA) were localized to chromosome 7, placing it in the spotlight of human genetics research. In 1985, the cystic fibrosis gene was mapped to chromosome 7 (3), setting off an international race to find the causative gene (CFTR). The resulting intensive search brought many of the first (rudimentary) genetic (4,5) and physical (6,7) mapping resources. Culminating in 1989 (8–10), the effort to identify the CFTR gene became a prototype for moving from a linked genetic marker to a disease gene by a positional cloning strategy (11). Notwithstanding this scientific success, there was also controversy surrounding the search for the CFTR gene including its initial mis-identification (12) and outrageous claims of ownership [with the CEO of one company stating they ‘owned chromosome 7’ (13)], which again placed the chromosome in the scientific spotlight.

In the later stages of the CFTR gene search, some then state-of-the-art genome-analysis methods were recruited to aid in the detailed study of the 7q31 region harboring the CFTR locus. These included yeast artificial chromosome (YAC) cloning (14) and physical mapping strategies involving the use of sequence-tagged sites (STSs) as chromosomal landmarks (15,16). Though these genomic tools were late-comers to the search and, ultimately, had no direct impact on the identification of the CFTR gene, their use initiated the establishment of an infrastructure for chromosome 7-wide mapping—one that made the chromosome a frequent ‘testing ground’ (in essence, a model) for developments in genome analysis that followed.

The first in a series of key genomic studies showcasing chromosome 7 involved the complete isolation and mapping of the greater CFTR region using YACs as the clones and STSs as the markers (17). Indeed, this study provided pivotal support for the proposal to construct first-generation physical maps of the entire human genome based on STSs (15). With the formal launch of the HGP in 1990, two independent groups proceeded to construct YAC-based physical maps of chromosome 7—one associated with a United States genome center (at Washington University) and the other emanating from one of the groups (at the Hospital for Sick Children in Canada) involved in the mapping and identification of the CFTR gene. Each group developed and used specialized YAC library resources enriched for chromosome 7 (18,19). In addition, large collections of STSs were generated and mapped (20) and extensive efforts were made to integrate the physical map with the available cytogenetic map and the rapidly advancing genetic map (21,22). The resulting YAC-based maps (21,23) were amongst the highest-quality first-generation physical maps generated for any human chromosome, and this then set the stage for the accelerated sequencing of chromosome 7 (see later). Through the 1990s, international workshops were held that compiled the accumulating data about chromosome 7, with relevant summaries published (24,25).

In the late 1990s, much of the HGP's effort shifted to genome-wide mapping and sequencing efforts. It became evident, however, that there was tremendous added value in maintaining centralized groups focused on generating primary resources and data for chromosome 7, as well as integrating that information with the emerging whole-genome data. In addition, such efforts could directly support clinical genetics research, as well as the search for chromosome 7 genes implicated in human disease. As a result (both direct and indirect), there are now more than 360 diseases associated with genes residing on chromosome 7. Some of the notable examples where the early availability of integrated chromosome 7 mapping and sequencing information facilitated the identification of medically relevant genes include those implicated in holoprosencephaly (26,27), Williams–Beuren syndrome (WBS) (28–32), Pendred syndrome (33), type II citrullinemia (34), cerebral cavernous malformations (35,36), renal tubular acidosis (37), speech and language disorder (38), Shwachman–Diamond syndrome (39), phenylthiocarbamide-induced bitter taste (40), asthma susceptibility (41), sacral agenesis and Currarino syndrome (42,43) and a form of Charcot–Marie–Tooth disease (44).


   SEQUENCING AND GENE ANNOTATION OF CHROMOSOME 7
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 ABSTRACT
 SEQUENCING AND GENE ANNOTATION...
GENOTYPE-PHENOTYPE AND...
 COMPARATIVE GENOMICS AND...
 UNSOLVED BIOLOGICAL PROBLEMS
 CONCLUSIONS
 REFERENCES
 
Chromosome 7 was amongst the first human chromosomes to be fully sequenced, and this was also carried out by two separate efforts. One of these (45) was performed under the auspices of the International Human Genome Sequencing Consortium (IHGSC), and involved hierarchical shotgun sequencing (genome-sequencing strategies are reviewed in 46) of well-mapped tiling paths of 1529 large-insert clones [mainly bacterial artificial chromosome (BAC) clones] spanning the chromosome. In this case, the STS-based physical map (23) was used as a framework for generating sequence-ready BAC contig maps, initially in a fashion that specifically targeted chromosome 7 (47) and later as part of a whole-genome BAC-mapping effort (48). The latest assembly of this highly refined chromosome 7 sequence (NCBI Build 34) encompasses 158 545 518 bases and contains 11 physical gaps, with an additional gap at the centromere (therefore containing 154 676 518 bases of finished sequence and an estimated 3 969 000 bases of undetermined sequence).

Another chromosome 7 sequence (32) was assembled by The Hospital for Sick Children group in conjunction with Celera Genomics. This effort aimed to capture all available sequence and annotation data in private and public databases including unpublished work and manually curate it for public release. The original assembly released in 2003 is CRA_TCAGchr7v1 (GenBank accession no. BL000001.1), and a subsequent 2004 release is CRA_TCAGchr7v2 (GenBank accession no. BL000001.2). About 85% of the CRA_TCAGchr7v2 assembly was derived from a subset of Celera whole-genome scaffolds for chromosome 7, with 15% (218 clone-based sequences) derived from the IHGSC and other sequences present in the public databases. The clone-based sequences were mainly selected for regions harboring large segmental duplications (e.g. 7p22, 7cen, 7q11.23, 7q22 and 7q36; Fig. 1F) or clustered, highly related gene families (e.g. T-cell receptor and mucin genes) in order to provide the most representative (and experimentally validated) coverage (30,49,50). The CRA_TCAGchr7v2 assembly encompasses 158 329 839 bases and contains five physical gaps, with an additional gap at the centromere (therefore containing 155 296 360 bases of determined sequence and an estimated 3 033 479 bases of undetermined sequence; Fig. 1B shows the location of physical gaps).



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  		Figure 1. Chromosome 7 structural, functional and disease-related features. (A) The relative positions of segments from the seven mouse chromosomes with synteny to human chromosome 7 are shown (combined data from 32, 69). (B) Red circles represent the locations of physical gaps remaining in the CRA_TCAGchr7v2 and NCBI Build 34 chromosome 7 sequence assemblies, black lines denote intra-scaffold gaps, and green triangles represent known chromosomal polymorphisms [HDAC9/TWIST at 7p21, 7cen, the WBS locus at 7q11.23 and the olfactory receptor at 7q35–q36 (31,51,86)]. (C) The location of nine fragile sites (FRA7E, FRA7G, FRA7H and FRA7I are characterized at the molecular level) and eight imprinted genes mapping in three clusters at 7p11.2, 7q21 and 7q32 are shown. (D) Distribution of 911 known genes on chromosome 7 (updated from 32). (E) Locations of 20 putative gene deserts [>500 kb region with no known genes in human or mouse (32)], and 18 genes larger than 500 kb [the 2300 kb CNTNAP2 gene at 7q34 being one of the largest in the genome (108)]. (F) Graphical views of paralogous relationships between recent segmental duplications. Each line pairs two related sequences (red, 99–100% identity; purple, 96–98%; blue, 90–92%). The size of each segmental duplication (kb) is graphed to the right. (G) Locations of patient rearrangement breakpoints with defined phenotypes described in the published literature or in databases. (H) Locations of all patient rearrangement breakpoints with defined phenotypes for which breakpoints could be anchored to the DNA sequence (www.chr7.org).

 
The major differences between the two chromosome 7 sequences include: (i) 704 297 bases of unmatched sequence at 185 sites, including 619 842 bases of additional sequence in CRA_TCAGchr7v2 not yet present in NCBI Build 34 (with the most notable differences being at the PDGFA locus at 7p22 and the COPG2 locus at 7q32); (ii) the presence of 11 and five physical gaps in NCBI Build 34 and CRA_TCAGchr7v2, respectively, with the former and latter assemblies substituting roughly 3 and 2.7 Mb of undetermined sequence at the centromere [note that the centromere is polymorphic, ranging in size from roughly 1.5 to 3.8 Mb at D7Z1 and 100–500 kb at D7Z2 (51)]; and (iii) two equivalent genomic segments in an inverted orientation relative to the two assemblies. These differences, which are highlighted in a browser associated with The Chromosome 7 Annotation Project (www.chr7.org), most likely reflect polymorphisms between the source chromosomal DNA samples (Fig. 1B), rearrangements arising during the cloning process and/or errors in the assembly. The availability of two well-characterized assemblies for chromosome 7 (so far unique to this chromosome) has provided a valuable resource for comparative studies to search for DNA sequence variations as well as confirmatory studies of assembly accuracy (32).

Multiple efforts to identify and annotate all genes on chromosome 7 are ongoing, both in genome-wide and chromosome 7-specific fashions. These are largely captured in the databases listed in Table 1. In this review, we have made no attempt to provide a detailed comparison of these gene annotation efforts, mainly because of their dynamic nature. The UCSC Genome Browser and The Chromosome 7 Annotation Project sites are notable for their overall data content, integration, presentation and reliability; they also replicate the most relevant data from the other sites. These sites have also made the most progress in assigning structural, functional and biomedical information to the chromosome 7 sequence assemblies. Moreover, The Chromosome 7 Annotation Project has an active effort to confirm computationally predicted genes and to extend partial transcripts using laboratory experimentation. This information is made available through an annotation track in the chromosome 7 database. At present, there are a total of 2131 ‘gene structures’ annotated, including 911 known genes, 135 novel genes, 48 partial genes, 332 predicted genes, 186 pseudogenes, 23 pseudogene segments, 381 putative genes, 36 non-coding RNAs and 79 gene segments (gene annotation criteria are described in 32).


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  		Table 1. Chromosome 7 databases and resources
 
A summary of the most relevant electronic databases and resources that catalog the wealth of genomic data about chromosome 7 is provided in Table 1, with an overview of some of its relevant structural and functional features shown in Figure 1.


   GENOTYPE–PHENOTYPE AND STRUCTURAL STUDIES OF HUMAN CHROMOSOME 7
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 ABSTRACT
 SEQUENCING AND GENE ANNOTATION...
 GENOTYPE-PHENOTYPE AND...
COMPARATIVE GENOMICS AND...
 UNSOLVED BIOLOGICAL PROBLEMS
 CONCLUSIONS
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To facilitate positional cloning studies and genotype–phenotype correlation for medical genetic applications, the group from The Hospital for Sick Children with multiple collaborators worldwide has made an effort to assimilate all medically relevant data with the chromosome 7 maps and sequence data (32). As far as we know, this initiative is unique to chromosome 7. A subset of the data is summarized in Figures 1 and 2. A particular emphasis has been on cataloguing all karyotypic anomalies (with defined phenotypes) in a community database (The Chromosome 7 Annotation Project website). Using fluorescence in situ hybridization (FISH) and other molecular genetic resources generated in earlier studies of human chromosome 7 and incorporating data from the literature and other databases, over 650 rearrangement breakpoints have been characterized at different resolutions at the molecular level (Fig. 1H). Correlation with phenotype has led to the identification of numerous candidate genes for disease study (32; Fig. 3). The study of the sequences at the rearrangement breakpoint(s) can also be used to provide insight into the regulation and function of genes (Figs 2 and 3). In cases where the breakpoints are located outside the coding regions of genes, it is possible that they separate critical regulatory elements causing dysregulation of expression during development.



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  		Figure 2. Browser view of a segment of chromosome 7 (from The Chromosome 7 Annotation Project; www.chr7.org). The split hand/split foot (SHFM1) or ectrodactyly region of 7q21.3 is shown as an example of integrating genomic data with chromosome rearrangement and clinical information. The positions of 14 deletion, translocation or inversion rearrangement breakpoints from SHFM1 patients are depicted along the chromosome 7 sequence and amongst other features. In this case, the inversion or translocation breakpoints do not collectively interrupt any gene, but they all reside within the commonly deleted interval defined by patients having chromosomal deletions. Reports that double-null knockouts of two murine Distalless homeobox genes, Dlx5 and Dlx6, exhibit ectrodactyly (109,110) strongly implicate the human orthologs (which map to the telomeric end of the region). In the simplest explanation, the chromosomal breakpoints located up to 1 Mb centromeric of DLX5 and DLX6 separate critical regulatory elements from the genes and lead to their dysregulation during development. Other structural features, including variations between the CRA_TCAGchr7v2 and NCBI Build 34 sequence assemblies, ultra-conserved sequence elements (111) and putative imprinted genes, are shown. Over 650 chromosomal rearrangement breakpoints from patients with defined phenotypes anchored to the DNA sequence can be found in the database.

 


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  		Figure 3. Putative ‘position-effect mutations’ in genes implicated in developmental diseases on human chromosome 7. (A–D) Gene-specific mutations and translocation or inversion breakpoints affecting the coding regions of GLI3, SHH, TWIST and FOXP2 in Grieg's polysyndactyly, holoprosecephaly and preaxial polydactyly, Saethre–Chotzen syndrome and speech and language disorder, respectively, have been described. In addition, translocation or inversions outside the coding regions of these genes have also been described in patients with identical phenotypes suggesting that rearrangements separate distal regulatory elements from the gene (termed ‘position effect’ mutations). (E) The explanation for DLX5 and DLX6 in ectrodactyly can be found in the legend of Figure 2. For all five of these transcription units there are nearby ‘gene deserts’, which is often characteristic of important developmental genes (32). The gene desert shown 5' of SHH (B) is listed as ‘putative’ because recently there has been a new gene mapped in this region (that still requires verification; hence it is not shown as a gene desert in Fig. 1). In some cases a rearrangement breakpoint and the gene it influences can be separated by independent transcriptional units (e.g. C; TWIST/HDAC9). There are also several examples of recurrent malignancy-associated breakpoints on chromosome 7, including t(7;12)(q36;p13) involving HLXB9 and ETV6 in myeloid disorders (112,113), t(7;11)(p15;p15) involving fusion of HOXA9 and NUP98 in human myeloid leukemia (114,115), t(2;7)(p12;q21) involving Ig kappa sequence with CDK6 in splenic marginal zone lymphoma (55), t(7;17)(p15;q21) involving JAZF1 and JJAZ1 in endometrial stromal tumors (116), and t(3;7)(q27;p12) involving BCL6 and Ikaros in diffuse large B-cell lymphoma (117,118). Note that several of the regions described in this legend are early targets for the NISC Comparative Sequencing Program (Table 2).

 
Using this type of genotype–phenotype correlation, position-effect mutations for the following known developmental genes on chromosome 7 have been demonstrated; GLI3, TWIST, SHH and CDK6 in Greig's cephalopolysyndactyly (up to 15 kb 3') (52), Saethre–Choetzen (up to 100 kb 5') (53), holoprosencephaly (up to 250 kb 5') (26) and triphalangeal thumb (up to 1000 kb 5') (54) and splenic marginal zone lymphoma (up to 66 kb 5') (55), respectively. Additional breakpoints have been observed near the DLX5/DLX6 genes on 7q21.3 (up to 1 Mb away) (32,56) and the FOXP2 gene on 7q31.2 (680 kb away) (32), which may be causing the split hand/split foot and speech and language developmental phenotypes, respectively, in the patients carrying the chromosome rearrangements (Fig. 3). Further study of the breakpoints including comparative DNA analysis will guide experiments to identify candidate regulatory sequences for testing in functional assays. Other structural studies of chromosome 7 have revealed that the FRA7E site at 7q21 comprises flexible sequences of AT-dinucleotides, which have the potential to form secondary structures and hence can affect replication (57), FRA7G at 7q31.2 is involved in the amplification of human oncogenes (58), and FRA7H at 7q32 (59,60) coincides with an SV40 integration site in an AT-rich segment of the chromosome.

A surprising observation from the analysis of the human chromosome 7 sequence has been the discovery that it contains the highest chromosomal content in the human genome (excluding the Y chromosome) of recently occurring large-scale segmental duplications (32,45,61,62) (Fig. 1F). Different analyses have indicated that ~6 and 2% of the chromosome are found as intra- and inter-chromosomal duplications, respectively. The largest segmental duplications identified (~400 kb) flanks the 1.5 Mb region usually deleted in WBS. These segmental duplications can be ‘hot spots’ or predisposition sites for the occurrence on non-allelic homologous recombination or unequal crossing-over leading to genomic mutations such as deletion (28,63) and inversion (31) of 7q11.23 in WBS. Additional WBS-like duplications are present at 7q22.1 (64), where a large number of breakpoints involved in malignancy are mapped (32). Other segmental duplications on chromosome 7 have been associated with gene conversion events in Shwachman–Diamond syndrome (39) and p47-phox-deficient chronic granulomatous disease (65).


   COMPARATIVE GENOMICS AND FUNCTIONAL ANALYSES OF CHROMOSOME 7
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 ABSTRACT
 SEQUENCING AND GENE ANNOTATION...
 GENOTYPE-PHENOTYPE AND...
 COMPARATIVE GENOMICS AND...
UNSOLVED BIOLOGICAL PROBLEMS
 CONCLUSIONS
 REFERENCES
 
With the completion of the human genome sequence, attention has quickly and intensely shifted to its functional interpretation. One of the most powerful approaches for identifying functional elements in the human genome sequence involves comparisons with other species' sequences. The early availability of chromosome 7 sequence catalyzed a number of comparative genomic studies. Initially, this involved construction of comparative BAC contig maps for orthologous mouse (66–69) and rat (70) genomic regions. Later, these efforts were extended to include the generation and comparative analyses of orthologous mouse sequence; among these were human–mouse comparative studies of the chromosome 7 regions encompassing the CFTR gene (71), deleted in WBS (72), and associated with evolutionary breakpoints (73). Such comparative studies have revealed a number of interesting findings, including: (i) the presence of two multidrug resistance genes in human, but three in mouse (74); (ii) regions of notably rapid evolution, such as those encompassing the zonadhesion (ZAN) (67), WBSCR15 (75), and FOXP2 (76) genes; (iii) a correlation between the presence of a human–mouse evolutionary breakpoint and pericentromeric duplications in the orthologous regions of the mouse genome (73); and (iv) functional differences in the MYH16 gene (encoding the predominant myosin heavy chain) among primates, which correlate with anatomical changes seen in the human lineage (77).

More recently, such comparative sequencing efforts have broadened to include multi-species sequence comparisons. In particular, the NISC Comparative Sequencing Program (www.nisc.nih.gov) aims to sequence and compare the same targeted genomic regions in multiple vertebrate species. Perhaps not surprisingly, the greater CFTR region represents the flagship target for this program, which now involves the sequencing of more than 150 different genomic regions—11 of which reside on chromosome 7 (totaling ~22 Mb; Table 2). The comparative sequencing of the greater CFTR region in the first set of 12 non-human vertebrates was reported by Thomas et al. (78). Among the initial analyses include the identification of small, discrete genomic regions conserved across multiple species [Multi-Species Conserved Sequences (MCSs) (79,80)]. Similar multi-species comparative sequence analysis of another chromosome 7 region has also been reported (81). Together, these studies are recruiting the newest methods of comparative analyses to unravel the functional and evolutionary histories of a sizeable portion of chromosome 7 (Table 2).


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  		Table 2. Regions of chromosome 7 being sequenced in multiple species by the NISC Comparative Sequencing Program
 
The recently launched ENCODE (Encyclopedia of DNA Elements) project aims to identify all of the functional elements in the human genome (genome.gov/ENCODE). As an initial pilot effort, 1% of the human genome (~30 Mb distributed across 44 regions) has been selected for study by a consortium of investigators using a number of different experimental and computational methods. The majority of these regions were selected randomly in a fashion that ensured diverse representation of the genome with respect to properties such as gene content and estimated rate of evolutionary changes, whereas others were chosen because of the pre-existing availability of valuable genomic data, historic interest and other factors. Once again, chromosome 7 is over-represented in the project. Specifically, five ENCODE regions reside on chromosome 7 (together encompassing ~5.7 Mb; Table 2), including the greater CFTR region (ENm001), the HOXA gene cluster (ENm010) and a segment containing the FOXP2 gene with some interesting evolutionary properties (ENm012). The intense and focused analyses being performed by the ENCODE project should yield unprecedented insight about the functional elements within these five regions of chromosome 7.


   UNSOLVED BIOLOGICAL PROBLEMS
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 SEQUENCING AND GENE ANNOTATION...
 GENOTYPE-PHENOTYPE AND...
 COMPARATIVE GENOMICS AND...
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There are increasing numbers of studies reporting apparent non-Mendelian anomalies and many previously undetected genomic variations between individual chromosome 7s, which in some cases may be associated with disease (82,83). Numerous other partial segmental UPDs (84), microdeletions (85), translocations/inversions/duplications (32) of chromosome 7, some being polymorphic in the population (31,86), are known. It is also known that heteromorphism can exist at the centromere (87) and that the expression of fragile sites along chromosome 7 (57) are also variable in the population. In these instances, as well as for the three disease conditions described in what follows and others, there is mounting evidence that resolution of the underlying mechanisms may require studies extending beyond one specific locus to perhaps multiple loci, adjacent regions (as with position-effect mutations), chromosomal bands or the unit-level.

For example, the first molecular description of the phenomena of uniparental disomy (UPD) in humans was observed in a female cystic fibrosis patient identified to inherit two chromosome 7s, both of maternal origin (with no paternal contribution) (88). Many individuals with maternal UPD have a growth deficiency disorder called Russell–Silver syndrome. Though there has been an intensive search to find the causative genes, which in part has led to the extensive characterization of three imprinted loci on chromosome 7 (Fig. 1C), none has been found. In fact, data might support the existence of two or more loci on chromosome 7 contributing to the etiology in the disease (84,89). Paternal UPD of chromosome 7 has been observed in a small number of individuals, but no consistent disease condition is associated with it (90).

In a second example, it has been postulated that the long arm of chromosome 7 contains multiple tumor suppressor genes and oncogenes (91,92), as well as an anti-senescence gene (93). Moreover, monosomy 7 is one of the most frequent chromosomal abnormalities observed in myelodysplasia and acute myelogenous leukemia (AML) (94). The incidence of monosomy 7 is particularly high in those individuals who have been previously exposed to drugs, radiotherapy or toxins and it is also observed in constitutional disorders such as Fanconi's anemia, congenital neutropenia and familial monosomy 7. Other cytogenetic abnormalities of chromosome 7 are found in many different types of human neoplasia, some of which present consistent patterns of genetic alteration (literature reviewed in 1, 2). So far, however, the MET protooncogene in hereditary papillary renal cell carcinoma (95), the CDK6 gene in splenic lymphoma (55), the ST7 tumor suppressor gene in colon cancer (96), and a few other fusion proteins have been identified. Intensive searches have been ongoing for more than a decade for a putative tumor suppressor gene at 7q22 (97,98) and another at 7q34–q35 (99,100) involved in AML. However, inconsistencies between the critical regions identified and proposed models (101,102) suggest a more complex etiology that might only be discerned using chromosome-intensive analyses.

In another example, several independent family-based linkage and cytogenetic studies have suggested that an autism-susceptibility gene (or genes) resides on chromosome 7 (103–106). The chromosome 7q21–q35 interval (>60 Mb) appears to be most often implicated but further localization has been complicated owing to the complex nature of the phenotype, as well as the underlying genetics, which can apparently include incomplete penetrance and allelic heterogeneity (107). Moreover, a potential preference for paternal (compared with maternal) linkage disequilibrium and recombination in autism families (compared with controls) has been described suggesting that imprinting or other non-Mendelian mechanisms may be involved (104). Taking all available data into consideration in the simplest explanation, there may be multiple genes on chromosome 7 involved. As with previous studies of many monogenic diseases future analyses of autism and other complex diseases, will benefit from the vast and ever-increasing wealth of resources, data and literature available for human chromosome 7. Ultimately, however, resolution of the aforementioned ‘chromosomal’ problems and others still to be described would likely benefit from organized efforts by multiple groups or consortia working together.


   CONCLUSIONS
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 GENOTYPE-PHENOTYPE AND...
 COMPARATIVE GENOMICS AND...
 UNSOLVED BIOLOGICAL PROBLEMS
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The initial studies of the human genome involved descriptions of its component chromosomes. Later, application of molecular genetic techniques culminating in the mapping and sequencing of the human genome benefited from pioneering investigations often modeled on studies of human chromosome 7, which in turn facilitated many significant disease-related breakthroughs. As a transition occurs from generating whole-genome data to more targeted comparative, functional and structural examinations, a challenge ahead will be to best collate complex and sometimes disparate data sets to facilitate biomedical discovery. Following past example, integrative studies around the common theme of chromosome 7 should continue to represent an effective paradigm for translating primary information into a fundamental understanding of the biology of the human genome.


   ACKNOWLEDGEMENTS
 
S.W.S is an investigator of the Canadian Institutes of Health Research and an international scholar of the Howard Hughes Medical Institute. This work is supported by grants from Genome Canada, the Canadian Foundation for Innovation, the Howard Hughes Medical Institute and the Hospital for Sick Children Foundation (to S.W.S.), as well as funding from the NHGRI Intramural Program (to E.D.G.).


   FOOTNOTES
 
* To whom correspondence should be addressed at: Department of Genetics and Genomic Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. Tel: +1 4168137613; Fax: +1 4168138319; Email: steve{at}genet.sickkids.on.ca


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