doi:10.1136/jmg.39.2.81 2002;39;81-90 J. Med. Genet. D Kamnasaran and D W Cox Current status of human chromosome 14 http://jmg.bmj.com/cgi/content/full/39/2/81 Updated information and services can be found at: These include: Rapid responses http://jmg.bmj.com/cgi/eletter-submit/39/2/81 You can respond to this article at: service Email alerting top right corner of the article Receive free email alerts when new articles cite this article - sign up in the box at the Topic collections (3961 articles) Genetics (956 articles) Cancer:other Articles on similar topics can be found in the following collections Notes http://www.bmjjournals.com/cgi/reprintform To order reprints of this article go to: http://www.bmjjournals.com/subscriptions/ go to: Journal of Medical Genetics To subscribe to on 23 February 2007 jmg.bmj.com Downloaded from REVIEW ARTICLE Current status of human chromosome 14 D Kamnasaran, D W Cox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . J Med Genet 2002;39:8190 Over the past three decades, extensive genetic,
physical, transcript, and sequence maps have assisted
in the mapping of over 30 genetic diseases and in the
identification of over 550 genes on human chromosome
14. Additional genetic disorders were assigned to
chromosome 14 by studying either constitutional or
acquired chromosome aberrations of affected subjects.
Studies of benign and malignant tumours by karyotype
analyses and by allelotyping with a panel of
polymorphic genetic markers have further suggested the
presence of several tumour suppressor loci on
chromosome 14. The search for disease genes on
human chromosome 14 has also been achieved by
exploiting the human-mouse comparative maps.
Research on uniparental disomy and on the search for
imprinted genes has supported evidence of epigenetic
inheritance as a result of imprinting on human
chromosome 14. This review focuses on the current
developments on human chromosome 14 with respect to
genetic maps, physical maps, transcript maps, sequence
maps, genes, diseases, mouse-human comparative
maps, and imprinting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I nterest in human chromosome 14 was stimu-
lated in the early 1970s when a duplicated dis-
tal cytogenetic band of chromosome 14 was associated with Burkitt lymphoma. 1 A few years later, a partial trisomy syndrome for chromosome
14q was suggested to be associated with growth
and mental retardation. 2 Purine nucleoside phos- phorylase was the rst gene mapped to chromo-
some 14, using a human-mouse somatic cell
hybrid panel retaining a t(14;22) chromosome, 3 and shortly afterwards was shown to be decient
through haplotype studies in a family. 4 A folic acid sensitive site at 14q23, 5 variegate porphyria ( VP), 6 alpha-1-antitrypsin ( AAT), 7 familial hyper- trophic cardiomyopathy ( CMH1), 8 and Krabbe disease ( GALC) 9 were the rst loci to be mapped to specic intervals on chromosome 14. Extensive
mapping efforts have been followed by sequenc-
ing of the chromosome. Although annotation of
the sequence is currently incomplete, the results
of the extensive sequencing efforts have allowed
identication of over 550 genes on chromosome
14. This review describes the developments for
human chromosome 14 with respect to genetic
maps, physical maps, transcript maps, sequence
maps, genes, diseases, mouse-human compara-
tive maps, and imprinting, and provides a guide to
resources available. GENETIC, PHYSICAL, TRANSCRIPT AND
SEQUENCE MAPPING RESOURCES FOR
CHROMOSOME 14 Genetic maps
Genetic maps of the human genome have been
constructed to increase the informativeness and
density of genetic markers. Rened chromosome
14 specic linkage maps were made by integrat-
ing markers from different genetic maps and by
reassessing the genotype data. The progress in
mapping was summarised annually at the Gene
Mapping Meetings and two Chromosome 14
Workshops were held. 10 11 Early chromosome 14 genetic maps had very few blood serotype, RFLP,
and VNTR genetic markers, and were biased with
the highest density of markers in the distal 10% of
the chromosome, 12 13 which showed above average recombination. 14 An STRP (short tandem repeat polymorphism) map comprising nine genetic
markers, with heterozygosity values between 0.48
and 0.81, provided the rst continuous linkage
map along chromosome 14. 15 The markers were placed with over 1000:1 odds on an estimated 101
cM sex averaged chromosome 14 genetic map by
linkage analysis on 40 CEPH reference families.
The EUROGEM map of chromosome 14, about
146.2 cM (sex averaged) in length, showed 23
markers spaced about 10-20 cM apart, using cor-
rected genotype data from the CEPH consortium. 16 A more gene rich map of 42 RFLP and STRP markers, 13 of them within known
genes, was reported on a 163 cM sex averaged
map, using data from 59 CEPH reference
families 17 and physical positioning using patients with chromosome 14 aberrations. 18 A rened chromosome 14 CEPH consortium genetic map
with 68 genetic markers included 13 genes, 37
STRP, one OLA (oligonucleotide ligation assay),
and 17 RFLP markers, positioned every 3.5 cM. 19 Another extensive linkage map of chromosome
14 using genotype data from CEPH database 7
included 147 markers (32 RFLP and 115 STRP)
that were placed on a 128 cM sex averaged genetic
map, with an average intermarker distance of
1.85 cM. 20 Sixty-nine loci were positioned with over 1000:1 odds and seven loci were anchored to
cytogenetic bands at the proximal, medial, and
distal intervals of chromosome 14 by FISH
mapping. All markers showed consistent posi-
tions with the markers of other genetic maps
except the D14S42 and TCRA loci that had ambiguous placements. The underlying problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abbreviations: STRP, short tandem repeat polymorphism; OLA, oligonucleotide ligation assay; SNP, single
nucleotide polymorphism; STS, sequence tagged site; EST,
expressed sequence tag; LOH, loss of heterozygosity; TS,
tumour suppressor See end of article for
authors affiliations . . . . . . . . . . . . . . . . . . . . . . . Correspondence to:
Dr D W Cox, 8-39 Medical
Sciences Building,
University of Alberta
Edmonton, Alberta T6G
2H7, Canada;
diane.cox@ualberta.ca . . . . . . . . . . . . . . . . . . . . . . . 81 www.jmedgenet.com on 23 February 2007 jmg.bmj.com Downloaded from with the early genetic maps are that many markers were not
common between the maps and the number of families geno-
typed could not always provide an unambiguous gene or
marker order. While microsatellite markers provide high heterozygosity, new technologies have made feasible the typing of more
frequent biallelic markers or single nucleotide polymorphisms
(SNPs). A dense genetic map of 459 novel non-redundant
SNPs and 21 small insertions/deletions were identied from
825 chromosome 14 expressed sequence tagged and sequence
tagged site sequences, by the screening of 12 unrelated
Nigerians. 21 An additional 501 SNPs, identied by the screen- ing of several world wide ethnic groups, were obtained from
the public SNP database (www.ncbi.nlm.nih.gov/SNP). Of the
981 non-redundant biallelic genetic markers, 273 SNPs were
located within 159 known genes with a range of two to 20
polymorphisms per gene. There are currently over 2100 SNPs
reported on chromosome 14 by the large scale SNP mapping
effort of the human genome project (www.ncbi.nlm.nih.gov/
SNP/index.html). These resources will be of benet in the
identication of additional diseases on chromosome 14
through conventional genetic mapping approaches. Physical maps
The Whitehead Institute for Genome Research (www-
genome.wi.mit.edu) physical map of chromosome 14 com-
prises 590 YAC clones. 22 These YAC clones, useful for position- ing of markers but unsuitable for sequencing, were arranged
into ve contigs by sequence tagged site (STS) content
mapping of over 350 chromosome 14 STS markers. 22 A scaffold of 27 BAC clones was also physically mapped to chromosome
14, with an average spacing of 1 to 3 Mb, using FISH. 23 The aim was to provide a framework of BAC clones that would serve as
nucleation points for sequencing of the human genome, and
as probes for molecular cytogenetic analyses. In addition to
these public efforts to construct physical contigs on chromo-
some 14, several small contigs consisting of YAC, BAC, cosmid
and a combination of these clones were reported by several
groups in the search for disease genes 2428 such as oculopharyn- geal muscular dystrophy at 14q11.2-q12 24 and tetramelic mir- ror image polydactyly at 14q13. 26 These physical contigs provided valuable resources for the initial identication of
chromosome 14 specic transcripts. The construction of these physical contigs was assisted by a framework of genetic markers, in addition to a framework of
STS markers that were mapped onto the G3 and/or
GeneBridge4 (GB4) radiation hybrid panels by the Sanger
Centre (www.sanger.ac.uk), Whitehead Institute for Genome
Research (www-genome.wi.mit.edu), and Stanford Human
Genome Centre (www-shgc.stanford.edu). One disadvantage
of mapping onto these panels is that a marker can be mapped
to an incorrect chromosome as a result of artefacts from PCR
or paralogous sequences. An alternate approach was used to
map 1001 novel STS markers with an average spacing of 90 kb
on chromosome 14, using an in vitro radiation hybrid
mapping approach, called Happy Mapping. Briey, chromo-
some 14 DNA isolated by ow cytometry was fragmented by
irradiation and used for mapping. The mapping resolution of
this technique was dependent on the size of the fragmented
DNA chosen. This method was different from mapping on
radiation hybrid panels in that there was more fragmented
DNA representative of the entire chromosome that allowed
more accurate positioning of markers. Transcript maps
Several transcript maps have been reported for limited regions
of chromosome 14. 3033 The public sequencing of cDNAs from several cDNA libraries led to the generation of expressed
sequence tags (ESTs), comprising predominantly 3 untrans- lated sequences. These were used to form UniGene clusters (proposed genes) of cDNAs with at least 97% identity to each
other. 34 . The assembly of physical maps has progressed by the mapping of ESTs, and the grouping of ESTs to form clusters of
possible genes. In 1996, 16 354 unique ESTs, from a total of
20 104 ESTs were mapped within a genome wide framework
of about 1100 G