As part of the Human Genome Project, the Washington University Genome Sequencing Center has commenced systematic sequencing of human chromsome 7. To organize and supply the effort, we have undertaken the construction of sequence-ready physical maps for defined chromosomal intervals. Map construction is a serial process composed of three main activities. First, candidate STS-positive large-insert PAC and BAC clones are identified. Next, these candidate clones are subjected to fingerprint analysis. Finally, the fingerprint data are used to assemble sequence-ready maps. The fingerprinting method we have devised is key to the success of the overall approach. We present here the details of the method and show that the fingerprints are of sufficient quality to permit the construction of megabase-size contigs in defined regions of the human genome. We anticipate that the high throughput and precision characteristic of our fingerprinting method will make it of general utility.

/pdf/high-throughput-fingerprint-analysis-of-large-insert-clones-4369fcftz3.pdf

High Throughput Fingerprint Analysis of Large-Insert Clones

Mouse Tabby (Ta) and X chromosome-linked human EDA share the features of hypoplastic hair, teeth, and eccrine sweat glands. We have cloned the Ta gene and find it to be homologous to the EDA gene. The gene is altered in two Ta alleles with a point mutation or a deletion. The gene is expressed in developing teeth and epidermis; no expression is seen in corresponding tissues from Ta mice. Ta and EDA genes both encode alternatively spliced forms; novel exons now extend the 3′ end of the EDA gene. All transcripts recovered have the same 5′ exon. The longest Ta cDNA encodes a 391-residue transmembrane protein, ectodysplasin-A, containing 19 Gly-Xaa-Yaa repeats. The isoforms of ectodysplasin-A may correlate with differential roles during embryonic development.

https://www.pnas.org/content/pnas/94/24/13069.full.pdf

The Tabby phenotype is caused by mutation in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains

Telomere-specific clones are a valuable resource for the characterization of chromosomal rearrangements. We previously reported a first-generation set of human telomere probes consisting of 34 genomic clones, which were a known distance from the end of the chromosome (∼300 kb), and 7 clones corresponding to the most distal markers on the integrated genetic/physical map (1p, 5p, 6p, 9p, 12p, 15q, and 20q). Subsequently, this resource has been optimized and completed: the size of the genomic clones has been expanded to a target size of 100–200 kb, which is optimal for use in genome-scanning methodologies, and additional probes for the remaining seven telomeres have been identified. For each clone we give an associated mapped sequence-tagged site and provide distances from the telomere estimated using a combination of fiberFISH, interphase FISH, sequence analysis, and radiation-hybrid mapping. This updated set of telomeric clones is an invaluable resource for clinical diagnosis and represents an important contribution to genetic and physical mapping efforts aimed at telomeric regions.

An optimized set of human telomere clones for studying telomere integrity and architecture.

DNA sequence variation has become a major source of insight regarding the origin and history of our species 1−5 as well as an important tool for the identification of allelic variants associated with disease. Comparative sequencing of DNA has to date focused mainly on mitochondrial (mt) DNA, which due to its apparent lack of recombination and high evolutionary rate lends itself well to the study of human evolution1. These advantages also entail limitations. For example, the high mutation rate of mtDNA results in multiple substitutions that make phylogenetic analysis difficult and, because mtDNA is maternally inherited, it reflects only the history of females. For the history of males, the non-recombining part of the paternally inherited Y chromosome can be studied2. The extent of varia

/pdf/dna-sequence-variation-in-a-non-coding-region-of-low-2waabfrq77.pdf

DNA sequence variation in a non-coding region of low recombination on the human X chromosome.

Androgenetic alopecia (AGA), or male-pattern baldness, is the most common form of hair loss. Its pathogenesis is androgen dependent, and genetic predisposition is the major requirement for the phenotype. We demonstrate that genetic variability in the androgen receptor gene (AR) is the cardinal prerequisite for the development of early-onset AGA, with an etiological fraction of 0.46. The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect. The X-chromosomal location of AR stresses the importance of the maternal line in the inheritance of AGA.

Genetic Variation in the Human Androgen Receptor Gene Is the Major Determinant of Common Early-Onset Androgenetic Alopecia

A YAC/STS map of the X chromosome has reached an inter-STS resolution of 75 kb. The map density is sufficient to provide YACs or other large-insert clones that are cross-validated as sequencing substrates across the chromosome. Marker density also permits estimates of regional gene content and a detailed comparison of genetic and physical map distances. Five regions are detected with relatively high G + C, correlated with gene richness; and a 17-Mb region with very low recombination is revealed between the Xq13.3 [XIST] and Xq21.3 XY homology loci.

/pdf/x-chromosome-map-at-75-kb-sts-resolution-revealing-extremes-2drgi8n179.pdf

X chromosome map at 75-kb STS resolution, revealing extremes of recombination and GC content.

Four collections of human X-specific YACs, derived from human cells containing supernumerary X chromosomes or from somatic cell hybrids containing only X human DNA were characterized. In each collection, 80 - 85% of YAC strains contained a single X YAC. Five thousand YACs from the various libraries were sized, and cocloning was assessed in subsets by the fraction of YAC insert-ends with non-X sequences. Cocloning was substantial, ranging up to 50% for different collections; and in agreement with previous indications, in all libraries the larger the YACs, the higher the level of cocloning. In libraries made from human - hamster hybrid cells, expected numbers of clones were recovered by STS-based screening; but unexpectedly, the two collections from cells with 4 or 5 X chromosomes yielded numbers of YACs corresponding to an apparent content of only about two X equivalents. Thus it is possible that the DNA of inactive X chromosomes is poorly cloned into YACs, speculatively perhaps because of its specialized chromatin structure.

/pdf/characterization-of-four-human-yac-libraries-for-clone-size-37z0lcm4mp.pdf

Characterization of four human YAC libraries for clone size, chimerism and X chromosome sequence representation

Fourcollections ofhumanX-specific YACs,derived fromhumancellscontaining supernumerary X chromosomes orfromsomatic cell hybrids containing onlyX humanDNA werecharacterized. Ineach collection, 80-85%ofYACstrains contained asingle XYAC.Five thousand YACsfromthevarious libraries weresized, andcocloning wasassessed insubsets by thefraction ofYACinsert-ends withnon-Xsequences. Cocloning wassubstantial, ranging upto50%for different collections; andinagreement withprevious indications, inalllibraries thelarger theYACs,the higher thelevel ofcocloning. Inlibraries madefrom human-hamster hybrid cells, expected numbersof clones wererecovered bySTS-based screening; but unexpectedly, thetwocollections fromcells with4or 5 X chromosomesyielded numbersof YACs corresponding toanapparent content ofonly about two X equivalents. Thusitispossible thattheDNAof inactive Xchromosomes ispoorly cloned intoYACs, speculatively perhaps becauseofitsspecialized chromatin structure.

Characterization offourhumanYAClibraries forclone size, chimerism andX chromosome sequence representation

YAC-based map of the X chromosome at 85 Kb inter-STS resolution reveals extremes of recombination activity and GC content

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X chromosome map at 75-kb STS resolution, revealing extremes of recombination and GC content.

Characterization of four human YAC libraries for clone size, chimerism and X chromosome sequence representation

Characterization offourhumanYAClibraries forclone size, chimerism andX chromosome sequence representation

YAC-based map of the X chromosome at 85 Kb inter-STS resolution reveals extremes of recombination activity and GC content