Biomedical subjects

B Gostout

Publications and source records attributed to B Gostout.

4 recordsLinked to original sources

PubMed1995

Nonrandom patterns of simple and cryptic triplet repeats in coding and noncoding sequences.

Triplet repeats of the sequence purine, purine, and pyrimidine [RRY(i)] are frequent and often polymorphic in humans. Some RRY(i) are composed predominantly of a continuous repeat of one sequence [simple RRY(i)], but the majority are cryptic RRY(i) that are not obvious until the bases are classified into R or Y before the full extent of the repeat becomes apparent. RRY(i) can be divided into 18 classes based on predominant nucleotides. These classes are highly nonrandom in abundance and in location within genes. In humans, simple or cryptic RRY(i), in which AAT or AAC triplets predominate, are preferentially located 3' of Alu repeats. RRY(i) with a predominance of AGC or GGC show a dramatic enrichment in coding sequence, and GGC also shows a dramatic enrichment in 5' untranslated regions of genes. Characterization of RRY(i) present in coding regions identify 10 protein motifs (An, Dn, Hn, Pn, Qn, Tn, GnS0-3Gm, (G/S)n, (S/G/N)n, and (L/P)n). Six of the protein motifs appear predominantly in DNA-binding proteins/transcription factors. Alignment of homologous protein sequences from other mammals reveals that both simple and cryptic RRY(i) are a major source of deletions or insertions in the genes that contain them. Cryptic RRY(i) may be candidates for triplet repeat genetic diseases and, when mutated in somatic cells, may contribute to carcinogenesis.

Animals↗

PubMed1993

The pattern of spontaneous germ-line mutation: relative rates of mutation at or near CpG dinucleotides in the factor IX gene.

Mutations at CpG dinucleotides were delineated in the factor IX gene of 38 hemophilia B patients. When transitions at CpG were considered with those previously reported by us and those compiled in the factor IX mutation database, the following patterns emerged. Many CpG sites were mutated with high frequency, while two CpG sites were infrequently mutated (R29-->Q and R116-->TGA). Of the 6 possible nonsense mutations and the 14 missense mutations that would produce a nonconservative change at conserved amino acids, all have been observed to cause hemophilia B except A-10-->T and R338-->Q. By contrast, none of the 6 missense changes at nonconserved amino acids have been observed to cause hemophilia B. At those CpG sites that are frequently mutated, the rate of transitions is estimated to be 20-fold higher than transitions at non-CpG sites. Point mutations in close proximity to CpG dinucleotides did not seem elevated.

DNA Mutational Analysis↗

PubMed1993

Germline mutations in the factor IX gene: a comparison of the pattern in Caucasians and non-Caucasians.

DNA samples of patients from around the world have been sequenced to precisely define the mutations in the factor IX gene resulting in hemophilia B. This study compares the patterns of independent mutation between 127 Caucasian and 44 non-Caucasian patients with hemophilia B. Caucasians and non-Caucasians are found to have similar patterns of transitions and transversions (both at CpG and at non-CpG sites) as well as insertions, deletions, microdeletions, and complex changes (chi 2 = 2.71, p = 0.922). An analysis of subgroups of transitions and transversions shows similar patterns among Caucasians and non-Caucasians (chi 2 = 2.98, p = 0.83). If the subset of non-Caucasian samples (24) in which the mutation is known to have occurred outside of the United States, Canada, and Europe (UCE) is compared to the Caucasian subset, the above conclusions are unchanged. The invariant nature of this pattern of mutation is most simply compatible with a predominance of endogenous processes or common mutagen exposure rather than mutagen exposure specifically associated with non-Caucasian status or non-Western lifestyle.

DNA Mutational Analysis↗

PubMed1993

"Cryptic" repeating triplets of purines and pyrimidines (cRRY(i)) are frequent and polymorphic: analysis of coding cRRY(i) in the proopiomelanocortin (POMC) and TATA-binding protein (TBP) genes.

Triplets of the form of purine, purine, pyrimidine (RRY(i)) are enhanced in frequency in the genomes of primates, rodents, and bacteria. Some RRY(i) are "cryptic" repeats (cRRY(i)) in which no one tandem run of a trinucleotide predominates. A search of human GenBank sequence revealed that the sequences of cRRY(i) are highly nonrandom. Three randomly chosen human cRRY(i) were sequenced in search of polymorphic alleles. Multiple polymorphic alleles were found in cRRY(i) in the coding regions of the genes for proopiomelanocortin (POMC) and TATA-binding protein (TBP). The highly polymorphic TBP cRRY(i) was characterized in detail. Direct sequencing of 157 unrelated human alleles demonstrated the presence of 20 different alleles which resulted in 29-40 consecutive glutamines in the amino-terminal region of TBP. These alleles are differentially distributed among the races. PCR was used to screen 1,846 additional alleles in order to characterize more fully the range of variation in the population. Three additional alleles were discovered, but there was no example of a substantial sequence amplification as is seen in the repeat sequences associated with X-linked spinal and bulbar muscular atrophy, myotonic dystrophy, or the fragile-X syndrome. The structure of the TBP cRRY(i) is conserved in the five monkey species examined. In the chimpanzee, examination of four individuals revealed that the cRRY(i) was highly polymorphic, but the pattern of polymorphism differed from that in humans. The TBP cRRY(i) displays both similarities with and differences from the previously described RRY(i) in the coding sequence of the androgen receptor. Our data suggest how simple tandem repeats could evolve from cryptic repeats.

Aged↗