Although many studies have been conducted to identify single nucleotide polymorphisms (SNPs) in humans, few studies have been conducted to identify alternative forms of natural genetic variation, such as insertion and deletion (INDEL) polymorphisms. In this report, we describe an initial map of human INDEL variation that contains 415,436 unique INDEL polymorphisms. These INDELs were identified with a computational approach using DNA re-sequencing traces that originally were generated for SNP discovery projects. They range from 1 bp to 9989 bp in length and are split almost equally between insertions and deletions, relative to the chimpanzee genome sequence. Five major classes of INDELs were identified, including (1) insertions and deletions of single-base pairs, (2) monomeric base pair expansions, (3) multi-base pair expansions of 2-15 bp repeat units, (4) transposon insertions, and (5) INDELs containing random DNA sequences. Our INDELs are distributed throughout the human genome with an average density of one INDEL per 7.2 kb of DNA. Variation hotspots were identified with up to 48-fold regional increases in INDEL and/or SNP variation compared with the chromosomal averages for the same chromosomes. Over 148,000 INDELs (35.7%) were identified within known genes, and 5542 of these INDELs were located in the promoters and exons of genes, where gene function would be expected to be influenced the greatest. All INDELs in this study have been deposited into dbSNP and have been integrated into maps of human genetic variation that are available to the research community.

Transposable genetic elements are abundant in the genomes of most organisms, including humans. These endogenous mutagens can alter genes, promote genomic rearrangements, and may help to drive the speciation of organisms. In this study, we identified almost 11,000 transposon copies that are differentially present in the human and chimpanzee genomes. Most of these transposon copies were mobilized after the existence of a common ancestor of humans and chimpanzees, approximately 6 million years ago. Alu, L1, and SVA insertions accounted for >95% of the insertions in both species. Our data indicate that humans have supported higher levels of transposition than have chimpanzees during the past several million years and have amplified different transposon subfamilies. In both species, approximately 34% of the insertions were located within known genes. These insertions represent a form of species-specific genetic variation that may have contributed to the differential evolution of humans and chimpanzees. In addition to providing an initial overview of recently mobilized elements, our collections will be useful for assessing the impact of these insertions on their hosts and for studying the transposition mechanisms of these elements.

Transposons and transposon-like repetitive elements collectively occupy 44% of the human genome sequence. In an effort to measure the levels of genetic variation that are caused by human transposons, we have developed a new method to broadly detect transposon insertion polymorphisms of all kinds in humans. We began by identifying 606,093 insertion and deletion (indel) polymorphisms in the genomes of diverse humans. We then screened these polymorphisms to detect indels that were caused by de novo transposon insertions. Our method was highly efficient and led to the identification of 605 nonredundant transposon insertion polymorphisms in 36 diverse humans. We estimate that this represents 25-35% of ‫5702ف‬ common transposon polymorphisms in human populations. Because we identified all transposon insertion polymorphisms with a single method, we could evaluate the relative levels of variation that were caused by each transposon class. The average human in our study was estimated to harbor 1283 Alu insertion polymorphisms, 180 L1 polymorphisms, 56 SVA polymorphisms, and 17 polymorphisms related to other forms of mobilized DNA. Overall, our study provides significant steps toward (i) measuring the genetic variation that is caused by transposon insertions in humans and (ii) identifying the transposon copies that produce this variation.

BACKGROUND:With positive results from diabetes prevention studies, there is interest in convenient ways to incorporate screening for glucose intolerance into routine care and to limit the need for fasting diagnostic tests.

The Intelligent Dosing System (IDS, Dimensional Dosing Systems, Inc., Wexford, PA) is a software suite that incorporates patient-specific, dose-response data in a mathematical model, and then calculates the new dose of agent needed to achieve the next desired therapeutic goal. We evaluated use of the IDS for titrating insulin therapy. The IDS was placed on handheld platforms and provided to practitioners to use in adjusting total daily insulin dose. Fasting glucose, random glucose, and hemoglobin A1c were used as markers against which insulin could be adjusted. Values of markers expected at the next follow-up visit, as predicted by the model, were compared with levels actually observed. For 264 patients, 334 paired visits were analyzed. Average age was 54 years, diabetes' duration was 10 years, and body mass index was 33.2 kg/m(2); 57% were female, 88% were African American, and 92% had type 2 diabetes. The correlation between IDS suggested and actual prescribed total daily dose was high (r = 0.99), suggesting good acceptability of the IDS by practitioners. Significant decreases in fasting glucose, random glucose, and hemoglobin A1c levels were seen (all P < 0.0001). No significant difference between average expected and observed follow-up fasting glucose values was found (145 vs. 149 mg/dL, P = 0.42), and correlation was high (r = 0.79). Mean observed random glucose value at follow-up was comparable to the IDS predicted level (167 vs. 168 mg/dL, P = 0.97), and correlation was high (r = 0.73). Observed follow-up hemoglobin A1c was higher than the value expected (7.9% vs. 7.4%, P< 0.0055), but correlation was good (r = 0.70). These analyses suggest the IDS is a useful adjunct for decisions regarding insulin therapy even when using a variety of markers of glucose control, and can be used by practitioners to assist in attainment of glycemic goals.