Sequence space coverage, entropy of genomes and the potential to detect non-human DNA in human samples

Background: Genomes store information for building and maintaining organisms. Complete sequencing of many genomes provides the opportunity to study and compare global information properties of those genomes. Results: We have analyzed aspects of the information content of Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, and Escherichia coli (K-12) genomes. Virtually all possible (\u3e 98%) 12 bp oligomers appear in vertebrate genomes while \u3c 2% of 19 bp oligomers are present. Other species showed different ranges of \u3e 98% to \u3c 2% of possible oligomers in D. melanogaster (12-17 bp), C. elegans (11-17 bp), A. thaliana (11-17 bp), S. cerevisiae (10-16 bp) and E. coli (9-15 bp). Frequencies of unique oligomers in the genomes follow similar patterns. We identified a set of 2.6 M 15-mers that are more than 1 nucleotide different from all 15-mers in the human genome and so could be used as probes to detect microbes in human samples. In a human sample, these probes would detect 100% of the 433 currently fully sequenced prokaryotes and 75% of the 3065 fully sequenced viruses. The human genome is significantly more compact in sequence space than a random genome. We identified the most frequent 5- to 20-mers in the human genome, which may prove useful as PCR primers. We also identified a bacterium, Anaeromyxobacter dehalogenans, which has an exceptionally low diversity of oligomers given the size of its genome and its GC content. The entropy of coding regions in the human genome is significantly higher than non-coding regions and chromosomes. However chromosomes 1, 2, 9, 12 and 14 have a relatively high proportion of coding DNA without high entropy, and chromosome 20 is the opposite with a low frequency of coding regions but relatively high entropy. Conclusion: Measures of the frequency of oligomers are useful for designing PCR assays and for identifying chromosomes and organisms with hidden structure that had not been previously recognized. This information may be used to detect novel microbes in human tissues

The evolution of biodiversity : a simulation approach

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1998.Vita.Includes bibliographical references (p. 186-195).by Carlo C. Maley.Ph.D

Animal Cell Differentiation Patterns Suppress Somatic Evolution

Cell differentiation in multicellular organisms has the obvious function during development of creating new cell types. However, in long-lived organisms with extensive cell turnover, cell differentiation often continues after new cell types are no longer needed or produced. Here, we address the question of why this is true. It is believed that multicellular organisms could not have arisen or been evolutionarily stable without possessing mechanisms to suppress somatic selection among cells within organisms, which would otherwise disrupt organismal integrity. Here, we propose that one such mechanism is a specific pattern of ongoing cell differentiation commonly found in metazoans with cell turnover, which we call “serial differentiation.” This pattern involves a sequence of differentiation stages, starting with self-renewing somatic stem cells and proceeding through several (non–self-renewing) transient amplifying cell stages before ending with terminally differentiated cells. To test the hypothesis that serial differentiation can suppress somatic evolution, we used an agent-based computer simulation of cell population dynamics and evolution within tissues. The results indicate that, relative to other, simpler patterns, tissues organized into serial differentiation experience lower rates of detrimental cell-level evolution. Self-renewing cell populations are susceptible to somatic evolution, while those that are not self-renewing are not. We find that a mutation disrupting differentiation can create a new self-renewing cell population that is vulnerable to somatic evolution. These results are relevant not only to understanding the evolutionary origins of multicellularity, but also the causes of pathologies such as cancer and senescence in extant metazoans, including humans

Chromosomal instability and copy number alterations in Barrett’s esophagus and esophageal adenocarcinoma

Purpose: Chromosomal instability, as assessed by many techniques, including DNA content aneuploidy, LOH, and comparative genomic hybridization, has consistently been reported to be common in cancer and rare in normal tissues. Recently, a panel of chromosome instability biomarkers, including LOH and DNA content, has been reported to identify patients at high and low risk of progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EA), but required multiple platforms for implementation. Although chromosomal instability involving amplifications and deletions of chromosome regions have been observed in nearly all cancers, copy number alterations (CNAs) in premalignant tissues have not been well characterized or evaluated in cohort studies as biomarkers of cancer risk. Experimental Design: We examined CNAs in 98 patients having either BE or EA using BAC array CGH to characterize CNAs at different stages of progression ranging from early BE to advanced EA. Results: CNAs were rare in early stages (<HGD) but were progressively more frequent and larger in later stages (HGD and EA), including high level amplifications. The number of CNAs correlated highly with DNA content aneuploidy. Patients whose biopsies contained CNAs involving more than 70 Mbp were at increased risk of progression to DNA content abnormalities or EA (HR=4.9, 95% CI 1.6-14.8, p=0.0047), and the risk increased as more of the genome was affected. Conclusions: Genome wide analysis of CNAs provides a common platform for evaluation of chromosome instability for cancer risk assessment as well as identification of common regions of alteration that can be further studied for biomarker discovery

The adipose tissue production of adiponectin is increased in end-stage renal disease.

Adiponectin has antidiabetic properties, and patients with obesity, diabetes, and insulin resistance have low plasma adiponectin levels. However, although kidney disease is associated with insulin resistance, adiponectin is elevated in end-stage renal disease. Here we determine whether adipose tissue production of adiponectin is increased in renal disease in a case-control study of 36 patients with end-stage renal disease and 23 kidney donors. Blood and tissue samples were obtained at kidney transplantation and donation. The mean plasma adiponectin level was significantly increased to 15.6 mg/ml in cases compared with 8.4 mg/ml in controls. Plasma levels of the inflammatory adipokines tumor necrosis factor α, interleukin 6, and high-sensitivity C-reactive protein were significantly higher in cases compared with controls. Adiponectin mRNA and protein expression in visceral and subcutaneous fat were significantly higher in cases than controls, while adiponectin receptor-1 mRNA expression was significantly increased in peripheral blood cells, muscle, and adipose tissue in cases compared with controls. Thus, our study suggests that adipose tissue production of adiponectin contributes to the high plasma levels seen in end-stage renal disease

Single nucleotide polymorphism-based genome-wide chromosome copy change, loss of heterozygosity, and aneuploidy in Barrett's esophagus neoplastic progression.

Chromosome copy gain, loss, and loss of heterozygosity (LOH) involving most chromosomes have been reported in many cancers; however, less is known about chromosome instability in premalignant conditions. 17p LOH and DNA content abnormalities have been previously reported to predict progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). Here, we evaluated genome-wide chromosomal instability in multiple stages of BE and EA in whole biopsies. Forty-two patients were selected to represent different stages of progression from BE to EA. Whole BE or EA biopsies were minced, and aliquots were processed for flow cytometry and genotyped with a paired constitutive control for each patient using 33,423 single nucleotide polymorphisms (SNP). Copy gains, losses, and LOH increased in frequency and size between early- and late-stage BE (P 30% in early and late stages, respectively. A set of statistically significant events was unique to either early or late, or both, stages, including previously reported and novel abnormalities. The total number of SNP alterations was highly correlated with DNA content aneuploidy and was sensitive and specific to identify patients with concurrent EA (empirical receiver operating characteristic area under the curve = 0.91). With the exception of 9p LOH, most copy gains, losses, and LOH detected in early stages of BE were smaller than those detected in later stages, and few chromosomal events were common in all stages of progression. Measures of chromosomal instability can be quantified in whole biopsies using SNP-based genotyping and have potential to be an integrated platform for cancer risk stratification in BE

Transplantation of Kidneys from Donors with Acute Renal Failure Five-Year Results from Double Center Experience

Background: Transplantation of kidneys from deceased donors with acute renal failure (ARF) has been described and represents an underutilized source of renal grafts. We reviewed retrospectively our double center experience with transplantation of ARF donor kidneys. Methods: Between January 2009 and June 2014, we performed a total of 397 kidney transplants at the two hospitals. Of which, 65 came from donors with ARF. The outcome was compared with 62 expanded criteria donor kidneys and 270 standard criteria donor kidneys. ARF was defined as donor terminal creatinine higher than 2. All kidneys from ARF donors had acceptable biopsies and were pumped. The immunosuppression was similar in all three groups (Thymoglobulin for induction and Prograf, Cellcept and steroids for maintenance). The outcome measurements included recipient serum creatinine, patient and graft survival at 6 months, 1 year and 3 years. We also reviewed the delayed graft function (DGF) rates and cold ischemic time in all groups. Results: Mean donor creatinine was 3.84±1.3. The 6 month, 1 and 3 year patient survival rates were 98.5%, 96.8% and 92.0% in ARF group, 98.1%, 97.0% and 93.4% SCD group and 98.4%, 93.2% and 77.7% in ECD group. The 6 month, 1 and 3 year death censored graft survival was 96.9%, 96.9%, 96.9% in ARF group, 97.7, 96.5, 91.8 in SCD group and 95.1%, 93.2%, 90.1% in ECD group. The mean 6mo, 1 year and 3 year recipient creatinine was 1.49, 1.46 and 1.51 in ARF group, 1.61, 1.72 and 1.77 in SCD group and 1.91, 1.92 and 2.15 in ECD group, respectively. ARF kidneys are noted to be associated with more DGF (58.5% in ARF group VS 41.5% in non ARF group), longer cold ischemic time (857.79 min in ARF group vs 589.32 min in non ARF group) and younger donor age (32.25 years in ARF group vs 40.65 years in non ARF group). Conclusion: Elevated terminal donor creatinine is not a risk factor for graft loss after deceased donor kidney transplantation. Although there is increased risk of DGF and longer cold ischemic time, transplantation of ARF kidneys provides comparable short and long term graft function and patient survival compared to kidneys from non ARF donors

Spatial structure increases the waiting time for cancer

Cancer results from a sequence of genetic and epigenetic changes which lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells, and thus, to a selective advantage of pre-cancerous cells. The notion of cancer progression as an evolutionary process has been experiencing increasing interest in recent years. Many efforts have been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a well-mixed cell population, even though pre-cancerous cells often evolve in highly structured epithelial tissues. We propose a novel model of cancer progression that considers a spatially structured cell population where clones expand via adaptive waves. This model is used to asses two different paradigms of asexual evolution that have been suggested to delineate the process of cancer progression. The standard scenario of periodic selection assumes that driver mutations are accumulated strictly sequentially over time. However, when the mutation supply is sufficiently high, clones may arise simultaneously on distinct genetic backgrounds, and clonal adaptation waves interfere with each other. We find that in the presence of clonal interference, spatial structure increases the waiting time for cancer, leads to a patchwork structure of non-uniformly sized clones, decreases the survival probability of virtually neutral (passenger) mutations, and that genetic distance begins to increase over a characteristic length scale, determined here. These characteristic features of clonal interference may help to predict the onset of cancers with pronounced spatial structure and to interpret spatially-sampled genetic data obtained from biopsies. Our estimates suggest that clonal interference likely occurs in the progressing colon cancer, and possibly other cancers where spatial structure matters.Comment: 21 page