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PubMed2004

Measures of diversity for populations and distances between individuals with highly reorganizable genomes.

In this paper we address the problem of defining a measure of diversity for a population of individuals whose genome can be subjected to major reorganizations during the evolutionary process. To this end, we introduce a measure of diversity for populations of strings of variable length defined on a finite alphabet, and from this measure we derive a semi-metric distance between pairs of strings. The definitions are based on counting the number of substrings of the strings, considered first separately and then collectively. This approach is related to the concept of linguistic complexity, whose definition we generalize from single strings to populations. Using the substring count approach we also define a new kind of Tanimoto distance between strings. We show how to extend the approach to representations that are not based on strings and, in particular, to the tree-based representations used in the field of genetic programming. We describe how suffix trees can allow these measures and distances to be implemented with a computational cost that is linear in both space and time relative to the length of the strings and the size of the population. The definitions were devised to assess the diversity of populations having genomes of variable length and variable structure during evolutionary computation runs, but applications in quantitative genomics, proteomics, and pattern recognition can be also envisaged.

Computational Biology↗
PubMed1983

Glucose-6-phosphate dehydrogenase as a probe for the study of X-chromosome inactivation in hunan females.

The electrophoretic variants of G6PD have provided evidence for a single active X-chromosome in human somatic cells, but two active X-chromosomes in germ cells and in triploid cells with a 69,XXY karyotype. Studies of clonal populations of cells heterozygous for G6PD-A but expressing a single isozyme have provided evidence that the maintenance of the inactivation process is extremely stable, but that an occasional localized derepression event may occur. Such populations have also been used to show that methylation of X-chromosome DNA is not obviously different for XA and XI; furthermore, methylation is surprisingly unstable at least at some sites on the X. Studies of derepressed loci on the inactive X-chromosome in these clonal cell populations show that the expression of loci that escape inactivation is greater on XA than XI. G6PD variants have provided significant insights into the consequences of X-chromosome inactivation, revealing the role of intercellular communication and cell selection in determining female phenotype. The evidence that is now available indicates that the regulation of the X-chromosome is complex. The mechanisms involved include: 1) initiation, an event that may be mediated through an autosomal product and 2) maintenance which is stable but subject to programmed derepression of the entire chromosome during ontogeny of germ cells and occasional unprogrammed localized derepression in somatic cells. In addition, there may be transcriptional differences between XI and XA to compensate for monosomy of X-linked genes. The molecular basis for this multilevel regulation is unclear, but it seems certain that the cloned DNA probe for G6PD [Persico et al, 1981] will provide further insights.

Alleles↗
PubMed2026

Diversity at the HYP1 locus in potato cyst nematodes does not result from developmentally-programmed somatic mutations.

Most genetic diversity stems from spontaneous mutations, that is, errors in DNA repair or replication. But for dozens of organisms across the tree of life, mutations at specific loci are not spontaneous but developmentally programmed: effectively, some organisms edit their own DNA sequences. This is perhaps most common among pathogens and parasites, many of which use editing to diversify genes that produce important antigens. Plant-parasitic potato cyst nematodes are damaging agricultural pests that establish a lifelong feeding site inside the root of their host plant. We previously observed extensive diversity of rare alleles at HYP1, the most highly expressed gene that encodes a protein secreted by potato cyst nematodes during parasitism. Importantly, HYP1 alleles differ from each other by complex, in-frame rearrangements of short repeated sequence motifs within a single exon. Combining several lines of evidence, we previously hypothesized that potato cyst nematodes use developmentally-programmed mutations, or editing, to diversify HYP1 alleles in the soma. In the current work, we now test this hypothesis. We employ highly accurate long-read DNA sequencing of a simplified genetic system to identify potential rare edited alleles, we use a transgenic yeast system to describe large de novo mutations at HYP1, and we interpret our findings in light of key population genetic parameters as well as the genetic diversity surrounding HYP1 and across the genome.

Animals↗
PubMed2006

Tools for the identification of variable and potentially variable tandem repeats.

BACKGROUND: Tandem repeat arrays showing variation between sequences within a population, between strains or across species may have functional effects. The increasing availability of genomic sequence data makes routine description of observed variation possible, creating a need for tools to describe such variability. RESULTS: We present a set of programs that facilitate the identification of tandem repeats showing variation across multiple sequences or genomes, and the prediction of potentially polymorphic tandem repeats. The VNTRfinder (Variable Number of Tandem Repeats finder) program enables the detection of sequence length variation between arrays of inter-specific or intra-specific tandem repeats. In the absence of comparable sequences to explore observed variation, predictions are provided describing which tandem repeats are more likely to be variable, to help guide and focus further experimental evaluation. CONCLUSION: These tools represent a resource for researchers interested in tandem repeats in nucleotide sequences that are most likely to be of clinical and evolutionary interest. The tools are available at http://bioinformatics.rcsi.ie/vntrfinder/. Downloadable versions for UNIX/LINUX and WINDOWS which permit the consideration of longer and more numerous sequences are also available.

Algorithms↗
PubMed1997

Effects of dietary fat modification on fibrinogen, factor VII, and plasminogen activator inhibitor-1 activity in subjects with impaired glucose tolerance.

Our aim was to assess the impact of a monounsaturated fat-enriched (Mono) diet and a diet recommended by the National Cholesterol Education Program (NCEP) on plasma levels of fibrinogen and activities of factor VII (FVII:C) and plasminogen activator inhibitor-1 (PAI-1) and the impact of genetic polymorphisms of these variables (HaeIII, MspI, and 4G/5G polymorphisms, respectively) in 28 subjects with impaired glucose tolerance ([IGT] 17 men and 11 women; mean age, 55.6 +/- 5.5 years). A diet rich in fat and saturated fatty acids served as a baseline diet for 3 weeks. Thereafter, subjects were randomized for the next 8 weeks to either the Mono diet (n = 12) or NCEP diet (n = 18). Fibrinogen levels or PAI-1 activities did not change with either of the diets, but fibrinogen levels were higher (3.4 +/- 0.5 v 4.0 +/- 0.6 g/L, P = .007 at baseline) throughout the study in heterozygous subjects with respect to HaeIII polymorphism. This polymorphism and age accounted for 38% of the variation of fibrinogen levels. MspI polymorphism together with body mass index explained 51% of the variation of FVII:C, which was higher in subjects with the M1M1 genotype compared with M1M2/M2M2 genotypes (127% +/- 21% v 90% +/- 12%, P < .001). FVII:C showed a decrease with the NCEP diet (P < .05), but the decline was confined to M1M1 subjects. PAI-1 activity did not differ significantly between the genotypes. The insulin sensitivity index (SI) obtained by the minimal model method was the main explanatory variable of PAI-1 activity. To conclude, despite good compliance, the fat-modified diet did not alter plasma levels of fibrinogen or PAI-1 in white subjects with IGT. FVII:C levels decreased with the NCEP diet, but this was confined to subjects with the M1M1 genotype.

Analysis of Variance↗
PubMed2004

Pityriasis rosea--evidence for and against an infectious aetiology.

Pityriasis rosea, first named as such in 1860, probably holds the longest record for an exanthem suspected to be associated with an infection but for which an exact cause has not been found. The distinctly programmed clinical course, the lack of recurrence for most patients, and the presence of temporal case clustering provide the strongest evidence to support an infectious aetiology. Further support comes from seasonal variation and the association with respiratory tract infections, the unfavourable social and economic background of cases, and a history in some cases of contact with patients with pityriasis rosea. The apparent therapeutic efficacy of several treatment modalities does not provide strong evidence for or against an infectious aetiology. The roles of human herpesvirus 7 and to a lesser extent human herpesvirus 6 remain controversial. There exists reasonable evidence that pityriasis rosea is not associated with cytomegalovirus, Epstein-Barr virus, parvovirus B19, picornavirus, influenza and parainfluenza viruses, Legionella spp., Mycoplasma spp. and Chlamydia spp. infections. Evidence is also unsubstantiated as yet for alternative aetiological hypotheses such as autoimmunity, atopy, and genetic predisposition.

Bacterial Infections↗
PubMed2000

The evolution of maladaptation.

This review contains a description of a research program for the study of maladaptation, defined here in terms of deviation from adaptive peaks. Maladaptation has many genetic causes, including mutation, inbreeding, drift, gene flow, heterozygote advantage and pleiotropy. Degrees of maladaptation are determined by genetic architecture and the relationship between the rates of selective, environmental change and the nature and extent of genetic responses to selection. The empirical analysis of maladaptation requires: (1) recognition of putative maladaptation, using methods from phylogenetics, teleonomy, development and genetics, followed by an assessment of the nature and degree of deviation from adaptation, using studies of natural selection and teleonomy; (2) determination of the causes of the deviation, using analyses of genetics, development, or other methods. Conditions for unambiguously identifying maladaptation are considerably more stringent than those for demonstrating adaptation and remarkably few studies have clearly identified and characterised maladaptative traits. A thorough understanding of the nature of phenotypic variation will never be achieved without an analysis of the scope and usual causes of maladaptation.

Adaptation, Physiological↗
PubMed2006

AccuTyping: new algorithms for automated analysis of data from high-throughput genotyping with oligonucleotide microarrays.

Microarray-based analysis of single nucleotide polymorphisms (SNPs) has many applications in large-scale genetic studies. To minimize the influence of experimental variation, microarray data usually need to be processed in different aspects including background subtraction, normalization and low-signal filtering before genotype determination. Although many algorithms are sophisticated for these purposes, biases are still present. In the present paper, new algorithms for SNP microarray data analysis and the software, AccuTyping, developed based on these algorithms are described. The algorithms take advantage of a large number of SNPs included in each assay, and the fact that the top and bottom 20% of SNPs can be safely treated as homozygous after sorting based on their ratios between the signal intensities. These SNPs are then used as controls for color channel normalization and background subtraction. Genotype calls are made based on the logarithms of signal intensity ratios using two cutoff values, which were determined after training the program with a dataset of approximately 160,000 genotypes and validated by non-microarray methods. AccuTyping was used to determine >300,000 genotypes of DNA and sperm samples. The accuracy was shown to be >99%. AccuTyping can be downloaded from http://www2.umdnj.edu/lilabweb/publications/AccuTyping.html.

Algorithms↗
PubMed2003

Analysis of Sepik populations of Papua New Guinea suggests an increase of CYP2C19 null allele frequencies during the colonization of Melanesia.

The cytochrome P450 (CYP) isozyme CYP2C19 metabolizes clinically important drugs, including the anti-malarial proguanil currently used for multi-drug resistant Plasmodium falciparum malaria. CYP2C19 activity varies among geographical regions due to high frequencies of two null alleles (CYP2C19*2/*3) in Asian and especially Pacific populations. Previously, we reported an unprecedentedly high frequency of CYP2C19 poor metabolizers (PM) within populations of Vanuatu, which suggested even higher PM frequencies in Papua New Guinea. We examined CYP2C19 allele frequencies of three malarious populations from inland East Sepik Province, Papua New Guinea to evaluate this prediction and the use of proguanil in malaria treatment programs. These Papua New Guinean populations have PM frequencies intermediate between island South-east Asia and Vanuatu, most likely resulting from genetic drift during the settlement of the Pacific. This study highlights the medical consequences of population origins and the need for a better understanding of the genetic diversity of our global species.

Adolescent↗
PubMed1997

Incidence of childhood-onset IDDM in black African-heritage populations in the Caribbean. The Caribbean African Heritage IDDM Study (CAHIS) Group.

OBJECTIVE: To compare incidence rates of childhood-onset IDDM among black African-heritage populations age 0-19 years in the Caribbean region. RESEARCH DESIGN AND METHODS: Population-based registries for IDDM were established on the eastern Caribbean islands of Antigua, Barbados, Dominica, St. Croix, St. Kitts, St. Thomas, and Tortola using standardized criteria from the World Health Organization (WHO) Multinational Project for Childhood Diabetes (DiaMond). Average annual incidence rates (IR) with 95% CI for 0-19 years olds were computed using the DiaMond Registry program for the 5-year period from 1989 to 1993. Poisson regression analysis was used to determine differences in incidence rates. RESULTS: The highest incidence rate for 0-19 year olds was for the black African-heritage population of St. Croix (IR 10.09 per 100,000; 95% CI 4.35-19.89), one of the U.S. Caribbean islands. A significant (P < 0.05) 3.9 variation in IDDM incidence across the registries was found when the IR for St. Croix was compared to the IR for Barbados (IR 2.57 per 100,000; 95% CI 0.90-4.64). CONCLUSIONS: The variation in childhood-onset IDDM incidence rates among the black populations of the eastern Caribbean islands is consistent with the geographic variation in IDDM incidence seen among African Americans in the U.S. Variation in incidence rates of childhood diabetes in black populations may reflect differences in level of white genetic admixture or exposure to environmental diabetogenic agents.

Adolescent↗
PubMed1984

The inheritance of cyanoglucoside content in Trifolium repens L.

A four generation backcross breeding program was undertaken. Analysis of the levels of cyanoglucoside in Acac progeny shows that the level of cyanoglucoside (linamarin and lotaustralin) is inherited and that part of the inherited variation in cyanoglucoside levels is attributable to the existence of different Ac alleles in the parent plant. In vitro microsomal cyanoglucoside biosynthetic activity was measured in a high-level and a low-level parent plant. There was no evidence for the presence of microsomes with different qualitative properties in the two plants. The Ac locus was shown to segregate independently of the S incompatibility locus.

Alleles↗
PubMed2006

Identification and evolutionary analysis of novel exons and alternative splicing events using cross-species EST-to-genome comparisons in human, mouse and rat.

BACKGROUND: Alternative splicing (AS) is important for evolution and major biological functions in complex organisms. However, the extent of AS in mammals other than human and mouse is largely unknown, making it difficult to study AS evolution in mammals and its biomedical implications. RESULTS: Here we describe a cross-species EST-to-genome comparison algorithm (ENACE) that can identify novel exons for EST-scanty species and distinguish conserved and lineage-specific exons. The identified exons represent not only novel exons but also evolutionarily meaningful AS events that are not previously annotated. A genome-wide AS analysis in human, mouse and rat using ENACE reveals a total of 758 novel cassette-on exons and 167 novel retained introns that have no EST evidence from the same species. RT-PCR-sequencing experiments validated approximately 50 approximately 80% of the tested exons, indicating high presence of exons predicted by ENACE. ENACE is particularly powerful when applied to closely related species. In addition, our analysis shows that the ENACE-identified AS exons tend not to pass the nonsynonymous-to-synonymous substitution ratio test and not to contain protein domain, implying that such exons may be under positive selection or relaxed negative selection. These AS exons may contribute to considerable inter-species functional divergence. Our analysis further indicates that a large number of exons may have been gained or lost during mammalian evolution. Moreover, a functional analysis shows that inter-species divergence of AS events may be substantial in protein carriers and receptor proteins in mammals. These exons may be of interest to studies of AS evolution. The ENACE programs and sequences of the ENACE-identified AS events are available for download. CONCLUSION: ENACE can identify potential novel cassette exons and retained introns between closely related species using a comparative approach. It can also provide information regarding lineage- or species-specificity in transcript isoforms, which are important for evolutionary and functional studies.

Algorithms↗
PubMed1977

[Genetic heterogeneity of G6PD deficiency: mutant alleles of G6PD in the Shekii district of Azerbaijan].

Examination on G6PD deficiency in 349 patients of Shekii district hospital (Azerbaijan) revealed 16 hemi-, 4 homo- and 9 heterozygotic carriers of the defect. Gd- frequency, calculated from the data obtained (7.7%), may be compared to neighbouring regions' frequencies (6-30%). Carriers of G6PD deficiency are residents of 11 villages located in Alasani-Aphtalan valley, highly endemic with malaria in the past; nearly all marriages are endogamic. Physico-chemical and kinetic study of 10 mutant forms of G6PD, according to WHO program, led to identification of 5 variants of the II class (Shekii, Bideiz, Shirin-Bulakh, Okhut I and Zakataly) and 2 variants of the III class (Okhut II and Martinique-like). Resemblance of the majority of variants in electrophoretic mobility and the level of erythrocyte enzyme activity permit to suggest the existence of a common parental mutant G6PD allele distributed in this area.

Alleles↗
PubMed2004

Gender-specific association of a perilipin gene haplotype with obesity risk in a white population.

OBJECTIVE: Perilipin is a class of protein-coating lipid droplets in adipocytes and steroidogenic cells. Our purpose was to examine the association between common single-nucleotide polymorphisms (SNPs) at the perilipin (PLIN) locus and obesity, as well as related phenotypes, in unrelated American adults. RESEARCH METHODS AND PROCEDURES: Four PLIN SNPs (PLIN 6209T>C, 11482G>A, 13041A>G, and 14995A>T) were typed in 734 white subjects (373 men and 361 women) attending a residential lifestyle intervention program. The baseline anthropometric and biochemical measures were used. Obesity was defined as BMI > or = 30 kg/m(2). RESULTS: Multivariate analysis demonstrated that, in women, two of the SNPs (13041A>G, and 14995A>T) were significantly associated with percentage body fat (p = 0.016 for 13041A>G and p = 0.010 for 14995A>T) and waist circumference (p = 0.020 for 13041A>G and p = 0.045 for 14995A>T). Moreover, haplotype analysis using these two SNPs indicated that haplotypes A/T and G/T were both associated with significantly increased obesity risk (odds ratio = 1.76, 95% confidence interval 1.07 to 2.90 for haplotype A/T, and odds ratio = 1.73, 95% confidence interval 1.06 to 2.82 for haplotype G/T) when compared with haplotype A/A. No significant associations between PLIN variations and obesity were found in men. DISCUSSION: Our data support the hypothesis that the PLIN locus may be a significant genetic determinant for obesity risk in whites and that women are more sensitive to the genetic effects of perilipin than men.

Adipose Tissue↗
PubMed2002

A quick and simple method for detecting subjects with abnormal genetic background in case-control samples.

It is important that case-control samples be drawn from a genetically homogeneous population in order to avoid artefactual false positive results and to enhance power to detect disease mutations and markers in linkage disequilibrium with them. Tests which simply compare overall marker allele frequencies between cases and controls will fail to identify a relatively small number of subjects drawn from a different genetic background who could usefully be discarded from the sample. Such subjects can be identified using multilocus tests, but previously described tests have been unnecessarily complex and cumbersome for this simple application. We describe a straightforward test, implemented in the CHECKHET program, which uses a measure of genetic difference and permutation procedures to rapidly identify such subjects using genotypes from multiple unlinked markers. It seems to perform reasonably well on simulated data, and with real data appears to identify two abnormal subjects within a case-control sample. We recommend that such tests be routinely applied to case-control samples once sufficient numbers of markers have been genotyped within them.

Case-Control Studies↗
PubMed2005

Quantitative trait loci associated with seed and seedling traits in Lactuca.

Seed and seedling traits related to germination and stand establishment are important in the production of cultivated lettuce (Lactuca sativa L.). Six seed and seedling traits segregating in a L. sativa cv. Salinas x L. serriola recombinant inbred line population consisting of 103 F8 families revealed a total of 17 significant quantitative trait loci (QTL) resulting from three seed production environments. Significant QTL were identified for germination in darkness, germination at 25 and 35 degrees C, median maximum temperature of germination, hypocotyl length at 72 h post-imbibition, and plant (seedling) quality. Some QTL for germination and early seedling growth characteristics were co-located, suggestive of pleiotropic loci regulating these traits. A single QTL (Htg6.1) described 25 and 23% of the total phenotypic variation for high temperature germination in California- and Netherlands-grown populations, respectively, and was significant between 33 and 37 degrees C. Additionally, Htg6.1 showed significant epistatic interactions with other Htg QTL and a consistent effect across all the three seed production environments. L. serriola alleles increased germination at these QTL. The estimate of narrow-sense heritability (h2) of Htg6.1 was 0.84, indicating potential for L. serriola as a source of germination thermotolerance for lettuce introgression programs.

Breeding↗
PubMed2004

Profiling catalase gene expression in Drosophila melanogaster during development and aging.

Catalase represents one of the key antioxidant enzymes (AOE) in the metabolism of oxygen free radicals. A comprehensive analysis was brought to bear on establishing catalase gene expression profiles during development and aging, with the underlying objective being to identify potential regulatory factors. Expression of the catalase gene exhibits substantial variations during development and aging in a stage- and tissue-specific manner. At the temporal level, previous observations of the coincidence of ecdysteroid pulses with peaks in catalase expression during developmental stages were largely corroborated. In adults, a small but significant decline in catalase expression was noted in adults as a function of age. Spatially, it was ascertained that catalase expression is mostly confined to tissues related to intermediary metabolism, digestive and adipose systems as well as oenocytes. By combining histochemical analysis of reporter gene expression with immunostaining of the endogenous product, it was possible to identify putative positive and negative regulatory elements that control catalase expression. Finally, when adult flies were subjected to various environmental insults, such as heat, paraquat, hyperoxia and H(2)O(2), no significant responses were observed, suggesting that catalase gene expression is largely governed by intrinsic genetic programs.

Aging↗
PubMed2002

Standardization of PCR amplification for fragile X trinucleotide repeat measurements.

To provide the clinical diagnostics community with accurate protocols and measurements for the detection of genetic disorders, we have established a quantitative measurement program for trinucleotide repeats associated with human disease. In this study, we have focused on the triplet repeat associated with fragile X syndrome. Five cell lines obtained from the Coriell Cell Repository were analyzed after polymerase chain reaction (PCR) amplification and size separation. These cell lines were reported to contain CGG repeat elements (ranging from 29 to 110 repeats). Our initial measurements focused on measurement variability: (a) between slab-PAGE and capillary (CE) separation systems (b) interlane variability (slab-PAGE) (c) intergel variability, and (d) variability associated with amplification. Samples were run in triplicate for all measurements, and the analysis performed using Gene Scan analysis software. The repeat sizes were verified by DNA sequence analyzes. The standard deviations for interlane measurements in slab-gels ranged from 0.05 to 0.35. There was also little variation in size measurements performed on different gels and among PCR amplifications. The CGG repeat measurements performed by capillary electrophoresis were more precise, with standard deviations ranging from 0.02 to 0.29. The slab-PAGE and CE size measurements were in agreement except for the pre-mutation alleles, which yielded significantly smaller sizes by CE.

Alleles↗