Isolates and their potential use in complex gene mapping efforts

Varilo, Teppo

doi:10.1016/j.gde.2004.04.008

Cited by 101 publications

(69 citation statements)

References 54 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An isolated population with genetic and environmental homogeneity provides an excellent model for the identifi cation of genetic variants. This has been demonstrated in other isolated populations, such as the Hutterites, Finish, and Amish, for multiple complex disorders like bipolar disease, allergic asthma, and familial combined hyperlipidemia, among others ( 39 ). Although the Tangier Island population is isolated and inbred, our previous work has demonstrated that inbreeding levels are refl ective of an avoidance of close consanguinity ( 26 ), rendering Tangier Island generalizable to other European-ancestry populations as refl ected in similar LD patterns and allele frequencies to publicly available databases ( Fig.…”

Section: ) With Thementioning

confidence: 74%

FADS genetic variants and ω-6 polyunsaturated fatty acid metabolism in a homogeneous island population

Mathias

Vergara

Gao

et al. 2010

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org Supplementary key words fatty acid desaturase • isolated population • genetic association Several changes in diet over the past century are hypothesized to have been maladaptive, thereby leading to an increase in the incidence of numerous chronic diseases in developed countries ( 1, 2 ). Many of these diseases (obesity, diabetes, asthma, allergies, arthritis and chronic joint disease, dementia, and cardiovascular disease) have a substantial infl ammatory component ( 3-6 ) with notable cooccurrences ( 7,8 ). Perhaps no changes in the modern diet have had a greater impact than the quantitative and qualitative changes in fat consumption. While the percentage of energy from fat ( ‫ف‬ 35%) is thought to be similar in ancestral and contemporary Western diets, the concentrations and ratios of the types of fat that humans eat ( 9, 10 ) have shifted, with marked increases in saturated and omega-6 ( 6) fatty acid consumption. Importantly, these changes have been suggested to alter human health and the incidence of chronic infl ammatory diseases ( 11-13 ).Long-chain serum polyunsaturated fatty acids (LC-PUFA; у 20 carbons), such as arachidonic acid (AA; C20:4 6), and their metabolic products orchestrate several critical events in immunity and infl ammation.Abstract Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and infl ammation through their capacity to be converted to potent infl ammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and fi ve ratios defi ning FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) ( P = 5.8 × 10؊ 7 -1.7 × 10 ؊ 8 ) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the -6 series ( P = 2.11 × 10 ؊ 13 -1.8 × 10 ؊ 20 ). The minor allele across all SNPs was consistently associated with decreased -6 PUFAs, with the exception of dihomo-␥ -linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our fi ndings in a geographically isolated population with a homogenous dietary environment suggest that variants in the ⌬ -5 desaturase enzymatic step likely regulate the effi ciency of conversion of medium-chain PUFAs to potentially infl ammatory PUFAs, such as AA. -Mathias, R. A., C. Vergara, L. Gao, N. Rafaels, T. Hand, M. Campbell, C. Bickel, P. Ivester, S. Sergeant, K. C. Barnes, and F. H. Chilton. FADS genetic variants and -6 polyunsaturated fatty acid metabolism in a homogeneous island population.

show abstract

Section: ) With Thementioning

confidence: 74%

FADS genetic variants and ω-6 polyunsaturated fatty acid metabolism in a homogeneous island population

Mathias

Vergara

Gao

et al. 2010

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…For the moment the greatest promise in identifying genes of major effect for complex diseases continues to reside in endogamous communities with extensive genealogical records (105). Convincing support for this approach is provided by the high frequencies of autosomal recessive disease genes diagnosed in numerically small, highly endogamous Arab Israeli communities (106).…”

Section: Discussionmentioning

confidence: 99%

Consanguinity, human evolution, and complex diseases

Bittles

Black

2010

Proc. Natl. Acad. Sci. U.S.A.

474

308

View full text Add to dashboard Cite

There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F ≥ 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is ≈3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates. community genetics | inbreeding | reproduction | health | social structure

show abstract

“…Although simulation of entire human genomes in large populations remains infeasible, 10-Mb chromosomes in a population of 10,000 diploid individuals can be simulated within 2 days using a standard desktop work station (.2 GB RAM) and approximated in ,1 hour using 10-fold rescaling, described below. Thus, direct simulation of the genetic history of population isolates that are of particular interest in gene mapping (Varilo and Peltonen 2004) is feasible, as is a good approximation of many aspects of global human genetic variation (Jobling et al 2004). Further, a genomic interval of 10 Mb suffices for accurate extrapolation to genomewide studies, so that false discovery rates (Storey and Tibshirani 2003) and statistical significance thresholds can be investigated under various design options.…”

Section: S Imulation Of Population Genomic Data Is Crucialmentioning

confidence: 99%

Sequence-Level Population Simulations Over Large Genomic Regions

et al. 2007

View full text Add to dashboard Cite

Simulation is an invaluable tool for investigating the effects of various population genetics modeling assumptions on resulting patterns of genetic diversity, and for assessing the performance of statistical techniques, for example those designed to detect and measure the genomic effects of selection. It is also used to investigate the effectiveness of various design options for genetic association studies. Backward-intime simulation methods are computationally efficient and have become widely used since their introduction in the 1980s. The forward-in-time approach has substantial advantages in terms of accuracy and modeling flexibility, but at greater computational cost. We have developed flexible and efficient simulation software and a rescaling technique to aid computational efficiency that together allow the simulation of sequence-level data over large genomic regions in entire diploid populations under various scenarios for demography, mutation, selection, and recombination, the latter including hotspots and gene conversion. Our forward evolution of genomic regions (FREGENE) software is freely available from www.ebi.ac.uk/projects/BARGEN together with an ancillary program to generate phenotype labels, either binary or quantitative. In this article we discuss limitations of coalescent-based simulation, introduce the rescaling technique that makes large-scale forward-in-time simulation feasible, and demonstrate the utility of various features of FREGENE, many not previously available. S IMULATION of population genomic data is crucialfor validating the analyses of many evolutionary and population genetics studies, and for assessing designs of genomewide association studies. As genotyping and resequencing technologies advance, it is important to simulate at the sequence level over large genomic regions, and under realistic models that include the effects of selection, both directional and balancing, and of gene conversion and crossover hotspots. The size of the region simulated will often need to be large, so that any boundary effects are minimized and to permit investigation of the long-range effects of multiple sites under different selection regimes on patterns of genetic variation such as linkage disequilibrium (LD).There already exists a range of software tools for performing population genetic simulations. The development of coalescent methods in the 1980s and 1990s allowed researchers to trace only the observed sample backward in time, ignoring other members of the pop- The first major limitation, both theoretical and practical, of coalescent methods, is in modeling large amounts of recombination. The coalescent with recombination is defined (Hudson 1983;Griffiths and Marjoram 1997) in terms of the limit as population size grows to infinity of a discrete-time Wright-Fisher model. Even without recombination, the coalescent process differs notably from the Wright-Fisher model for small population sizes (Fu 2006). With recombination, however, this discrepancy becomes much more marked because chromos...

show abstract

Isolates and their potential use in complex gene mapping efforts

Cited by 101 publications

References 54 publications

FADS genetic variants and ω-6 polyunsaturated fatty acid metabolism in a homogeneous island population

FADS genetic variants and ω-6 polyunsaturated fatty acid metabolism in a homogeneous island population

Consanguinity, human evolution, and complex diseases

Sequence-Level Population Simulations Over Large Genomic Regions

Contact Info

Product

Resources

About