Prediction of total genetic value using genome-wide dense marker maps

Recent advances in molecular genetic techniques will make dense marker maps available and genotyping many individuals for these markers feasible. Here we attempted to estimate the effects of approximately 50,000 marker haplotypes simultaneously from a limited number of phenotypic records. A genome of 1000 cM was simulated with a marker spacing of 1 cM. The markers surrounding every 1-cM region were combined into marker haplotypes. Due to finite population size N(e) = 100, the marker haplotypes were in linkage disequilibrium with the QTL located between the markers. Using least squares, all haplotype effects could not be estimated simultaneously. When only the biggest effects were included, they were overestimated and the accuracy of predicting genetic values of the offspring of the recorded animals was only 0.32. Best linear unbiased prediction of haplotype effects assumed equal variances associated to each 1-cM chromosomal segment, which yielded an accuracy of 0.73, although this assumption was far from true. Bayesian methods that assumed a prior distribution of the variance associated with each chromosome segment increased this accuracy to 0.85, even when the prior was not correct. It was concluded that selection on genetic values predicted from markers could substantially increase the rate of genetic gain in animals and plants, especially if combined with reproductive techniques to shorten the generation interval.     

An analysis of genetic diversity across the maize genome using microsatellites

How domestication bottlenecks and artificial selection shaped the amount and distribution of genetic variation in the genomes of modern crops is poorly understood. We analyzed diversity at 462 simple sequence repeats (SSRs) or microsatellites spread throughout the maize genome and compared the diversity observed at these SSRs in maize to that observed in its wild progenitor, teosinte. The results reveal a modest genome-wide deficit of diversity in maize relative to teosinte. The relative deficit of diversity is less for SSRs with dinucleotide repeat motifs than for SSRs with repeat motifs of more than two nucleotides, suggesting that the former with their higher mutation rate have partially recovered from the domestication bottleneck. We analyzed the relationship between SSR diversity and proximity to QTL for domestication traits and observed no relationship between these factors. However, we did observe a weak, although significant, spatial correlation for diversity statistics among SSRs within 2 cM of one another, suggesting that SSR diversity is weakly patterned across the genome. Twenty-four of 462 SSRs (5%) show some evidence of positive selection in maize under multiple tests. Overall, the pattern of genetic diversity at maize SSRs can be explained largely by a bottleneck effect with a smaller effect from selection.     

Constructing dense genetic linkage maps

This paper describes a novel combination of techniques for the construction of dense genetic linkage maps. The construction of such maps is hampered by the occurrence of even small proportions of typing errors. Simulated annealing is used to obtain the best map according to the optimality criterion: the likelihood or the total number of recombination events. Spatial sampling of markers is used to obtain a framework map. The construction of a framework map is essential if the steps used for simulated annealing are required to be simple. For missing-data imputation the Gibbs sampler is used. Map construction using simulated annealing and missing-data imputation are used in an iterative way. In order to obtain some measure of precision of the genetic linkage map obtained, the Metropolis-Hastings algorithm is used to obtain posterior intervals for the positions of markers. The process of map construction is embedded in a framework of pre-mapping and post-mapping diagnostics. The techniques described are illustrated using a practical application. Received: 1 June 2000 / Accepted: 21 September 2000     

Natural selection affects multiple aspects of genetic variation at putatively neutral sites across the human genome

A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.     

Finding associations in dense genetic maps: a genetic algorithm approach

Large-scale association studies hold promise for discovering the genetic basis of common human disease. These studies will consist of a large number of individuals, as well as large number of genetic markers, such as single nucleotide polymorphisms (SNPs). The potential size of the data and the resulting model space require the development of efficient methodology to unravel associations between phenotypes and SNPs in dense genetic maps. Our approach uses a genetic algorithm (GA) to construct logic trees consisting of Boolean expressions involving strings or blocks of SNPs. These blocks or nodes of the logic trees consist of SNPs in high linkage disequilibrium (LD), that is, SNPs that are highly correlated with each other due to evolutionary processes. At each generation of our GA, a population of logic tree models is modified using selection, cross-over and mutation moves. Logic trees are selected for the next generation using a fitness function based on the marginal likelihood in a Bayesian regression frame-work. Mutation and cross-over moves use LD measures to pro pose changes to the trees, and facilitate the movement through the model space. We demonstrate our method and the flexibility of logic tree structure with variable nodal lengths on simulated data from a coalescent model, as well as data from a candidate gene study of quantitative genetic variation.     

The spatio-temporal dynamics of neutral genetic diversity

The notions of pulled and pushed solutions of reaction-dispersal equations introduced by Garnier et al. (2012) and Roques et al. (2012) are based on a decomposition of the solutions into several components. In the framework of population dynamics, this decomposition is related to the spatio-temporal evolution of the genetic structure of a population. The pulled solutions describe a rapid erosion of neutral genetic diversity, while the pushed solutions are associated with a maintenance of diversity. This paper is a survey of the most recent applications of these notions to several standard models of population dynamics, including reaction-diffusion equations and systems and integro-differential equations. We describe several counterintuitive results, where unfavorable factors for the persistence and spreading of a population tend to promote diversity in this population. In particular, we show that the Allee effect, the existence of a competitor species, as well as the presence of climate constraints are factors which can promote diversity during a colonization. We also show that long distance dispersal events lead to a higher diversity, whereas the existence of a nonreproductive juvenile stage does not affect the neutral diversity in a range-expanding population.     

High-definition genome profiling for genetic marker discovery

Genetic mapping is a key step towards isolating genes and genetic markers associated with phenotypic traits by elucidating their genetic positions. The success of this approach depends on precision in pinpointing genetic positions and the effectiveness of the discovery process. Recent advances in microarray technology and the increasing availability of genomic information have provided an opportunity to use microarrays to scan effectively for genetic variations at the whole-genome scale, enabling the production of high-definition gene-based genetic maps, in combination with functional analyses and identification of trait-associated genetic marker candidates with high precision. In this review, we discuss the concept, process, tools and applications of microarray-based high-definition genetic analysis. This post-genomics approach should help to identify causative genetic variation by uniting genetic and functional information.     

Geography predicts neutral genetic diversity of human populations

A leading theory for the origin of modern humans, the ‘recent African origin’ (RAO) model [1], postulates that the ancestors of all modern humans originated in East Africa and that, around 100,000 years ago, some modern humans left the African continent and subsequently colonised the entire world, displacing previously established human species such as Neanderthals in Europe 2., 3.. This scenario is supported by the observation that human populations from Africa are genetically the most diverse [2] and that the genetic diversity of non-African populations is negatively correlated with their genetic differentiation towards populations from Africa [3].     

Preliminary interspecific genetic maps of the populus genome constructed from RAPD markers.

We have constructed RAPD-based linkage maps for an interspecific cross between two species of the genus Populus (P. adenopoda and P. alba), based on a double pseudo-test-cross strategy. Of a total of 360 polymorphic fragments scored, 290 showed a test-cross configuration, corresponding to DNA polymorphisms heterozygous in one parent and null in the other. In the female parent, P. adenopoda, 82 markers were grouped in 19 different linkage groups (553 cM), whereas in the male parent P. alba, 197 markers established a much more complete framework map with an observed genome length of 2300 cM covering 87% of the total P. alba genome. The larger number of test-cross markers detected for the P. alba parent than for the P. adenopoda parent might be due to a higher level of heterozygosity in the former than in the latter. In this study, we detected only a small percentage (2%) of the intercross dominant markers heterozygous in both parents and segregating 3:1 in the progeny. The further focus in this mapping study should be on the identification of more intercross markers, to align the two parent-specific maps into a consensus map for mapping important genes causing species differentiation during long evolutionary divergences.     

Estimating quantitative genetic parameters using sibships reconstructed from marker data

Previous techniques for estimating quantitative genetic parameters, such as heritability in populations where exact relationships are unknown but are instead inferred from marker genotypes, have used data from individuals on a pairwise level only. At this level, families are weighted according to the number of pairs within which each family appears, hence by size rather than information content, and information from multiple relationships is lost. Estimates of parameters are therefore not the most efficient achievable. Here, Markov chain Monte Carlo techniques have been used to partition the population into complete sibships, including, if known, prior knowledge of the distribution of family sizes. These pedigrees have then been used with restricted maximum likelihood under an animal model to estimate quantitative genetic parameters. Simulations to compare the properties of parameter estimates with those of existing techniques indicate that the use of sibship reconstruction is superior to earlier methods, having lower mean square errors and showing nonsignificant downward bias. In addition, sibship reconstruction allows the estimation of population allele frequencies that account for the relationships within the sample, so prior knowledge of allele frequencies need not be assumed. Extensions to these techniques allow reconstruction of half sibships when some or all of the maternal genotypes are known.     

中国人群参考基因组及基因组变异图谱资源库

随着人类基因组计划和国际千人基因组计划的实施,已公开数百个中国人个体的全基因组数据。建立高精度的中国人群参考基因组序列,发现并解析中国人群特有的序列变异,是我国未来精准医学研究的基础。为满足未来精准医学研究中国人基因组数据持续增长的科学管理和深入研究的需求,中国科学院北京基因组研究所发展并建立了基于中国人群全基因组测序数据的虚拟中国人基因组数据库(Virtual Chinese Genome Database, VCGDB)和中国人群基因组变异数据库(Genome Variation Map, GVM),面向国内外用户提供数据检索、共享、下载和在线分析服务。本文重点介绍了这两个数据库的特点和功能,以及未来发展与应用前景,以期为中国人群参考基因组及基因组变异图谱资源库的推广使用、发展完善提供有益信息。     

Social heterosis and the maintenance of genetic diversity at the genome level

Social heterosis is when individuals in groups or neighbourhoods receive a mutualistic benefit from across‐individual genetic diversity. Although it can be a viable evolutionary mechanism to maintain allelic diversity at a given locus, its efficacy at maintaining genome‐wide diversity is in question when multiple loci are being simultaneously selected. Therefore, we modelled social heterosis in a population of haploid genomes of two‐ or three‐linked loci. With such linkages, social heterosis decreases gametic diversity, but maintains allelic diversity. Genomes tend to survive as complimentary pairs, with alternate alleles at each locus (e.g. the pair AbC and aBc). The outcomes of selection appear similar to fitness epistasis but are novel in the sense that phenotypic interactions occur across rather than within individuals. The model’s results strongly suggest that strong linkage across gene loci actually increases the probability that social heterosis maintains significant genetic diversity at the level of the genome.     

Analysis of genetic diversity in Ganoderma population with a novel molecular marker SRAP

Genetic marker technology designed to detect naturally occurring polymorphisms at the DNA level had become an invaluable and revolutionizing tool for both applied and basic studies of fungi. To eliminate the confusion on the taxonomy of Ganoderma strains, in this study, a collection of 31 accessions representative of morphotypes and some unclassified types was used for analyzing molecular diversity using a novel molecular marker sequence-related amplified polymorphism (SRAP). This collection included commercial cultivars and wild varieties that represented the great diversification of types from different countries and regions. The experimental results showed that 50 out of 95 combinations of primers turned out to be polymorphic, and 85 polymorphism bands were obtained using six combinations. Based on the appearances of markers, the genetic similarity coefficients were calculated, and genetic variations were observed (0∼1) among the 31 different Ganoderma strains. The group of Ganoderma lucidum showed significant differences from the group of Ganoderma sinense. Moreover, G. lucidum in China was also different from G. lucidum in Yugoslavia. At the same time, cluster analysis successfully categorized these 31 Ganoderma strains into five groups. These results revealed the genetic diversity of Ganoderma strains and their correlation with geographic environments. It also suggested SRAP marker could be used in the taxonomic analysis of fungi. To our knowledge, this is the first application of SRAP marker on the systematics of Ganoderma strains within basidiomycetes.     

Origin,genetic diversity,and genome structure of the domestic dog

Comparative analysis of mammalian genomes provides important insight into the structure and function of genes. However, the comparative analysis of gene sequences from individuals of the same and different species also provides insight into the evolution of genes, populations, and species. We exemplify these two uses of genomic information. First, we document the evolutionary relationships of the domestic dog to other carnivores by using a variety of DNA-based information. A phylogenetic comparison of mitochondrial DNA sequences in dogs and gray wolves shows that dogs may have originated from multiple wolf populations at a time much earlier than suggested by the archaeologic record. We discuss previous theories about dog development and evolution in light of the new genetic data. Second, we review recent progress in dog genetic mapping due to the development of hypervariable markers and specific chromosome paints. Extensive genetic homology in gene order and function between humans and dogs has been discovered. The dog promises to be a valuable model for identifying genes that control morphologic differences between mammals as well as understanding genetically based disease. BioEssays 21:247–257, 1999. © 1999 John Wiley & Sons, Inc.     

Small‐ and large‐scale heterogeneity in genetic variation across the collard flycatcher genome: implications for estimating genetic diversity in nonmodel organisms

Population genetic studies in nonmodel organisms are often hampered by a lack of reference genomes that are essential for whole‐genome resequencing. In the light of this, genotyping methods have been developed to effectively eliminate the need for a reference genome, such as genotyping by sequencing or restriction site‐associated DNA sequencing (RAD‐seq). However, what remains relatively poorly studied is how accurately these methods capture both average and variation in genetic diversity across an organism's genome. In this issue of Molecular Ecology Resources, Dutoit et al. (2016) use whole‐genome resequencing data from the collard flycatcher to assess what factors drive heterogeneity in nucleotide diversity across the genome. Using these data, they then simulate how well different sequencing designs, including RAD sequencing, could capture most of the variation in genetic diversity. They conclude that for evolutionary and conservation‐related studies focused on the estimating genomic diversity, researchers should emphasize the number of loci analysed over the number of individuals sequenced.     

Castor bean organelle genome sequencing and worldwide genetic diversity analysis

Castor bean is an important oil-producing plant in the Euphorbiaceae family. Its high-quality oil contains up to 90% of the unusual fatty acid ricinoleate, which has many industrial and medical applications. Castor bean seeds also contain ricin, a highly toxic Type 2 ribosome-inactivating protein, which has gained relevance in recent years due to biosafety concerns. In order to gain knowledge on global genetic diversity in castor bean and to ultimately help the development of breeding and forensic tools, we carried out an extensive chloroplast sequence diversity analysis. Taking advantage of the recently published genome sequence of castor bean, we assembled the chloroplast and mitochondrion genomes extracting selected reads from the available whole genome shotgun reads. Using the chloroplast reference genome we used the methylation filtration technique to readily obtain draft genome sequences of 7 geographically and genetically diverse castor bean accessions. These sequence data were used to identify single nucleotide polymorphism markers and phylogenetic analysis resulted in the identification of two major clades that were not apparent in previous population genetic studies using genetic markers derived from nuclear DNA. Two distinct sub-clades could be defined within each major clade and large-scale genotyping of castor bean populations worldwide confirmed previously observed low levels of genetic diversity and showed a broad geographic distribution of each sub-clade.     

Estimating optimum number of marker loci for genetic analyses in Cynodon accessions

This study was carried out to determine genome sampling size of Cynodon accessions collected from Turkey for estimating genetic relatioships. One hundred and eighty-two Cynodon accessions collected in Turkey from an area south of the Taurus Mountains along the Mediterranean cost and ten known genotypes were genotyped using sequence related amplified polymorphism (SRAP) and the samples include diploids, triploids, tetraploids, pentaploids, and hexaploids. In this study, 182-markers were available from a previous work. We created 7 different data file, which include 5, 10, 20, 40, 60, 80, and 100 markers randomly selected from a 182-marker data file. First, similarity matrices was produced based on Dice’ and, alternatively, simple matching’ similarity coefficients for each data files. Then, a two-way mantel test was used to estimate Mantel correlation coefficients between each pair of similarity matrices. Mantel correlation coefficients between 5 and 10, 10 and 20, 20 and 40, 40 and 60, 60 and 80, and 80 and 100 marker-based simple matching’ similarity matrices were 0.718, 0.802, 0.826, 0.929, 0.977, and 0.975, respectively. Correlation estimates for the matrices based on Dice’s procedure for the same data sets were 0.863, 0.916, 0.930, 0.966, 0.965, and 0.984. The lower number of markers (10 or 20) was required with Dice’s procedure to achieve the higher correlation values (r > 0.9), and about random genome sampling size of 10 or 20 markers appeared to be sufficent in Cynodon accessions with a series of ploidy. This approach may apply to other plant species with ploidy series.     

微卫星DNA标记技术及其在遗传多样性研究中的应用

微卫星DNA的高突变率、中性、共湿性及其在真核基因组中的普遍性,使其成为居群遗传学研究、种质资源鉴定、亲缘关系分析和图谱构建的优越的分子标记。本研究系统介绍了微卫星DNA在结构和功能上的特点,并对微卫星DNA标记技术应用的遗传学机理和一般方法进行了扼要的阐述。另外,本研究还探讨了微卫星DNA标记技术在遗传多样性研究中的应用现状,并进一步提出其发展前景。