Contrasting evolutionary histories of chloroplast thioredoxins f and m

Fourteen thioredoxin sequences were used to construct a minimal phylogenetic tree by using parsimony. The bacterial thioredoxins clustered into three groups: one containing the photosynthetic purple bacteria, Escherichia and Corynebacterium; a second containing the photosynthetic green bacterium, Chlorobium; and a third containing cyanobacteria. These groupings are similar to those generated from earlier 16s RNA analyses. Animal thioredoxins formed a fourth group. The two thioredoxins of chloroplasts (f and m) showed contrasting phylogenetic patterns. As predicted from prior studies, spinach chloroplast thioredoxin m grouped with its counterparts from cyanobacteria and eukaryotic algae, but, unexpectedly, thioredoxin f grouped with the animal thioredoxins. The results indicate that, during evolution, thioredoxin m of contemporary photosynthetic eukaryotic cells was derived from a prokaryotic symbiont, whereas thioredoxin f descended from an ancestral eukaryote common to plants and animals. The findings illustrate the potential of thioredoxin as a phylogenetic marker and suggest a relationship between the animal and f-type thioredoxins.      

Genetic analysis of eight loci tightly linked to neurofibromatosis 1

The genetic locus for neurofibromatosis 1 (NF1) has recently been mapped to the pericentromeric region of chromosome 17. We have genotyped eight previously identified RFLP probes on 50 NF1 families to determine the placement of the NF1 locus relative to the RFLP loci. Thirty-eight recombination events in the pericentromeric region were identified, eight involving crossovers between NF1 and loci on either chromosomal arm. Multipoint linkage analysis resulted in the unique placement of six loci at odds greater than 100:1 in the order of pter-A10-41-EW301-NF1-EW207-CRI-L581-CRI-L946 -qter. Owing to insufficient crossovers, three loci--D17Z1, EW206, and EW203--could not be uniquely localized. In this region female recombination rates were significantly higher than those of males. These data were part of a joint study aimed at the localization of both NF1 and tightly linked pericentromeric markers for chromosome 17.     

Contrasting evolutionary histories of two introns of the duchenne muscular dystrophy gene, Dmd, in humans

The Duchenne muscular dystrophy (Dmd) locus lies in a region of the X chromosome that experiences a high rate of recombination and is thus expected to be relatively unaffected by the effects of selection on nearby genes. To provide a picture of nucleotide variability at a high-recombination locus in humans, we sequenced 5. 4 kb from two introns of Dmd in a worldwide sample of 41 alleles from Africa, Asia, Europe, and the Americas. These same regions were also sequenced in one common chimpanzee and one orangutan. Dramatically different patterns of genetic variation were observed at these two introns, which are separated by >500 kb of DNA. Nucleotide diversity at intron 44 pi = 0.141% was more than four times higher than nucleotide diversity at intron 7 pi = 0.034% despite similar levels of divergence for these two regions. Intron 7 exhibited significant linkage disequilibrium extending over 10 kb and also showed a significant excess of rare polymorphisms. In contrast, intron 44 exhibited little linkage disequilibrium and no skew in the frequency distribution of segregating sites. Intron 7 was much more variable in Africa than in other continents, while intron 44 displayed similar levels of variability in different geographic regions. Comparison of intraspecific polymorphism to interspecific divergence using the HKA test revealed a significant reduction in variability at intron 7 relative to intron 44, and this effect was most pronounced in the non-African samples. These results are best explained by positive directional selection acting at or near intron 7 and demonstrate that even genes in regions of high recombination may be influenced by selection at linked sites.     

Esterase D and retinoblastoma gene loci are tightly linked to Wilson's disease in Chinese pedigrees from Taiwan

Summary Wilson's disease (WD) is a rare autosomal recessive disorder and has been mapped to the long arm of chromosome 13 (q14.1). We have analyzed the segregation of esterase D (ESD) and retinoblastoma (RB) gene loci in ten families of Chinese WD subjects living in Taiwan. The polymorphic information content (PIC) for ESD and RB was 0.18 and 0.31, respectively. We confirmed a tight linkage between these loci and WD with a lod score of 3.33 by multipoint linkage analysis. The data from this limited number of pedigrees also suggested the following order: centromere-WD-RB-ESD or centromere-ESD-RB-WD. ESD in conjunction with RB polymorphism would be useful in prenatal and presymptomatic diagnosis, as well as in carrier detection in informative pedigrees.     

Family-based association analysis with tightly linked markers

Refining genomic regions which have been identified by linkage analysis to contain a disease susceptibility locus has proven to be a challenging task. Detecting association between the disease and a genetic marker can significantly narrow down the candidate region. Since an adequate sample of families is already available from the genome scan, family-based association tests may be used to search for association. The use of haplotypes consisting of tightly linked markers can be more powerful for detecting association than the use of individual markers. An extension of the transmission/disequilibrium test to allow the simultaneous analysis of more than one marker locus is complicated by ambiguity of phase in some families of the sample. The present paper shows that a recently proposed method for the analysis of nuclear families with a single affected child can be viewed as a special application of a more general principle. This observation justifies several modifications, potentially increasing the power, as well as an extension of the method to allow the analysis of general nuclear families. Finally, the problem of missing parental genotypes is discussed.     

Genotyping error detection through tightly linked markers

The identification of genotyping errors is an important issue in mapping complex disease genes. Although it is common practice to genotype multiple markers in a candidate region in genetic studies, the potential benefit of jointly analyzing multiple markers to detect genotyping errors has not been investigated. In this article, we discuss genotyping error detections for a set of tightly linked markers in nuclear families, and the objective is to identify families likely to have genotyping errors at one or more markers. We make use of the fact that recombination is a very unlikely event among these markers. We first show that, with family trios, no extra information can be gained by jointly analyzing markers if no phase information is available, and error detection rates are usually low if Mendelian consistency is used as the only standard for checking errors. However, for nuclear families with more than one child, error detection rates can be greatly increased with the consideration of more markers. Error detection rates also increase with the number of children in each family. Because families displaying Mendelian consistency may still have genotyping errors, we calculate the probability that a family displaying Mendelian consistency has correct genotypes. These probabilities can help identify families that, although showing Mendelian consistency, may have genotyping errors. In addition, we examine the benefit of available haplotype frequencies in the general population on genotyping error detections. We show that both error detection rates and the probability that an observed family displaying Mendelian consistency has correct genotypes can be greatly increased when such additional information is available.     

Reconstructing reticulate evolutionary histories of plants

Identifying signatures of hybridization in molecular data and distinguishing them from other causes of phylogenetic incongruence is important for evaluating the evolutionary significance of hybridization in plants. Consensus networks and supernetworks provide a means for doing this. In this review, we explain these methodologies, discuss their potential and illustrate their application with examples from the Brassicaceae.     

Molecular and quantitative genetic divergence among populations of house mice with known evolutionary histories

Evolutionary biologists have long been interested in the processes influencing population differentiation, but separating the effects of neutral and adaptive evolution has been an obstacle for studies of population subdivision. A recently developed method allows tests of whether disruptive (ie, spatially variable) or stabilizing (ie, spatially uniform) selection is influencing phenotypic differentiation among subpopulations. This method, referred to as the F(ST) vs Q(ST) comparison, separates the total additive genetic variance into within- and among-population components and evaluates this level of differentiation against a neutral hypothesis. Thus, levels of neutral molecular (F(ST)) and quantitative genetic (Q(ST)) divergence are compared to evaluate the effects of selection and genetic drift on phenotypic differentiation. Although the utility of such comparisons appears great, its accuracy has not yet been evaluated in populations with known evolutionary histories. In this study, F(ST) vs Q(ST) comparisons were evaluated using laboratory populations of house mice with known evolutionary histories. In this model system, the F(ST) vs Q(ST) comparisons between the selection groups should reveal quantitative trait differentiation consistent with disruptive selection, while the F(ST) vs Q(ST) comparisons among lines within the selection groups should suggest quantitative trait differentiation in agreement with drift. We find that F(ST) vs Q(ST) comparisons generally produce the correct evolutionary inference at each level in the population hierarchy. Additionally, we demonstrate that when strong selection is applied between populations Q(ST) increases relative to Q(ST) among populations diverging by drift. Finally, we show that the statistical properties of Q(ST), a variance component ratio, need further investigation.     

Log-linear models for linked loci

A clarification is given of the difference between a multiplicative model (Haber, 1984, Biometrics 40, 189-198) and an additive model (Weir, 1979, Biometrics 35, 235-254) for association between genes at two loci. Although the parametrization of Haber contains both intergametic and intragametic linkage disequilibrium terms, there are problems in separating these terms when the two types of double heterozygote cannot be distinguished. An alternative formulation that contains the sum and product of these terms also contains measures of association between three or four genes at two loci, and a reexamination of data discussed by Haber shows that the inclusion of trigenic disequilibria can significantly improve the fit of the model.     

Transmission/disequilibrium tests using multiple tightly linked markers

Transmission/disequilibrium tests have attracted much attention in genetic studies of complex traits because (a) their power to detect genes having small to moderate effects may be greater than that of other linkage methods and (b) they are robust against population stratification. Highly polymorphic markers have become available throughout the human genome, and many such markers can be studied within short physical distances. Studies using multiple tightly linked markers are more informative than those using single markers. However, such information has not been fully utilized by existing statistical methods, resulting in possibly substantial loss of information in the identification of genes underlying complex traits. In this article, we propose novel statistical methods to analyze multiple tightly linked markers. Simulation studies comparing our methods versus existing methods suggest that our methods are more powerful. Finally, we apply the proposed methods to study genetic linkage between the dopamine D2 receptor locus and alcoholism.     

A survey on haplotyping algorithms for tightly linked markers

Two grand challenges in the postgenomic era are to develop a detailed understanding of heritable variation in the human genome, and to develop robust strategies for identifying the genetic contribution to diseases and drug responses. Haplotypes of single nucleotide polymorphisms (SNPs) have been suggested as an effective representation of human variation, and various haplotype-based association mapping methods for complex traits have been proposed in the literature. However, humans are diploid and, in practice, genotype data instead of haplotype data are collected directly. Therefore, efficient and accurate computational methods for haplotype reconstruction are needed and have recently been investigated intensively, especially for tightly linked markers such as SNPs. This paper reviews statistical and combinatorial haplotyping algorithms using pedigree data, unrelated individuals, or pooled samples.     

A confidence-set approach for finding tightly linked genomic regions

As more studies adopt the approach of whole-genome screening, geneticists are faced with the challenge of having to interpret results from traditional approaches that were not designed for genome-scan data. Frequently, two-point analysis by the LOD method is performed to search for signals of linkage throughout the genome, for each of hundreds or even thousands of markers. This practice has raised the question of how to adjust the significance level for the fact that multiple tests are being performed. Various recommendations have been made, but no consensus has emerged. In this article, we propose a new method, the confidence-set approach, that circumvents the need to correct for the level of significance according to the number of markers tested. In the search for the gene location of a monogenic disorder, multiplicity adjustment is not needed in order to maintain the desired level of confidence. For complex diseases involving multiple genes, one needs only to adjust the level of significance according to the number of disease genes--a much smaller number than the number of markers in a genome screen-to ensure a predetermined genomewide confidence level. Furthermore, our formulation of the tests enables us to localize disease genes to small genomic regions, an extremely desirable feature that the traditional LOD method lacks. Our simulation study shows that, for sib-pair data, even when the coverage probability of the confidence set is chosen to be as high as 99%, our approach is able to implicate only the markers that are closely linked to the disease genes.     

Contrasting evolutionary patterns and target specificities among three Tourist-like MITE families in the maize genome

Miniature inverted-repeat transposable elements (MITEs) are short, non autonomous DNA elements that are widespread and abundant in plant genomes. The high sequence and size conservation observed in many MITE families suggest that they have spread recently throughout their respective host genomes. Here we present a maize genome wide analysis of three Tourist-like MITE families, mPIF, and two previously uncharacterized families, ZmV1 and Zead8. We undertook a bioinformatic analysis of MITE insertion sites, developed methyl-sensitive transposon display (M-STD) assays to estimate the associated level of CpG methylation at MITE flanking regions, and conducted a population genetics approach to investigate MITE patterns of expansion. Our results reveal that the three MITE families insert into genomic regions that present specific molecular features: they are preferentially AT rich, present low level of cytosine methylation as compared to the LTR retrotransposon Grande, and target site duplications are flanked by large and conserved palindromic sequences. Moreover, the analysis of MITE distances from predicted genes shows that 73% of 263 copies are inserted at less than 5 kb from the nearest predicted gene, and copies from Zead8 family are significantly more abundant upstream of genes. By employing a population genetic approach we identified contrasting patterns of expansion among the three MITE families. All elements seem to have inserted roughly 1 million years ago but ZmV1 and Zead8 families present evidences for activity of several master copies within the last 0.4 Mya.     

Contrasting life histories in neighbouring populations of a large mammal

Background

A fundamental life history question is how individuals should allocate resources to reproduction optimally over time (reproductive allocation). The reproductive restraint hypothesis predicts that reproductive effort (RE; the allocation of resources to current reproduction) should peak at prime-age, whilst the terminal investment hypothesis predicts that individuals should continue to invest more resources in reproduction throughout life, owing to an ever-decreasing residual reproductive value. There is evidence supporting both hypotheses in the scientific literature.

Methodology/Principal Findings

We used an uncommonly large, 38 year dataset on Alpine chamois (Rupicapra rupicapra) shot at various times during the rutting period to test these two hypotheses. We assumed that body mass loss in rutting males was strongly related to RE and, using a process-based approach, modelled how male relative mass loss rates varied with age. For different regions of our study area, we provide evidence consistent with different hypotheses for reproductive allocation. In sites where RE declined in older age, this appears to be strongly linked to declining body condition in old males. In this species, terminal investment may only occur in areas with lower rates of body mass senescence.

Conclusions/Significance

Our results show that patterns of reproductive allocation may be more plastic than previously thought. It appears that there is a continuum from downturns in RE at old age to terminal investment that can be manifest, even across adjacent populations. Our work identifies uncertainty in the relationship between reproductive restraint and a lack of competitive ability in older life (driven by body mass senescence); both could explain a decline in RE in old age and may be hard to disentangle in empirical data. We discuss a number of environmental and anthropogenic factors which could influence reproductive life histories, underlining that life history patterns should not be generalised across different populations.     

Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency

Deficient arylsulfatase A activity causes the neurodegenerative disease metachromatic leukodystrophy. However, some individuals with deficient enzyme activity appear clinically normal. This “pseudodeficiency” allele commonly found among many reported populations (frequency ∼ 0.10) is associated with two A→G transitions in cis in the arylsulfatase A gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, we studied 400 individuals in the African, European, Indian and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varied from 0.01 in Indians, 0.06 in Europeans, 0.21 in East Asians to 0.32 in Africans. The frequencies of both mutations occurring together ranged from almost non-existent in the Africans and East Asians, to 0.075 in the Europeans and 0.125 in the Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and eight multi-generation families with six polymorphic enzymes showed that, of the five haplotypes found in the general population, only one was linked to the double mutations. Alleles among the four populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans whose alleles were discordant. These results are consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among the Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa at ∼100 000–200 000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages. Received: 23 December 1996 / Accepted: 21 July 1997     

The life histories of American stepfathers in evolutionary perspective

This paper presents an analysis of the characteristics of men who become stepfathers, and their subsequent fertility patterns and lifetime reproductive success. Because women who already have children are ranked lower in the marriage market than women without children, men who marry women with children (e.g., stepfathers) are likely to have lower rankings in the marriage market as well. Using retrospective fertility and marital histories from the Panel Study of Income Dynamics (PSID), I show that men who become stepfathers have lower levels of education, less income, and are more likely to have been divorced before and to already have children, all characteristics that lower their rankings in the marriage market. Men with one or two stepchildren are just as likely to have children within a marriage as non-stepfathers, although men with three stepchildren show decreased fertility. Among men age 45 and older, stepfathers have lower lifetime fertility than non-stepfathers, although the difference disappears when men’s age at first marriage is controlled for. Additionally, stepfathers have significantly higher fertility than men who never marry. The results suggest that some men become stepfathers to procure mates and fertility benefits that they would otherwise have been unlikely to obtain; for these men, raising other men’s children serves as a form of mating effort. Preliminary versions of this paper were presented at the Evolution and Human Adaptation Program at the University of Michigan, and the Human Behavior and Evolution Society’s annual meeting at Amherst. Kermyt G. Anderson received his Ph.D. in anthropology from the University of New Mexico in 1999. He is currently a Mellon Postdoctoral Research Fellow at the Population Studies Center of the Institute for Social Research at the University of Michigan. His current research examines the relationship between family structure, parental investment, and children’s educational and employment outcomes in South Africa.     

Footprints of intragenic recombination at HLA loci

 To evaluate the effect of balancing selection and intragenic recombination (or gene conversion) at six individual HLA loci, synonymous nucleotide diversity in different exon groups is examined within (π_w) and between (π_b) allelic lineages that may be defined by either serological or DNA sequence differences. Both π values are high in exons which encode for the peptide binding region (PBR) and tend to decrease in other exons. The value of π_w is significantly smaller than that of π_b in any exon of any locus. However, even π_w is much greater than nucleotide diversity at non-HLA loci. These observations provide additional strong evidence for the operation of balancing selection in PBR-encoding exons and its indirect effects on polymorphism at linked neighboring regions. It appears that allelic lineages have generally evolved in isolation but the linkage relationships within and between exons are incomplete throughout the long evolutionary history. To quantify intragenic recombination and account for the large discrepancy between the HLA and non-HLA diversity, a population genetics model is analyzed with special reference to the evolution of modern humans. The analysis suggests that the recombination rate between two sites 1000 base pairs apart is about 10^–5 per generation and that the effective size of human populations (equivalent roughly to the number of breeding individuals in a randomly mating population) has dropped from 10⁵ to 10⁴ in most of the Quaternary. One possibility for this reduction is discussed. Received: 11 August 1997 / Revised: 8 October 1997     

Fine-scale community and genetic structure are tightly linked in species-rich grasslands

Recent evidence indicates that grassland community structure and species diversity are influenced by genetic variation within species. We review what is known regarding the impact of intraspecific diversity on grassland community structure, using an ancient limestone pasture as a focal example. Two genotype-dependent effects appear to modify community structure in this system. First, the abundance of individual constituent species can depend upon the combined influence of direct genetic effects stemming from individuals within the population. Second, the outcome of localized interspecific interactions occurring within the community can depend on the genotypes of participating individuals (indicating indirect genetic effects). Only genotypic interactions are thought to be capable of allowing the long-term coexistence of both genotypes and species. We discuss the implications of these effects for the maintenance of diversity in grasslands. Next, we present new observations indicating that losses of genotypic diversity from each of two species can be predicted by the abundance of other coexisting species within experimental grassland communities. These results suggest genotype-specific responses to abundance in other coexisting species. We conclude that both direct and indirect genetic effects are likely to shape community structure and species coexistence in grasslands, implying tight linkage between fine-scale genetic and community structure.