Runs of homozygosity have utility in mammalian conservation and evolutionary studies

Runs of homozygosity (ROHs) arise due the transmission from parents to offspring of segments that are either identical by decent (IBD) or identical by state (IBS). The former is due to consanguineous matings whereas the latter is due to demographic processes. ROHs reduce individual nucleotide diversity (θ) as a function of homozygosity, and thus ROH distributions and θ are expected to vary among species because inbreeding levels, recombination rates, and demographic histories vary widely. To help interpret genetic diversity within and among species, we utilized genome sequence data from 78 mammalian species to compare θ and ROH burden (i.e., number and length of ROHs in the genome) among groups of mammals to assess genomic signatures of inbreeding. We compared θ and ROHs: (i) among threatened and non-threatened mammals to determine the significance of contemporary conservation status; (ii) among carnivorous and non-carnivorous mammals to determine the relevance of trophic effects; (iii) relative to body size because mutation rates generally vary with body mass; and (iv) across mammals from different latitudes to test for gradients in genomic diversity (e.g., due to effects of historic climatic regimes). Our results illustrate the considerable variance in genomic diversity across mammals, and that trophic level, body mass, and latitude have significant effects on θ and ROH burden. However, conservation status was not a reliable indicator of genomic diversity. We argue that genetic or genomic diversity should be an explicit component of conservation status, as such diversity is critical to the long-term sustainability of populations, and anticipate that ROHs will become more commonly used to estimate inbreeding in wild animals.     

Do complex population histories drive higher estimates of substitution rate in phylogenetic reconstructions?

Our curiosity about biodiversity compels us to reconstruct the evolutionary past of species. Molecular evolutionary theory now allows parameterization of mathematically sophisticated and detailed models of DNA evolution, which have resulted in a wealth of phylogenetic histories. But reconstructing how species and population histories have played out is critically dependent on the assumptions we make, such as the clock-like accumulation of genetic differences over time and the rate of accumulation of such differences. An important stumbling block in the reconstruction of evolutionary history has been the discordance in estimates of substitution rate between phylogenetic and pedigree-based studies. Ancient genetic data recovered directly from the past are intermediate in time scale between phylogenetics-based and pedigree-based calibrations of substitution rate. Recent analyses of such ancient genetic data suggest that substitution rates are closer to the higher, pedigree-based estimates. In this issue, Navascués & Emerson (2009) model genetic data from contemporary and ancient populations that deviate from a simple demographic history (including changes in population size and structure) using serial coalescent simulations. Furthermore, they show that when these data are used for calibration, we are likely to arrive at upwardly biased estimates of mutation rate.     

Evaluation of model fit of inferred admixture proportions

Model based methods for genetic clustering of individuals, such as those implemented in structure or ADMIXTURE, allow the user to infer individual ancestries and study population structure. The underlying model makes several assumptions about the demographic history that shaped the analysed genetic data. One assumption is that all individuals are a result of K homogeneous ancestral populations that are all well represented in the data, while another assumption is that no drift happened after the admixture event. The histories of many real world populations do not conform to that model, and in that case taking the inferred admixture proportions at face value might be misleading. We propose a method to evaluate the fit of admixture models based on estimating the correlation of the residual difference between the true genotypes and the genotypes predicted by the model. When the model assumptions are not violated, the residuals from a pair of individuals are not correlated. In the case of a bad fitting admixture model, individuals with similar demographic histories have a positive correlation of their residuals. Using simulated and real data, we show how the method is able to detect a bad fit of inferred admixture proportions due to using an insufficient number of clusters K or to demographic histories that deviate significantly from the admixture model assumptions, such as admixture from ghost populations, drift after admixture events and nondiscrete ancestral populations. We have implemented the method as an open source software that can be applied to both unphased genotypes and low depth sequencing data.     

Evolution by phenotype: a biomedical perspective

Genes are widely assumed to play a major role in the epidemiology of complex chronic diseases, yet attempts to characterize the genetic architecture of such traits have been frustrating. Understanding that evolution works by screening phenotypes rather than genotypes can help explain the source of this frustration. Complex traits are usually the result of long-term, often subtle, gene-environment interactions, such that individual life histories may be as important as population histories in predicting and explaining these traits. Recognizing that the problem is not due to technological limitations can help temper expectations and guide the design of future work in biomedical genetics, by allowing us to focus on better approaches where they exist and on those problems most likely to yield a genetic solution. We may even be forced to re-conceive complex biological causation.     

分子生态学重要概念——遗传距离及其测度的理论研究概况

综述了遗传距离的概念、背景,有关遗传距离的几种基本的突变模型以及和遗传距离有关的参量和几种常用统计量,指出在处理蛋白质数据、分子数据以及序列数据时,如何选择相应的统计量和可用的软件包,同时还着重指明了各种模型的假设前提,为处理实际的蛋白质或分子数据时选择合适的模型,和对数据的最终解释提供一些帮助。     

Measuring and Testing Genetic Differentiation with Ordered versus Unordered Alleles

Estimates and variances of diversity and differentiation measures in subdivided populations are proposed that can be applied to haplotypes (ordered alleles such as DNA sequences, which may contain a record of their own histories). Hence, two measures of differentiation can be compared for a single data set: one (G(ST)) that makes use only of the allelic frequencies and the other (N(ST)) for which similarities between the haplotypes are taken into account in addition. Tests are proposed to compare N(ST) and G(ST) with zero and with each other. The difference between N(ST) and G(ST) can be caused by several factors, including sampling artefacts, unequal effect of mutation rates and phylogeographic structure. The method presented is applied to a published data set where a nuclear DNA sequence had been determined from individuals of a grasshopper distributed in 24 regions of Europe. Additional insights into the genetic subdivision of these populations are obtained by progressively combining related haplotypes and reanalyzing the data each time.     

Genetic profile of cosmopolitan populations: effects of hidden subdivision

Natural populations of many organisms exhibit excess of rare alleles in comparison with the predictions of the neutral mutation hypothesis. It has been shown before that either a population bottleneck or the presence of slightly deleterious mutations can explain this phenomenon. A third explanation is presented in this work, showing that hidden subdivision within a population can also lead to an excess of rare alleles in the total population when the expectations of the neutral model are based on the allele frequency profile of the entire population data. With two examples (mitochondrial DNA-morph distribution and isozyme allele frequency distributions), it is shown that most cosmopolitan human populations exhibit excess of rare as well as total allele counts, when these are compared with the expectations of the neutral mutation hypothesis. The mitochondrial data demonstrate that such excesses can be detected from genetic variation at a single locus as well, and this is not due to stochastic error of allele frequency distributions. Contrast of the present observations with the allele frequency profiles in agglomerated tribal populations from South and Central America shows that even when the neutral expectations hold for individual subpopulations, if all subpopulations are grouped into a single population, the pooled data exhibit an excess of total number of alleles that is mainly due to the excess of rare alleles. Therefore, a primary cause of the excess number of rare alleles could be the hidden subdivision, and the magnitude of the excess indicates the extent of substructuring. The two components of hidden subdivision are: 1) Number of subpopulations, and 2) the average genetic distance among them. The implications of this observation in estimating mutation rate are discussed indicating the difficulties of comparing mutation rates from different population surveys.     

Age-specific reproduction in a long-lived species: the combined effects of senescence and individual quality

Apparent changes in breeding performance with age measured at the population level can be due to changes in individual capacity at different ages, or to the differential survival of individuals with different capabilities. Estimating the relative importance of the two is important for understanding ageing patterns in natural populations, but there are few studies of such populations in which these effects have been disentangled. We analysed laying date and clutch size as measures of individual performance in a population of mute swans (Cygnus olor) studied over 25 years at Abbotsbury, UK. On both measures of breeding performance, individuals tended to improve up to the age of 6 or 7, and to decline after about the age of 12. Individuals with longer lifespans performed better at all ages (earlier laying, larger clutches) than animals that ceased breeding earlier. We conclude that the apparent mean increase in performance with age in mute swans is due to both individual improvement and differential survival of individuals who perform well, while the decline in older age groups is due to individual loss of function. Our results underline the need to take individual differences into account when testing hypotheses about life histories in wild populations.     

What can DNA tell us about biological invasions?

It is often hoped that population genetics can answer questions about the demographic and geographic dynamics of recent biological invasions. Conversely, invasions with well-known histories are sometimes billed as opportunities to test methods of population genetic inference. In both cases, underappreciated limitations constrain the usefulness of genetic methods. The most significant is that human-caused invasions have occurred on historical timescales that are orders of magnitude smaller than the timescales of mutation and genetic drift for most multicellular organisms. Analyses based on the neutral theory of molecular evolution cannot resolve such rapid dynamics. Invasion histories cannot be reconstructed in the same way as biogeographic changes occurring over millenia. Analyses assuming equilibrium between mutation, drift, gene flow, and selection will rarely be applicable, and even methods designed for explicitly non-equilibrium questions often require longer timescales than the few generations of most invasions of current concern. We identified only a few population genetic questions that are tractable over such short timescales. These include comparison of alternative hypotheses for the geographic origin of an invasion, testing for bottlenecks, and hybridization between native and invasive species. When proposing population genetic analysis of a biological invasion, we recommend that biologists ask (i) whether the questions to be addressed will materially affect management practice or policy, and (ii) whether the proposed analyses can really be expected to address important population genetic questions. Despite our own enthusiasm for population genetic research, we conclude that genetic analysis of biological invasions is justified only under exceptional circumstances.     

Assessing and managing breast cancer risk: clinical tools for advising patients

Using breast cancer risk assessment tools and going through the process of assessing breast cancer risk can answer many women's questions about what puts them at relatively higher or lower risk. This effectively engages both the clinician and the patient in a discussion about breast cancer, the chances of getting it, and the family's involvement--making the process as important as the actual tools. Examples of selected case histories demonstrate risk assessment using available tools such as the Gail-NCI and the Claus models. For some women, such as those considering tamoxifen or prophylactic surgeries, it may be desirable to prescreen for the inheritance of hereditary mutations and to follow with genetic testing, if indicated. Testing for mutations of breast cancer susceptibility genes or for their diminished expression adds to our ability to assess breast cancer risk at an individual level. The literature contains general interventions that are widely accepted to reduce the severity and the burden of breast cancer, and these are brought together here. The risk assessment process is an important part of a risk reduction program and can help motivate women to engage in prevention activities. This paper uses 2 hypothetical but fact-based and typical case histories to discuss the utility of risk assessment tools for informing women about their options.     

Latent multinomial models for extended batch-mark data

Batch marking is common and useful for many capture–recapture studies where individual marks cannot be applied due to various constraints such as timing, cost, or marking difficulty. When batch marks are used, observed data are not individual capture histories but a set of counts including the numbers of individuals first marked, marked individuals that are recaptured, and individuals captured but released without being marked (applicable to some studies) on each capture occasion. Fitting traditional capture–recapture models to such data requires one to identify all possible sets of capture–recapture histories that may lead to the observed data, which is computationally infeasible even for a small number of capture occasions. In this paper, we propose a latent multinomial model to deal with such data, where the observed vector of counts is a non-invertible linear transformation of a latent vector that follows a multinomial distribution depending on model parameters. The latent multinomial model can be fitted efficiently through a saddlepoint approximation based maximum likelihood approach. The model framework is very flexible and can be applied to data collected with different study designs. Simulation studies indicate that reliable estimation results are obtained for all parameters of the proposed model. We apply the model to analysis of golden mantella data collected using batch marks in Central Madagascar.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper 5/1: Perspectives in mutation epidemiology. 1. Incidence and prevalence of genetic disease (excluding chromosomal aberrations) in human populations

Detailed knowledge of the birth frequency or the cumulative incidence over all ages of genetic diseases in human populations is a prerequisite for assessing the magnitude of possible genetic hazards caused by environmental mutagens. However, both theoretical and practical difficulties are involved in precisely measuring the total frequency of these diseases. Two sets of data from large-scale population studies, one from Northern Ireland and the other from British Columbia, are compared with each other and with the results from ad hoc surveys for individual monogenic disorders. With due allowance for differences in approach, examination indicates that the data from the large-scale population studies are inadequate. However, it could provide a crude estimate of the total frequency of genetic diseases and a fairly reliable estimate of the individual frequency of certain genetic disorders with early onset that are familiar and readily diagnosed. In addition to environmental mutagens, there are a number of factors associated with current human activity that may change the incidence of genetic diseases. In order to monitor the human population for environmental mutagens, the change in frequency of sporadic cases of those genetic diseases that arose from fresh mutation and that can be easily detected as early as possible should be followed closely. The mechanism of data collection currently being employed in some countries for childhood cancers, certain congenital malformations, and inborn errors of metabolism could be extended to include the so-called sentinel phenotypes. The rationale and feasibility of using retinoblastoma and Wilms' tumor (nephroblastoma) as examples of such population monitoring are described.     

Floating-Harbor syndrome in two sisters: autosomal recessive inheritance or germinal mosaicism?

We describe the clinical histories and physical findings most compatible with the diagnosis of Floating-Harbor syndrome in two sisters. The genetic basis of the Floating-Harbor syndrome is still unclear, and family data are in favour of autosomal recessive inheritance although germinal mosaicism for an autosomal dominant gene mutation cannot be fully excluded.     

Variants of uncertain clinical significance as a result of BRCA1/2 testing: impact of an ambiguous breast cancer risk message

The identification of an increasing number of variants of uncertain clinical significance (VUCS) in genetic testing for hereditary breast cancer poses serious problems for genetic counseling, because no data are available about the psychosocial impact of discussing such an unclear risk message. The current study is the first to present data on how test applicants actually understand and cope with such a result if communicated by a geneticist. We compared 10 women who received a VUCS result with 34 women who carried the deleterious mutation, 37 women who did not carry the deleterious mutation or 'true negatives,' and 160 women who received a so-called inconclusive result before and after test disclosure. Women, with whom a VUCS result was discussed, reported quite a high level of comprehension of the result. In addition, compared with the pretest measures, they did not report a higher level of perceived risk (p = 0.58) and even reported a decrease in breast cancer distress (p = 0.03). They were very comparable to women who received an inconclusive result on all post-disclosure measures. Our results suggest that discussing a VUCS result in genetic counseling does not give rise for concern.     

Why are some genetic diseases common?

Various processes (selection, mutation, migration and genetic dirft) are known to determine the frequency of genetic disease in human populations, but so far it has proved almost impossible to decide to what extent each is responsible for the presence of a particular genetic disease. The techniques of gene and haplotype analysis offer new hope in addressing this issue, and we review relevant studies of three haemoglobinopathies: sickle cell anaemia, and and thalassaemia. We show how for each disease it is possible to recognize a pattern of regionally specific mutations, found in association with one or a few haplotypes, that is best explained as the result of selection; other patterns are due to population migration and genetic drift. However, we caution that such conclusions can be drawn in special circumstances only. In the case of the haemoglobinopathies it is possible because a selective agent (malaria) was already suspected, and the investigations could be carried out in relatively genetically homogenous populations whose migratory histories are known. Moreover, some data reviewed here suggest that gene conversion and the haplotype composition of a population may affect the frequency of a mutation, making interpretation of gene frequencies difficult on the basis of standard population genetics theory. Hence attempts to use the same approaches with other genetic diseases are likely to be frustrated by a lack of suitably untrammelled populations and by difficulties accounting for poorly understood genetic processes. We conclude that although this combination of molecular and population genetics is successful when applied to the study of haemoglobinopathies, it may not be so easy to apply it to the study of other genetic diseases.     

The impact of induced mutations on human populations

The major impact of an increase in genetic damage will be expressed as an increase in autosomal dominant and X-linked traits as well as chromosomal disorders. The present incidence of dominant traits has been estimated as 1% of live births, but recent data from British Columbia indicate the true value in that population may be an order of magnitude lower. These estimates are important if one measures the damage in terms of doubling dose. Neither the average mutation rate nor the number of loci capable of mutating to dominant detrimental form is known. Mutations that cause sterility or early embryonic loss are determental in the Darwinian sense but have little impact on society. Mutations that are more fit biologically may be a heavy burden to society if the affected persons require medical or institutional care. Since exposure to some mutagens is unavoidable, these factors must ultimately be included in a cost-benefit analysis.     

Untangling the hybrid nature of modern pig genomes: a mosaic derived from biogeographically distinct and highly divergent Sus scrofa populations

The merging of populations after an extended period of isolation and divergence is a common phenomenon, in natural settings as well as due to human interference. Individuals with such hybrid origins contain genomes that essentially form a mosaic of different histories and demographies. Pigs are an excellent model species to study hybridization because European and Asian wild boars diverged ~1.2 Mya, and pigs were domesticated independently in Europe and Asia. During the Industrial Revolution in England, pigs were imported from China to improve the local pigs. This study utilizes the latest genomics tools to identify the origin of haplotypes in European domesticated pigs that are descendant from Asian and European populations. Our results reveal fine‐scale haplotype structure representing different ancient demographic events, as well as a mosaic composition of those distinct histories due to recently introgressed haplotypes in the pig genome. As a consequence, nucleotide diversity in the genome of European domesticated pigs is higher when at least one haplotype of Asian origin is present, and haplotype length correlates negatively with recombination frequency and nucleotide diversity. Another consequence is that the inference of past effective population size is influenced by the background of the haplotypes in an individual, but we demonstrate that by careful sorting based on the origin of haplotypes, both distinct demographic histories can be reconstructed. Future detailed mapping of the genomic distribution of variation will enable a targeted approach to increase genetic diversity of captive and wild populations, thus facilitating conservation efforts in the near future.     

Inbreeding in human populations and its influence on fertility and health

In many Asian and African countries, marriages between close biological relatives account for 20 to over 50 percent of all unions, with no evidence of any significant decline to popularity. Inbred unions are characterized by greater fertility, although they also result in higher levels of post-natal morbidity and mortality due to the expression of detrimental recessive genes inherited from a common ancestor(s). Improved public health regimes will lead to a continuing global reduction in the prevalence of infectious diseases, and as a result genetic disorders can be expected to account for an increasing proportion of ill-health. This burden will fail disproportionately on populations in which consanguinity is strongly favoured, including migrant communities from less developed countries now resident in Western Europe, North America and Oceania. However, the nature and degree of the biological problems associated with consanguinity remain to be clearly defined, and it is important that the social and economic benefits of marriage to a dose relative also are taken into consideration. Thus there is an urgent need for extended studies into the entire topic of human inbreeding, which to date has been the focus of little inter-disciplinary research.     

Epigenetic and genetic burden measures are associated with tumor characteristics in invasive breast carcinoma

The development and progression of invasive breast cancer is characterized by alterations to the genome and epigenome. However, the relationship between breast tumor characteristics, disease subtypes, and patient outcomes with the cumulative burden of these molecular alterations are not well characterized. We determined the average departure of tumor DNA methylation from adjacent normal breast DNA methylation using Illumina 450K methylation data from 700 invasive breast tumors and 90 adjacent normal breast tissues in The Cancer Genome Atlas. From this we generated a novel summary measure of altered DNA methylation, the DNA methylation dysregulation index (MDI), and examined the relation of MDI with tumor characteristics and summary measures that quantify cumulative burden of genetic mutation and copy number alterations. Our analysis revealed that MDI was significantly associated with tumor stage (P = 0.017). Across invasive breast tumor subtypes we observed significant differences in genome-wide DNA MDIs (P = 4.9E–09) and in a fraction of the genome with copy number alterations (FGA) (P = 4.6E–03). Results from a linear regression adjusted for subject age, tumor stage, and estimated tumor purity indicated a positive significant association of MDI with both MCB and FGA (P = 0.036 and P < 2.2E–16). A recursively partitioned mixture model of all 3 somatic alteration burden measures resulted in classes of tumors whose epigenetic and genetic burden profile were associated with the PAM50 subtype and mutations in TP53, PIK3CA, and CDH1. Together, our work presents a novel framework for characterizing the epigenetic burden and adds to the understanding of the aggregate impact of epigenetic and genetic alterations in breast cancer.