Population genetics of malaria resistance in humans

The high mortality and widespread impact of malaria have resulted in this disease being the strongest evolutionary selective force in recent human history, and genes that confer resistance to malaria provide some of the best-known case studies of strong positive selection in modern humans. I begin by reviewing JBS Haldane''s initial contribution to the potential of malaria genetic resistance in humans. Further, I discuss the population genetics aspects of many of the variants, including globin, G6PD deficiency, Duffy, ovalocytosis, ABO and human leukocyte antigen variants. Many of the variants conferring resistance to malaria are ‘loss-of-function'' mutants and appear to be recent polymorphisms from the last 5000–10 000 years or less. I discuss estimation of selection coefficients from case–control data and make predictions about the change for S, C and G6PD-deficiency variants. In addition, I consider the predicted joint changes when the two β-globin alleles S and C are both variable in the same population and when there is a variation for α-thalassemia and S, two unlinked, but epistatic variants. As more becomes known about genes conferring genetic resistance to malaria in humans, population genetics approaches can contribute both to investigating past selection and predicting the consequences in future generations for these variants.     

Mouse mutants and phenotypes: accessing information for the study of mammalian gene function

Recent advances in high-throughput gene targeting and conditional mutagenesis are creating new and powerful resources to study the in vivo function of mammalian genes using the mouse as an experimental model. Mutant ES cells and mice are being generated at a rapid rate to study the molecular and phenotypic consequences of genetic mutations, and to correlate these study results with human disease conditions. Likewise, classical genetics approaches to identify mutations in the mouse genome that cause specific phenotypes have become more effective. Here, we describe methods to quickly obtain information on what mutant ES cells and mice are available, including recombinase driver lines for the generation of conditional mutants. Further, we describe means to access genetic and phenotypic data that identify mouse models for specific human diseases.     

Development aid: on ontogeny and ethics

Human development is a matter of complex interactions between nutritional regimes, genes, educational regimes and other diverse developmental resources. I argue that there is no ethically salient difference between the contributions made to development by genes and the contributions made by these other resources. Since we think nutrition and schooling should be included in the calculus of distributive justice, we should include at least some genes in this calculus too. What is more, under the right circumstances genetic engineering may become a useful tool for the distribution of developmental resources. This said, attention to the parity of genetic and environmental causation can also help to articulate the legitimate suspicions many groups have of genetic engineering.     

Concepts and strategies for human gene therapy.

Methods of modern molecular genetics have been developed that allow stable transfer and expression of foreign DNA sequences in human and other mammalian somatic cells. It is therefore no surprise that the methods have been applied in attempts to complement genetic defects and correct disease phenotypes. Two decades of research have now led to the first clinically applicable attempts to introduce genetically modified cells into human beings to cure diseases caused at least partially by genetic defects. We discuss here some of the strategies being followed for both in vitro and in vivo application of therapeutic gene transfer and summarize some of the technical and conceptual difficulties associated with somatic-cell gene therapy.     

Selfish Genes and Plant Speciation

A key to understand the process of speciation is to uncover the genetic basis of hybrid incompatibilities. Selfish genetic elements (SGEs), DNA sequences that can spread in a population despite being associated with a fitness cost to the individual organism, make up the largest component in many plant genomes, but their role in the genetics of speciation has long been controversial. However, the realization that many organisms have evolved a variety of suppressor mechanisms that reduce the deleterious effects of SGEs has spurred renewed interest in their importance for speciation. The relationship between SGEs and their suppressors often results in strong selection on at least two interacting loci and this arms race therefore creates a situation where SGEs may give rise to hybrid dysgenesis due to Bateson–Dobzhansky–Muller incompatibilities (BDMIs). Here, I argue that examples of SGEs underlying BDMIs may be particularly common among plants compared to other taxa and that a focus on loci involved in genetic conflicts may be especially useful for workers interested in the genetics of plant speciation. I first discuss why the frequent mating system shifts and hybridization events in plants make for a specifically dynamic relationship between SGEs and plant host genomes. I then review some recent empirical observations consistent with SGE-induced speciation in plants. Lastly, I suggest some future directions to test fully the utility of this perspective.     

遗传伦理问题起源的研究与对策

遗传伦理问题是生命科学领域最具争议并最难以妥善解决的问题之一。近年来, 此类问题的研究主要是围绕遗传伦理问题的种类及解决方法进行的。但关于遗传伦理问题起源的系统研究尚不多见, 这也使相应对策的提出显得缺乏理论支撑。文章从人类生物进化与文化进化的双重角度深入探讨了遗传伦理问题发生的进化根源和演化规律。人类是生物进化与文化进化的双重产物, 是地球上唯一既具有生物属性又具有文化属性的物种。通过对人类生物进化与文化进化及其生物属性与文化属性特点的比较研究, 文章提出了任何伦理问题都可以从人类的生物进化与文化进化之间相互作用所产生的冲突中找到其发生根源的观点, 其目的是为研究遗传伦理问题及其对策的提出寻求理论和实践上的依据。同时, 提出了一系列关于遗传伦理问题的对应策略。文章的最终目的并非仅仅为某种观点能被接受, 而是希望通过对遗传伦理问题及其起源的了解和认识, 使遗传学领域的决策者和研究者更具使命感与责任感, 使一般公众对遗传学研究及其应用少一些误解, 多一些理性, 从而使遗传学事业能健康、持续发展, 造福人类。     

Method of path coefficients: a trademark of Sewall Wright

This address is a tribute to a pioneer of population genetics, including human population genetics. The unique methodology employed by Sewall Wright in many genetic problems is the method of path coefficients. This essay traces the historical landmarks in the development of the path method and then shows how some of the conventional statistical results can be converted into expressions involving path coefficients. The construction of a path diagram to represent such statistical results is explained in terms of examples. In the last section an example of applying the path method to the problem of genetic linkage in a random mating population is given. I hope that, despite the ending of the Sewall Wright era, the path method will continue to serve the scientific world.     

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.     

Assessing the Effect of Sequencing Depth and Sample Size in Population Genetics Inferences

Next-Generation Sequencing (NGS) technologies have dramatically revolutionised research in many fields of genetics. The ability to sequence many individuals from one or multiple populations at a genomic scale has greatly enhanced population genetics studies and made it a data-driven discipline. Recently, researchers have proposed statistical modelling to address genotyping uncertainty associated with NGS data. However, an ongoing debate is whether it is more beneficial to increase the number of sequenced individuals or the per-sample sequencing depth for estimating genetic variation. Through extensive simulations, I assessed the accuracy of estimating nucleotide diversity, detecting polymorphic sites, and predicting population structure under different experimental scenarios. Results show that the greatest accuracy for estimating population genetics parameters is achieved by employing a large sample size, despite single individuals being sequenced at low depth. Under some circumstances, the minimum sequencing depth for obtaining accurate estimates of allele frequencies and to identify polymorphic sites is , where both alleles are more likely to have been sequenced. On the other hand, inferences of population structure are more accurate at very large sample sizes, even with extremely low sequencing depth. This all points to the conclusion that under various experimental scenarios, in cost-limited population genetics studies, large sample sizes at low sequencing depth are desirable to achieve high accuracy. These findings will help researchers design their experimental set-ups and guide further investigation on the effect of protocol design for genetic research.     

Canine behavioral genetics: pointing out the phenotypes and herding up the genes

An astonishing amount of behavioral variation is captured within the more than 350 breeds of dog recognized worldwide. Inherent in observations of dog behavior is the notion that much of what is observed is breed specific and will persist, even in the absence of training or motivation. Thus, herding, pointing, tracking, hunting, and so forth are likely to be controlled, at least in part, at the genetic level. Recent studies in canine genetics suggest that small numbers of genes control major morphologic phenotypes. By extension, we hypothesize that at least some canine behaviors will also be controlled by small numbers of genes that can be readily mapped. In this review, we describe our current understanding of a representative subset of canine behaviors, as well as approaches for phenotyping, genome-wide scans, and data analysis. Finally, we discuss the applicability of studies of canine behavior to human genetics.     

Some legal implications of advances in human genetics.

The law which, to some extent at least, reflects contemporary mores, has not kept pace with the recent scientific advances in genetics. Because of the rate of advance in the science of genetics there is a real risk that we shall know how to change the traditional nature of man before we possess the knowledge necessary to enable us to use the new knowledge for humane purposes. Clonal reproduction may produce a creature who, for the purposes of the law, especially the criminal law, which defines when a child becomes a human being in terms of "old-fashioned" motherhood, may not be a human being, so that putting him to death may not be homicide. Similarly, in vitro fertilization and development in an artificial uterus may result in the "birth" of one who, though having human attributes, may not, in law, be a human being. While cloning and in vitro fertilization may not have immediate legal implications because of the state of the art, genetic manipulation in the form of amniocentesis has very real legal implications now because it is a matter of current practice. The assumption that detection of genetic abnormality in the foetus is a beneficial development because it enables parents to have the option of terminating the pregnancy, though valid in the United Kingdom and the United States, is invalid in Canada. Abortion on demand is not part of the law in Canada and the liberalization of the abortion provisions of the Criminal Code of Canada in 1969 expressly avoided including as a criterion for therapeutic abortion the risk that the child, if born, would be likely to suffer from such physical or mental abnormalities as to be seriously handicapped. Beyond the more technical issues raised by scientific advances, however, lies the fundamental question whether a handicapped life is a life not worth living.     

Perceptions of genetics research as harmful to society: differences among samples of African-Americans and European-Americans

Genetics has the potential not only to find cures for diseases, but to possess the mechanisms to change the bio-social make-up of populations. A specific question that has arisen on this issue is how developments in genetic technology may intersect with existing race and ethnic relations. Evidence of the racialization of some genetic disorders has been demonstrated elsewhere. The purpose of this study is to compare and contrast African-American and European-American attitudes on the benefits of genetics research for society. Findings show that African-Americans were more likely to say genetics research is harmful for society. This relationship remained statistically significant after controls were introduced in a regression model. Demographic characteristics and self-rated knowledge of genetics had no effect on attitudes among African-Americans. A willingness to use genetic services correlated with favorable attitudes. Differences in social position may lead some groups to opposing interpretations and symbolic meanings of genetics. This may be true in the context of this study because the social meanings of genetics may be tainted by racialization, historical attempts at eugenics, and the potential abuse of genetics targeting groups partially defined by superficial genetic characteristics.     

Three puzzles and eight gaps: what heritability studies and critical commentaries have not paid enough attention to

This article examines eight “gaps” in order to clarify why the quantitative genetics methods of partitioning variation of a trait into heritability and other components has very limited power to show anything clear and useful about genetic and environmental influences, especially for human behaviors and other traits. The first two gaps should be kept open; the others should be bridged or the difficulty of doing so should be acknowledged: 1. Key terms have multiple meanings that are distinct; 2. Statistical patterns are distinct from measurable underlying factors; 3. Translation from statistical analyses to hypotheses about measurable factors is difficult; 4. Predictions based on extrapolations from existing patterns of variation may not match outcomes; 5. The partitioning of variation in human studies does not reliably estimate the intended quantities; 6. Translation from statistical analyses to hypotheses about the measurable factors is even more difficult in light of the possible heterogeneity of underlying genetic or environmental factors; 7. Many steps lie between the analysis of observed traits and interventions based on well-founded claims about the causal influence of genetic or environmental factors; 8. Explanation of variation within groups does not translate to explanation of differences among groups. At the start, I engage readers’ attention with three puzzles that have not been resolved by past debates. The puzzles concern generational increases in IQ test scores, the possibility of underlying heterogeneity, and the translation of methods from selective breeding into human genetics. After discussing the gaps, I present each puzzle in a new light and point to several new puzzles that invite attention from analysts of variation in quantitative genetics and in social science more generally. The article’s critical perspectives on agricultural, laboratory, and human heritability studies are intended to elicit further contributions from readers across the fields of history, philosophy, sociology, and politics of biology and in the sciences.     

I3:A Self-organising Learning Workflow for Intuitive Integrative Interpretation of Complex Genetic Data

We propose a computational workflow(I3) for intuitive integrative interpretation of complex genetic data mainly building on the self-organising principle.We illustrate the use in interpreting genetics of gene expression and understanding genetic regulators of protein phenotypes,particularly in conjunction with information from human population genetics and/or evolutionary history of human genes.We reveal that loss-of-function intolerant genes tend to be depleted of tissue-sharing genetics of gene expression in brains,and if highly expressed,have broad effects on the protein phenotypes studied.We suggest that this workflow presents a general solution to the challenge of complex genetic data interpretation.I3 is available at http://suprahex.r-forge.r-project.org/I3.html.     

Proportion of Genes Survived in Offspring Conditional on Inheritance of Flanking Markers

In mammalian genetics and perhaps in human genetics as well, it is an interesting question as to how many offspring are needed in order to have a desired chance of preserving part or the entire genome of an individual. A more practical and perhaps more important question is: given k children and DNA marker data on a particular region of interest, what proportion of one's genes has been actually passed on to his children? To answer this question, I define the concept of identity by descent proportion, or IBDP for short. The IBDP is defined to be the proportion of genetic material shared identical by descent by a group of relatives in a specified chromosomal region. I provide a novel approach to computing the mean and variance of IBDP for k (>/=2) half-sibs based on marker data, thus providing a means to compute the mean and variance of proportion of genes survived. I first show that each chromosome in an offspring can be represented by a two-state Markov chain, with the time parameter being the map distance along the chromosome. On this basis, I will show that IBDP can be written as a stochastic integral and that the computation of the EIBDP can be reduced to evaluating an integral of some elementary functions. Numerical examples are provided to illustrate the calculation.     

Inferential Genotyping of Y Chromosomes in Latter-Day Saints Founders and Comparison to Utah Samples in the HapMap Project

One concern in human genetics research is maintaining the privacy of study participants. The growth in genealogical registries may contribute to loss of privacy, given that genotypic information is accessible online to facilitate discovery of genetic relationships. Through iterative use of two such web archives, FamilySearch and Sorenson Molecular Genealogy Foundation, I was able to discern the likely haplotypes for the Y chromosomes of two men, Joseph Smith and Brigham Young, who were instrumental in the founding of the Latter-Day Saints Church. I then determined whether any of the Utahns who contributed to the HapMap project (the “CEU” set) is related to either man, on the basis of haplotype analysis of the Y chromosome. Although none of the CEU contributors appear to be a male-line relative, I discovered that predictions could be made for the surnames of the CEU participants by a similar process. For 20 of the 30 unrelated CEU samples, at least one exact match was revealed, and for 17 of these, a potential ancestor from Utah or a neighboring state could be identified. For the remaining ten samples, a match was nearly perfect, typically deviating by only one marker repeat unit. The same query performed in two other large databases revealed fewer individual matches and helped to clarify which surname predictions are more likely to be correct. Because large data sets of genotypes from both consenting research subjects and individuals pursuing genetic genealogy will be accessible online, this type of triangulation between databases may compromise the privacy of research subjects.     

Mitochondrial DNA mutations and human disease

Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to oxidative phosphorylation (OXPHOS) defects. Since the identification of the first human pathological mitochondrial DNA (mtDNA) mutations in 1988, significant efforts have been spent in cataloguing the vast array of causative genetic defects of these disorders. Currently, more than 250 pathogenic mtDNA mutations have been identified. An ever-increasing number of nuclear DNA mutations are also being reported as the majority of proteins involved in mitochondrial metabolism and maintenance are nuclear-encoded. Understanding the phenotypic diversity and elucidating the molecular mechanisms at the basis of these diseases has however proved challenging. Progress has been hampered by the peculiar features of mitochondrial genetics, an inability to manipulate the mitochondrial genome, and difficulties in obtaining suitable models of disease. In this review, we will first outline the unique features of mitochondrial genetics before detailing the diseases and their genetic causes, focusing specifically on primary mtDNA genetic defects. The functional consequences of mtDNA mutations that have been characterised to date will also be discussed, along with current and potential future diagnostic and therapeutic advances.