Psychiatric genetics: progress amid controversy

Several psychiatric disorders--such as bipolar disorder, schizophrenia and autism--are highly heritable, yet identifying their genetic basis has been challenging, with most discoveries failing to be replicated. However, inroads have been made by the incorporation of intermediate traits (endophenotypes) and of environmental factors into genetic analyses, and through the identification of rare inherited variants and novel structural mutations. Current efforts aim to increase sample sizes by gathering larger samples for case-control studies or through meta-analyses of such studies. More attention on unique families, rare variants, and on incorporating environment and the emerging knowledge of biological function and pathways into genetic analysis is warranted.     

Schizophrenia genetics: progress, at last

The heritability of schizophrenia is well established, and has motivated the search for genetic variation that contributes to susceptibility. Recent progress from both genome-wide association and copy number variant studies have identified risk loci, however, these are at very different ends of the susceptibility spectrum with respect to allele frequency and effect size. It is likely that investigations of common variants have surrendered their full yield, but rare variant exploration is at the very beginning.     

The genetics and evolution of female choice

Darwin based his theory of evolution on the central theme of 'the struggle for existence', 'the preservation of favoured races', 'the survival of the fittest'. In addition to this 'natural selection', he proposed a second type of selection, sexual selection. 'This depends, not on a struggle for existence, but on a struggle between males for possession of the females; the result is not death to the unsuccessful competitor, but few or no offspring. Males would compete for females, and females would choose between males. Since Darwin's work, many examples of natural selection have been observed in nature and in laboratory experiments, and knowledge of genetics has given natural selective theory a sound basis. The theory of sexual selection through male competition has also been widely accepted. However, the theory of sexual selection through female choice has had a much more chequered passage.     

Recent progress in the genetics of generalized vitiligo

Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo (GV), the predominant form of the disorder, results from autoimmune loss of melanocytes from affected regions. GV is a “complex trait”, inherited in a non-Mendelian polygenic, multifactorial manner. GV is epidemiologically associated with other autoimmune diseases, both in GV patients and in their close relatives, suggesting that shared genes underlie susceptibility to this group of diseases. Early candidate gene association studies yielded a few successes, such as PTPN22, but most such reports now appear to be false-positives. Subsequent genomewide linkage studies identified NLRPI and XBPI, apparent true GV susceptibility genes involved in immune regulation, and recent genome-wide association studies (GWAS) of GV in Caucasian and Chinese populations have yielded a large number of additional validated GV susceptibility genes.Together, these genes highlight biological systems and pathways that reach from the immune cells to the melanocyte, and provide insights into both disease pathogenesis and potential new targets for both treatment and even prevention of GV and other autoimmune diseases in genetically susceptible individuals.     

Mate choice for genetic quality when environments vary: suggestions for empirical progress

Mate choice for good-genes remains one of the most controversial evolutionary processes ever proposed. This is partly because strong directional choice should theoretically deplete the genetic variation that explains the evolution of this type of female mating preference (the so-called lek paradox). Moreover, good-genes benefits are generally assumed to be too small to outweigh opposing direct selection on females. Here, we review recent progress in the study of mate choice for genetic quality, focussing particularly on the potential for genotype by environment interactions (GEIs) to rescue additive genetic variation for quality, and thereby resolve the lek paradox. We raise five questions that we think will stimulate empirical progress in this field, and suggest directions for research in each area: (1) How is condition-dependence affected by environmental variation? (2) How important are GEIs for maintaining additive genetic variance in condition? (3) How much do GEIs reduce the signalling value of male condition? (4) How does GEI affect the multivariate version of the lek paradox? (5) Have mating biases for high-condition males evolved because of indirect benefits?     

Chemical genetics: where genetics and pharmacology meet

Genetics and pharmacology can elicit surprisingly different phenotypes despite targeting the same protein. This Essay explores these unexpected differences and their implications for biology and medicine.     

Recent progress in the study of the genetics of height

Adult height is a classic polygenic trait of high narrow-sense heritability (h ² = 0.8). In the late nineteenth to early twentieth century, variation in adult height was used as a model to set the foundation of the fields of statistics and quantitative genetics. More recently, with our increasing knowledge concerning the extent of genetic variation in the human genome, human geneticists have used genome-wide association studies to identify hundreds of loci robustly associated with adult height, providing new insights into human growth and development, and into the architecture of complex human traits. In this review, I highlight the progress made in the last 2 years in understanding how genetic variation controls height variation in humans, including non-Caucasian populations and children.     

Precocious puberty: growth and genetics

The precise neuroendocrine mechanisms underlying activation of hypothalamic-pituitary-gonadal (HPG) axis maturation are elusive. The wide age range of pubertal onset among normal individuals throughout the world may suggest that both genetic and environmental factors modulate the timing of puberty. Early activation of the HPG axis, termed central precocious puberty (CPP), causes psychosocial difficulties and may lead to compromised final height, especially if medical intervention is delayed. Although CPP is considered to be idiopathic in the majority of patients, we have recently reported a 27.5% prevalence of familial cases among 147 patients with idiopathic CPP. Segregation analysis of this cohort suggested an autosomal dominant transmission with incomplete sex-dependent penetrance. Allelic variants of candidate genes that regulate the timing of puberty may cause familial CPP. Detection of these genes will provide a tool for identification of children at risk of developing CPP, enabling early intervention with the aim of preventing its distressing outcomes.     

Early 20th-century research at the interfaces of genetics, development, and evolution: reflections on progress and dead ends

Three early 20th-century attempts at unifying separate areas of biology, in particular development, genetics, physiology, and evolution, are compared in regard to their success and fruitfulness for further research: Jacques Loeb's reductionist project of unifying approaches by physico-chemical explanations; Richard Goldschmidt's anti-reductionist attempts to unify by integration; and Sewall Wright's combination of reductionist research and vision of hierarchical genetic systems. Loeb's program, demanding that all aspects of biology, including evolution, be studied by the methods of the experimental sciences, proved highly successful and indispensible for higher level investigations, even though evolutionary change and properties of biological systems up to now cannot be fully explained on the molecular level alone. Goldschmidt has been appraised as pioneer of physiological and developmental genetics and of a new evolutionary synthesis which transcended neo-Darwinism. However, this study concludes that his anti-reductionist attempts to integrate genetics, development and evolution have to be regarded as failures or dead ends. His grand speculations were based on the one hand on concepts and experimental systems that were too vague in order to stimulate further research, and on the other on experiments which in their core parts turned out not to be reproducible. In contrast, Sewall Wright, apart from being one of the architects of the neo-Darwinian synthesis of the 1930s, opened up new paths of testable quantitative developmental genetic investigations. He placed his research within a framework of logical reasoning, which resulted in the farsighted speculation that examinations of biological systems should be related to the regulation of hierarchical genetic subsystems, possibly providing a mechanism for development and evolution. I argue that his suggestion of basing the study of systems on clearly defined properties of the components has proved superior to Goldschmidt's approach of studying systems as a whole, and that attempts to integrate different fields at a too early stage may prove futile or worse.     

Huntington disease: genetics and epidemiology

Huntington disease (HD) is an autosomal dominant disorder in which the major gene expression occurs in the central nervous system. It is characterized by the appearance of progressive chorea and dementia, usually in adult life. One tragic aspect of the disorder, due to its late age of onset and, until recently, lack of a presymptomatic marker, is that transmission of the disease to offspring invariably occurs before symptoms develop in the parent. Although the onset of symptoms and the rate of progression may vary, the prognosis is one of relentless deterioration. The major pathological features of HD are a primary loss of cells in the caudate nucleus and putamen (striatum) but other regions of the basal ganglia, hypothalamus, and brain stem are also involved. Not only is there neuronal loss but there is also a decrease in the level of a number of neurotransmitters and associated enzymes, together with abnormalities in some receptor sites. Martin [1] described the disease as "genetically programmed cell death in the human central nervous system."     

Governing stem cell banks and registries: Emerging Issues

The expansion of national and international research efforts in stem cell research is increasingly paired with the trend of establishing stem cell banks and registries. In jurisdictions crossing the spectrum of restrictive to liberal stem cell policies, banks and registries are emerging as an essential resource for transnational access to quality-controlled and ethically sourced stem cell lines. In this study, we report the preliminary findings of a survey of stem cell banks participating in the International Stem Cell Forum's International Stem Cell Banking Initiative (ISCBI). The questionnaire circulated to all ISCBI members addressed both general issues surrounding research policies (e.g., national policies regulating the permissibility of conducting embryonic stem cell research (hESCR)) and, more specifically, issues relating to the governance of stem cell banking projects. The results of the questionnaire were complemented by scholarly research conducted by the authors. This article provides an overview of the current international hESC banking landscape (I). For this purpose, the policy and governance approaches adopted in the surveyed stem cell banks at the national level will be analyzed and areas of convergence and variance will be identified (II). It is beyond the scope of this paper to provide a comprehensive analysis of the wide range of possible governance approaches, policy responses, and their implications. However, we want to provide a starting point for discussion surrounding key questions and challenges as concerns provenance, access, and deposit of hESC lines (III). Finally, while our analysis is focused on research grade hESCs, the lessons to be gleaned from this examination will encourage further thought, analysis, and research into the issues raised in the banking and governance of other sources of stem cell lines (e.g., SCNT, parthenogenesis, iPs) (IV).