Five reasons why inbreeding may have considerable effect on post-reproductive human health

As the genetic architecture of common complex diseases of late onset is emerging through intensive research, it is intriguing to assess the predicted effect of inbreeding on those diseases. In this paper, we propose five reasons why we believe inbreeding may have a considerable effect on post-reproductive human health. (i) The joint effect of inbreeding depression on all polygenic quantitative phenotypes that confer risk for late-onset diseases is predicted to be multiplicative rather than additive. (ii) The "genetic load" of rare "Mendelian" variants with large deleterious effects in post-reproductive adults is unknown, but could be much greater than expected as these variants were invisible to selection through human history. (iii) Deleterious effects resulting from autozygosity in hundreds of affected rare recessive variants of small effect under common disease/rare variant (CD/RV) hypothesis could result in epistatic effects that could jointly impair capacity to compensate against environmental risks. (iv) Heterozygote advantage in loci under balancing selection could be reduced by inbreeding. (v) Published empirical evidence in animals and humans consistently report large inbreeding effects on late-onset traits. Since inbreeding is common in many populations and the effects of inbreeding depression could substantially contribute to disease burden and reduced life expectancy we believe there is now a clear need for further genetic epidemiological research in humans to investigate this issue.     

A current perspective on genetic testing for breast and ovarian cancer: the oral contraceptive decision

A clinician faces a problem in how best to counsel the woman with a family history of breast or ovarian cancer about her options for pregnancy prevention. The physician must guide her as she makes new and complex decisions. Recent data strongly support an amplified effect of the estrogens in oral contraceptives for the woman with a genetic risk for breast cancer. Nonetheless, a woman's immediate need to prevent pregnancy may be much more important to her than worrying about the long-term risk of breast cancer. Another factor is that oral contraceptives prevent ovarian cancer, so the physician may wish to prescribe them to protect her from ovarian cancer. In some genetic backgrounds, however, oral contraceptives not only do not prevent ovarian cancer, but they may raise the risk of breast cancer so significantly that they should not be taken. With other genetic backgrounds, oral contraceptives will protect the woman from ovarian cancer without much effect on her breast cancer risk. When does each of these cancer risks or benefits become significant? The clinician can provide an important benefit to a woman who must prevent pregnancy yet worries about her cancer risk. The physician can help her evaluate the evidence, with its gaps and uncertainties, in the context of her own preferences. To assist in this evaluation, this decision aid provides base-line estimates of the cancer risk that accompanies each of a woman's options. In some cases, genetic testing is likely to provide valuable information as she makes choices about contraception and the risks vs. benefits of different alternatives available to her.     

The US national antimicrobial resistance monitoring system.

The use of antimicrobial agents in food animals can select for resistant bacterial pathogens that may be transmitted to humans via the commercial meat supply. In the USA, the FDA's Center for Veterinary Medicine regulatory duties require a determination that antimicrobial drugs are safe and effective for use in food animals. In addition, a qualitative assessment of risks to human health from antimicrobial resistance requires development. This risk assessment process is supported by data generated by the FDA's National Antimicrobial Resistance Monitoring System (NARMS) for enteric bacteria. NARMS data on antimicrobial susceptibility among Salmonella, Campylobacter, Escherichia coli and Enterococcus is collected. Research activities defining the genetic bases of resistance helps to understand the potential public health risks posed by the spread of antimicrobial resistance from food animal antimicrobial use. These activities help insure that antimicrobials are used judiciously to promote human and animal health.     

Sensitivity of germ cells and embryos to ionizing radiation

Experiments performed in laboratory animals suggest that ionizing radiation can induce DNA damage in the germ cells of exposed individuals and lead to various deleterious effects in their progeny, including miscarriage, low birth weight, congenital abnormalities and perhaps cancer. However, no clear evidence for such effects has been found in epidemiological studies of people exposed to radiation. The predicted risks of hereditary effects of any kinds resulting from parental exposure to relatively low doses of ionizing radiation remain very low, compared to the spontaneous risks in the absence of irradiation. Irradiation of the mouse embryo can lead to various effects (lethality, growth retardation, congenital abnormalities), depending on the period of gestation at which irradiation occurs. In humans, prenatal irradiation has only been exceptionally associated with congenital abnormalities, but irradiation between weeks 8-25 has been shown to be able to induce severe mental retardation. Although being not proven, the risk of developing a childhood cancer following prenatal irradiation may also not be excluded. Like for genetic effects, the risk of adverse effects following exposure of the embryo to relatively low doses remains quite low compared to the natural risks.     

Partnership

Individuals are called partners when it is in their best interest to help each other, if by doing so they increase the probability of being together in the future when, for similar reasons, they will continue to help each other. Kinsmen or individuals who often face (hedonic) situations in which helping is the dominating strategy are committed to help each other. Partnership may develop among them since the loss of the other means the loss of a guaranteed helper. Thus, they may be willing to take additional risks to help each other. Partnership may occur among unrelated individuals and with no hedonic situations. Partnership creates bonds between partners which may be much stronger than those between kinsmen; an individual may take more risks for his partner than he will ever take for a kin. Partnership may evolve without the sophistication and memory required for reciprocation altruism. Although kin selection, partnership and reciprocation are likely to appear fused as the causes for altruism, we argue that it may be possible to distinguish between them in some situations. We show that as the partners get older partnership may become less important to them. We also show that like cooperation, and for analogous reasons, malice may evolve among partners so that each will be willing to take additional risks in order to eliminate the other.     

The challenges of modeling mammalian biocomplexity

Understanding the relationships between human genetic factors, the risks of developing major diseases and the molecular basis of drug efficacy and toxicity is a fundamental problem in modern biology. Predicting biological outcomes on the basis of genomic data is a major challenge because of the interactions of specific genetic profiles with numerous environmental factors that may conditionally influence disease risks in a nonlinear fashion. 'Global' systems biology attempts to integrate multivariate biological information to better understand the interaction of genes with the environment. The measurement and modeling of such diverse information sets is difficult at the analytical and bioinformatic modeling levels. Highly complex animals such as humans can be considered 'superorganisms' with an internal ecosystem of diverse symbiotic microbiota and parasites that have interactive metabolic processes. We now need novel approaches to measure and model metabolic compartments in interacting cell types and genomes that are connected by cometabolic processes in symbiotic mammalian systems.     

GENETIC CONSTRAINTS UNDERLYING HUMAN REPRODUCTIVE TIMING IN A PREMODERN SWISS VILLAGE

The trade‐off between reproductive investment in early versus late life is central to life‐history theory. Despite abundant empirical evidence supporting different versions of this trade‐off, the specific trade‐off between age at first reproduction (AFR) and age at last reproduction (ALR) has received little attention, especially in long‐lived species with a pronounced reproductive senescence such as humans. Using genealogical data for a 19th‐century Swiss village, we (i) quantify natural selection acting on reproductive timing, (ii) estimate the underlying additive genetic (co)variances, and (iii) use these to predict evolutionary responses. Selection gradients were computed using multiple linear regression, and the additive genetic variance–covariance matrix was estimated using a restricted maximum‐likelihood animal model. We found strong selection for both an early AFR and a late ALR, which resulted from selection for an earlier and longer reproductive period (RP, i.e., ALR‐AFR). Furthermore, postponing AFR shortened RP in both sexes, but twice as much in women. Finally, AFR and ALR were strongly and positively genetically correlated, which led to a considerable reduction in the predicted responses to selection, or even rendered them maladaptive. These results provide evidence for strong genetic constraints underlying reproductive timing in humans, which may have contributed to the evolution of menopause.     

The Caenorhabditis Elegans Sel-1 Gene, a Negative Regulator of Lin-12 and Glp-1, Encodes a Predicted Extracellular Protein

The Caenorhabditis elegans lin-12 and glp-1 genes encode members of the LIN-12/NOTCH family of receptors. The sel-1 gene was identified as an extragenic suppressor of a lin-12 hypomorphic mutant. We show in this report that the sel-1 null phenotype is wild type, except for an apparent elevation in lin-12 and glp-1 activity in sensitized genetic backgrounds, and that this genetic interaction seems to be lin-12 and glp-1 specific. We also find that sel-1 encodes a predicted extracellular protein, with a domain sharing sequence similarity to predicted proteins from humans and yeast. SEL-1 may interact with the LIN-12 and GLP-1 receptors and/or their respective ligands to down-regulate signaling.     

Population genetics of genomics-based crop improvement methods

Many genome-wide association studies (GWAS) in humans are concluding that, even with very large sample sizes and high marker densities, most of the genetic basis of complex traits may remain unexplained. At the same time, recent research in plant GWAS is showing much greater success with fewer resources. Both GWAS and genomic selection (GS), a method for predicting phenotypes by the use of genome-wide marker data, are receiving considerable attention among plant breeders. In this review we explore how differences in population genetic histories, as well as past selection for traits of interest, have produced trait architectures and patterns of linkage disequilibrium (LD) that frequently differ dramatically between domesticated plants and humans, making detection of quantitative trait loci (QTL) effects in crops more rewarding and less costly than in humans.     

Evolutionary,structural and biochemical evidence for a new interaction site of the leptin obesity protein

The Leptin protein is central to the regulation of energy metabolism in mammals. By integrating evolutionary, structural, and biochemical information, a surface segment, outside of its known receptor contacts, is predicted as a second interaction site that may help to further define its roles in energy balance and its functional differences between humans and other mammals.     

Tick-Borne Viruses

Ticks are important vectors for the transmission of pathogens including viruses. The viruses carried by ticks also known as tick-borne viruses (TBVs), contain a large group of viruses with diverse genetic properties and are concluded in two orders, nine families, and at least 12 genera. Some members of the TBVs are notorious agents causing severe diseases with high mortality rates in humans and livestock, while some others may pose risks to public health that are still unclear to us. Herein, we review the current knowledge of TBVs with emphases on the history of virus isolation and identification, tick vectors, and potential pathogenicity to humans and animals, including assigned species as well as the recently discovered and unassigned species. All these will promote our understanding of the diversity of TBVs, and will facilitate the further investigation of TBVs in association with both ticks and vertebrate hosts.     

Biological races in humans

Races may exist in humans in a cultural sense, but biological concepts of race are needed to access their reality in a non-species-specific manner and to see if cultural categories correspond to biological categories within humans. Modern biological concepts of race can be implemented objectively with molecular genetic data through hypothesis-testing. Genetic data sets are used to see if biological races exist in humans and in our closest evolutionary relative, the chimpanzee. Using the two most commonly used biological concepts of race, chimpanzees are indeed subdivided into races but humans are not. Adaptive traits, such as skin color, have frequently been used to define races in humans, but such adaptive traits reflect the underlying environmental factor to which they are adaptive and not overall genetic differentiation, and different adaptive traits define discordant groups. There are no objective criteria for choosing one adaptive trait over another to define race. As a consequence, adaptive traits do not define races in humans. Much of the recent scientific literature on human evolution portrays human populations as separate branches on an evolutionary tree. A tree-like structure among humans has been falsified whenever tested, so this practice is scientifically indefensible. It is also socially irresponsible as these pictorial representations of human evolution have more impact on the general public than nuanced phrases in the text of a scientific paper. Humans have much genetic diversity, but the vast majority of this diversity reflects individual uniqueness and not race.     

Application of genome-wide SNP data for uncovering pairwise relationships and quantitative trait loci

The genetic analysis of quantitative traits in humans is changing as a result of the availability of whole-genome SNP data. Heritability analysis can make use of actual genetic sharing between pairs of individuals estimated from the genotype data, rather than the expected genetic sharing implied by their family relationship. This could provide more accurate heritability estimates and help to overcome the equal environment assumption. Quantitative trait locus (QTL) linkage mapping can make use of local genetic sharing inferred from very dense local genotype data from pedigree members or individuals not previously known to be related. This approach may be particularly suited for detecting loci that contain rare variants with major effect on the phenotype. Finally, whole-genome SNP data can be used to measure the genetic similarity between individuals to provide matched sets for association studies, in order to avoid spurious association from population stratification.     

Long-term genetic effects of radiation exposure

To date, there has been little experimental knowledge on the genetic risks of human exposure to ionising radiation for humans. Recent data suggest that hypervariable tandem repeat minisatellite loci provide a useful and sensitive experimental approach for monitoring radiation-induced germline mutation in humans. Here, I review the results of studies on minisatellite mutation rates in human populations exposed to radioactive fallout after the Chernobyl accident and nuclear weapon tests in Kazakhstan.     

Zoonotic potential of Giardia

Giardia duodenalis (syn. Giardia lamblia and Giardia intestinalis) is a common intestinal parasite of humans and mammals worldwide. Assessing the zoonotic transmission of the infection requires molecular characterization as there is considerable genetic variation within G. duodenalis. To date eight major genetic groups (assemblages) have been identified, two of which (A and B) are found in both humans and animals, whereas the remaining six (C to H) are host-specific and do not infect humans. Sequence-based surveys of single loci have identified a number of genetic variants (genotypes) within assemblages A and B in animal species, some of which may have zoonotic potential. Multi-locus typing data, however, has shown that in most cases, animals do not share identical multi-locus types with humans. Furthermore, interpretation of genotyping data is complicated by the presence of multiple alleles that generate “double peaks” in sequencing files from PCR products, and by the potential exchange of genetic material among isolates, which may account for the non-concordance in the assignment of isolates to specific assemblages. Therefore, a better understanding of the genetics of this parasite is required to allow the design of more sensitive and variable subtyping tools, that in turn may help unravel the complex epidemiology of this infection.     

Modeling human arthritic diseases in nonhuman primates

Models of rheumatoid arthritis (RA) in laboratory animals are important tools for research into pathogenic mechanisms and the development of effective, safe therapies. Rodent models (rats and mice) have provided important information about the pathogenic mechanisms. However, the evolutionary distance between rodents and humans hampers the translation of scientific principles into effective therapies. The impact of the genetic distance between the species is especially seen with treatments based on biological molecules, which are usually species-specific. The outbred nature and the closer anatomical, genetic, microbiological, physiological, and immunological similarity of nonhuman primates to humans may help to bridge the wide gap between inbred rodent strain models and the heterogeneous RA patient population. Here we review clinical, immunological and pathological aspects of the rhesus monkey model of collagen-induced arthritis, which has emerged as a reproducible model of human RA in nonhuman primates.     

The evolution of parental care

Our understanding of parental care behavior can be significantly advanced through the application of Williams's Principle, which states that reproduction has not only a benefit but also a cost to lifetime fitness. My laboratory has formalized Williams's Principle into the relative value theorem and found that its application to fishes, the taxa with the most diverse patterns of parental care, can help to explain which sex provides care and how much. In fishes, it is often the male that provides parental care, not because the male obtains greater benefits from this care, but probably because he pays fewer costs. Fish dynamically adjust their investment into parental care according to the number of offspring in their brood, past investment, genetic relatedness, and alternative mating opportunities, all of which affect the value of current offspring relative to potential future offspring. These results may also help us understand the joy and the challenges of parental care in humans.     

Ionizing radiation and genetic risks. X. The potential "disease phenotypes" of radiation-induced genetic damage in humans: perspectives from human molecular biology and radiation genetics.

Estimates of genetic risks of radiation exposure of humans are traditionally expressed as expected increases in the frequencies of genetic diseases (single-gene, chromosomal and multifactorial) over and above those of naturally-occurring ones in the population. An important assumption in expressing risks in this manner is that gonadal radiation exposures can cause an increase in the frequency of mutations and that this would result in an increase in the frequency of genetic diseases under study. However, despite compelling evidence for radiation-induced mutations in experimental systems, no increases in the frequencies of genetic diseases of concern or other adverse effects (i.e., those which are not formally classified as genetic diseases), have been found in human studies involving parents who have sustained radiation exposures. The known differences between spontaneous mutations that underlie naturally-occurring single-gene diseases and radiation-induced mutations studied in experimental systems now permit us to address and resolve these issues to some extent. The fact that spontaneous mutations (among which are point mutations and DNA deletions generally restricted to the gene) originate through a number of different mechanisms and that the latter are intimately related to the DNA organization of the genes, are now well-documented. Further, spontaneous mutations include those that cause diseases through loss of function as well as gain of function of genes. In contrast, most radiation-induced mutations studied in experimental systems (although identified through the phenotypes of the marker genes) are predominantly multigene deletions which cause loss of function; the recoverability of an induced deletion in a livebirth seems dependent on whether the gene and the genomic region in which it is located can tolerate heterozygosity for the deletion and yet be compatible with viability. In retrospect, the successful mutation test systems (such as the mouse specific locus test) used in radiation studies have involved genes which are non-essential for survival and are also located in genomic regions, likewise non-essential for survival. In contrast, most of the human genes at which induced mutations have been looked for, do not seem to have these attributes. The inference therefore is that the failure to find induced germline mutations in humans is not due to the resistance of human genes to induced mutations but due to the structural and functional constraints associated with their recoverability in livebirths. Since the risk of inducible genetic diseases in humans is estimated using rates of "recovered" mutations in mice, there is a need to introduce appropriate correction factors to bridge the gap between these rates and the rates at which mutations causing diseases are potentially recoverable in humans. Since the whole genome is the "target" for radiation-induced genetic damage, the failure to find increases in the frequencies of specific single-gene diseases of societal concern does not imply that there are no genetic risks of radiation exposures: the problem lies in delineating the phenotypes of recoverable genetic damage that are recognizable in livebirths. Data from studies of naturally-occurring microdeletion syndromes in humans and those from mouse radiation studies are instructive in this regard. They (i) support the view that growth retardation, mental retardation and multisystem developmental abnormalities are likely to be among the quantitatively more important adverse effects of radiation-induced genetic damage than mutations in a few selected genes and (ii) underscore the need to expand the focus in risk estimation from known genetic diseases (as has been the case thus far) to include these induced adverse developmental effects although most of these are not formally classified as "genetic diseases". (ABSTRACT TRUNCATED)     

Detecting lineage-specific adaptive evolution of brain-expressed genes in human using rhesus macaque as outgroup

Comparative genetic analysis between human and chimpanzee may detect genetic divergences responsible for human-specific characteristics. Previous studies have identified a series of genes that potentially underwent Darwinian positive selection during human evolution. However, without a closely related species as outgroup, it is difficult to identify human-lineage-specific changes, which is critical in delineating the biological uniqueness of humans. In this study, we conducted phylogeny-based analyses of 2633 human brain-expressed genes using rhesus macaque as the outgroup. We identified 47 candidate genes showing strong evidence of positive selection in the human lineage. Genes with maximal expression in the brain showed a higher evolutionary rate in human than in chimpanzee. We observed that many immune-defense-related genes were under strong positive selection, and this trend was more prominent in chimpanzee than in human. We also demonstrated that rhesus macaque performed much better than mouse as an outgroup in identifying lineage-specific selection in humans.